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Moshtaghioon S, Elahi M, Ebrahim Soltani Z, Ahmadi E, Nabian MH. MicroRNA regulation in neural tube defects: Insights into pathogenesis and potential therapeutic targets. Gene 2025; 945:149311. [PMID: 39914791 DOI: 10.1016/j.gene.2025.149311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/30/2024] [Accepted: 02/03/2025] [Indexed: 02/22/2025]
Abstract
Neural tube defects (NTDs) represent a significant burden on global pediatric health, contributing to high rates of infant mortality and morbidity. Despite extensive research into their etiology, NTDs continue to pose challenges in diagnosis and treatment. MicroRNAs (miRNAs) have emerged as promising candidates for understanding the molecular mechanisms underlying NTDs and potentially offering avenues for improved diagnosis and therapeutic intervention. This review explores the multifaceted roles of miRNAs in the context of NTD pathogenesis. Studies have identified specific miRNA profiles associated with NTDs, providing insights into their potential as diagnostic biomarkers. Furthermore, dysregulation of certain miRNAs has been implicated in the pathophysiology of NTDs, highlighting their role as potential therapeutic targets. Additionally, animal models and deep sequencing approaches have expanded our understanding of the diverse miRNA expression patterns associated with NTDs. By unraveling the intricate molecular mechanisms underlying NTD pathogenesis, miRNAs offer promising avenues for early detection and intervention, ultimately improving outcomes for affected individuals.
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Affiliation(s)
- Seyedali Moshtaghioon
- Department of Orthopaedic and Trauma Surgery Dr. Shariaty Hospital Tehran University Medical Science Tehran Iran
| | - Mohammad Elahi
- Center for Orthopedic Trans-disciplinary Applied Research Tehran University of Medical Science Tehran Iran
| | | | - Elham Ahmadi
- School of Medicine Tehran University Medical Science Tehran Iran
| | - Mohammad Hossein Nabian
- Center for Orthopedic Trans-disciplinary Applied Research Tehran University of Medical Science Tehran Iran
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2
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Courraud J, Quartier A, Drouot N, Zapata-Bodalo I, Gilet J, Benchoua A, Mandel JL, Piton A. DYRK1A roles in human neural progenitors. Front Neurosci 2025; 19:1533253. [PMID: 40182141 PMCID: PMC11966461 DOI: 10.3389/fnins.2025.1533253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Accepted: 01/21/2025] [Indexed: 04/05/2025] Open
Abstract
Introduction Mutations in dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) represent one of the most prevalent monogenic causes of neurodevelopmental disorders (NDDs), often associated with intellectual developmental disorder and autism spectrum disorder. DYRK1A encodes a dual-specificity kinase (tyrosine and serine/threonine) that plays a key role in various cellular processes and is a critical regulator of nervous system development. Methods For the first time, we have characterized the DYRK1A interactome and study the consequences of DYRK1A depletion in human neural stem cells (hNSCs). Results We identified 35 protein partners of DYRK1A involved in essential pathways such as cell cycle regulation and DNA repair. Notably, five of these interactors are components of the anaphase-promoting complex (APC), and one is an additional ubiquitin ligase, RNF114 (also known as ZNF313), which is known to target p21. Many of these identified partners are also linked to other human NDDs, and several others (e.g., DCAF7 and GSPT1) may represent novel candidate genes for NDDs. DYRK1A knockdown (KD) in hNSCs using siRNA revealed changes in the expression of genes encoding proteins involved in extracellular matrix composition and calcium binding (e.g., collagens, TGFβ2 and UNC13A). While the majority of genes were downregulated following DYRK1A depletion, we observed an upregulation of early growth factors (EGR1 and EGR3), as well as E2F2 and its downstream targets. In addition, DYRK1A-KD led to a reduction in p21 protein levels, despite an increase in the expression of a minor transcript variant for this gene, and a decrease in ERK pathway activation. Discussion Together, the DYRK1A interactome in hNSCs and the gene expression changes induced by its depletion highlight the significant role of DYRK1A in regulating hNSC proliferation. Although the effects on various growth signaling pathways may appear contradictory, the overall impact is a marked reduction in hNSC proliferation. This research underscores the pivotal role of DYRK1A in neurodevelopment and identifies, among DYRK1A's protein partners and differentially expressed genes, potential novel candidate genes for NDDs and promising therapeutic targets for DYRK1A syndrome.
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Affiliation(s)
- Jeremie Courraud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | - Angélique Quartier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | - Nathalie Drouot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | - Irene Zapata-Bodalo
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | - Johan Gilet
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | | | - Jean-Louis Mandel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
| | - Amélie Piton
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Strasbourg University, Illkirch, France
- Genetic Diagnosis Laboratory, Strasbourg University Hospital, Strasbourg, France
- Institut Universitaire de France, Paris, France
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3
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Xu Z, Wang Z, Wang L, Qi YB. Essential function of transmembrane transcription factor MYRF in promoting transcription of miRNA lin-4 during C. elegans development. eLife 2024; 12:RP89903. [PMID: 38963411 PMCID: PMC11223767 DOI: 10.7554/elife.89903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/05/2024] Open
Abstract
Precise developmental timing control is essential for organism formation and function, but its mechanisms are unclear. In C. elegans, the microRNA lin-4 critically regulates developmental timing by post-transcriptionally downregulating the larval-stage-fate controller LIN-14. However, the mechanisms triggering the activation of lin-4 expression toward the end of the first larval stage remain unknown. We demonstrate that the transmembrane transcription factor MYRF-1 is necessary for lin-4 activation. MYRF-1 is initially localized on the cell membrane, and its increased cleavage and nuclear accumulation coincide with lin-4 expression timing. MYRF-1 regulates lin-4 expression cell-autonomously and hyperactive MYRF-1 can prematurely drive lin-4 expression in embryos and young first-stage larvae. The tandem lin-4 promoter DNA recruits MYRF-1GFP to form visible loci in the nucleus, suggesting that MYRF-1 directly binds to the lin-4 promoter. Our findings identify a crucial link in understanding developmental timing regulation and establish MYRF-1 as a key regulator of lin-4 expression.
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Affiliation(s)
- Zhimin Xu
- School of Life Science and Technology, ShanghaiTech UniversityShanghaiChina
| | - Zhao Wang
- School of Life Science and Technology, ShanghaiTech UniversityShanghaiChina
| | - Lifang Wang
- School of Life Science and Technology, ShanghaiTech UniversityShanghaiChina
| | - Yingchuan B Qi
- School of Life Science and Technology, ShanghaiTech UniversityShanghaiChina
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Tahmasebi F, Asl ER, Vahidinia Z, Barati S. Stem Cell-Derived Exosomal MicroRNAs as Novel Potential Approach for Multiple Sclerosis Treatment. Cell Mol Neurobiol 2024; 44:44. [PMID: 38713302 PMCID: PMC11076329 DOI: 10.1007/s10571-024-01478-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 04/09/2024] [Indexed: 05/08/2024]
Abstract
Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation and demyelination of CNS neurons. Up to now, there are many therapeutic strategies for MS but they are only being able to reduce progression of diseases and have not got any effect on repair and remyelination. Stem cell therapy is an appropriate method for regeneration but has limitations and problems. So recently, researches were used of exosomes that facilitate intercellular communication and transfer cell-to-cell biological information. MicroRNAs (miRNAs) are a class of short non-coding RNAs that we can used to their dysregulation in order to diseases diagnosis. The miRNAs of microvesicles obtained stem cells may change the fate of transplanted cells based on received signals of injured regions. The miRNAs existing in MSCs may be displayed the cell type and their biological activities. Current studies show also that the miRNAs create communication between stem cells and tissue-injured cells. In the present review, firstly we discuss the role of miRNAs dysregulation in MS patients and miRNAs expression by stem cells. Finally, in this study was confirmed the relationship of microRNAs involved in MS and miRNAs expressed by stem cells and interaction between them in order to find appropriate treatment methods in future for limit to disability progression.
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Affiliation(s)
- Fatemeh Tahmasebi
- Department of Anatomy, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elmira Roshani Asl
- Department of Biochemistry, Saveh University of Medical Sciences, Saveh, Iran
| | - Zeinab Vahidinia
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Shirin Barati
- Department of Anatomy, Saveh University of Medical Sciences, Saveh, Iran.
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Li YM, Chung YL, Wu YF, Wang CK, Chen CM, Chen YH. Maternal exposure to hyperbaric oxygen at the preimplantation stages increases apoptosis and ectopic Cdx2 expression and decreases Oct4 expression in mouse blastocysts via Nrf2-Notch1 upregulation and Nf2 downregulation. Dev Dyn 2024; 253:467-489. [PMID: 37850827 DOI: 10.1002/dvdy.671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 09/21/2023] [Accepted: 10/07/2023] [Indexed: 10/19/2023] Open
Abstract
BACKGROUND The environmental oxygen tension has been reported to impact the blastocyst quality and cell numbers in the inner cell mass (ICM) during human and murine embryogenesis. While the molecular mechanisms leading to increased ICM cell numbers and pluripotency gene expression under hypoxia have been deciphered, it remains unknown which regulatory pathways caused the underweight fetal body and overweight placenta after maternal exposure to hyperbaric oxygen (HBO). RESULTS The blastocysts from the HBO-exposed pregnant mice revealed significantly increased signals of reactive oxygen species (ROS) and nuclear Nrf2 staining, decreased Nf2 and Oct4 expression, increased nuclear Tp53bp1 and active caspase-3 staining, and ectopic nuclear signals of Cdx2, Yap, and the Notch1 intracellular domain (N1ICD) in the ICM. In the ICM of the HBO-exposed blastocysts, both Nf2 cDNA microinjection and Nrf2 shRNA microinjection significantly decreased the ectopic nuclear expression of Cdx2, Tp53bp1, and Yap whereas increased Oct4 expression, while Nrf2 shRNA microinjection also significantly decreased Notch1 mRNA levels and nuclear expression of N1ICD and active caspase-3. CONCLUSION We show for the first time that maternal exposure to HBO at the preimplantation stage induces apoptosis and impairs ICM cell specification via upregulating Nrf2-Notch1-Cdx2 expression and downregulating Nf2-Oct4 expression.
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Grants
- MAB-108-027 Medical Affairs Bureau, Ministry of National Defense, R.O.C., Taiwan
- MAB-109-029 Medical Affairs Bureau, Ministry of National Defense, R.O.C., Taiwan
- MND-MAB-110-031 Medical Affairs Bureau, Ministry of National Defense, R.O.C., Taiwan
- MND-MAB-C06-111022 Medical Affairs Bureau, Ministry of National Defense, R.O.C., Taiwan
- MND-MAB-C14-112058 Medical Affairs Bureau, Ministry of National Defense, R.O.C., Taiwan
- MOST-111-2635-B-016-002 Ministry of Science and Technology, Taiwan
- TSGH-D-109177 Tri-Service General Hospital in Taiwan, R.O.C.
- TSGH-E-109261 Tri-Service General Hospital in Taiwan, R.O.C.
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Affiliation(s)
- Yu-Ming Li
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Internal Medicine, Taichung Veterans General Hospital, Taichung City, Taiwan
| | - Yu Lang Chung
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei City, Taiwan
| | - Yung-Fu Wu
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Chien-Kuo Wang
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei City, Taiwan
| | - Chieh-Min Chen
- Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei City, Taiwan
| | - Yi-Hui Chen
- Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei City, Taiwan
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Courraud J, Engel C, Quartier A, Drouot N, Houessou U, Plassard D, Sorlin A, Brischoux-Boucher E, Gouy E, Van Maldergem L, Rossi M, Lesca G, Edery P, Putoux A, Bilan F, Gilbert-Dussardier B, Atallah I, Kalscheuer VM, Mandel JL, Piton A. Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome. Mol Psychiatry 2024; 29:287-296. [PMID: 38030819 DOI: 10.1038/s41380-023-02323-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 10/18/2023] [Accepted: 11/13/2023] [Indexed: 12/01/2023]
Abstract
Mutations in the PQBP1 gene (polyglutamine-binding protein-1) are responsible for a syndromic X-linked form of neurodevelopmental disorder (XL-NDD) with intellectual disability (ID), named Renpenning syndrome. PQBP1 encodes a protein involved in transcriptional and post-transcriptional regulation of gene expression. To investigate the consequences of PQBP1 loss, we used RNA interference to knock-down (KD) PQBP1 in human neural stem cells (hNSC). We observed a decrease of cell proliferation, as well as the deregulation of the expression of 58 genes, comprising genes encoding proteins associated with neurodegenerative diseases, playing a role in mRNA regulation or involved in innate immunity. We also observed an enrichment of genes involved in other forms of NDD (CELF2, APC2, etc). In particular, we identified an increase of a non-canonical isoform of another XL-NDD gene, UPF3B, an actor of nonsense mRNA mediated decay (NMD). This isoform encodes a shorter protein (UPF3B_S) deprived from the domains binding NMD effectors, however no notable change in NMD was observed after PQBP1-KD in fibroblasts containing a premature termination codon. We showed that short non-canonical and long canonical UPF3B isoforms have different interactomes, suggesting they could play distinct roles. The link between PQBP1 loss and increase of UPF3B_S expression was confirmed in mRNA obtained from patients with pathogenic variants in PQBP1, particularly pronounced for truncating variants and missense variants located in the C-terminal domain. We therefore used it as a molecular marker of Renpenning syndrome, to test the pathogenicity of variants of uncertain clinical significance identified in PQPB1 in individuals with NDD, using patient blood mRNA and HeLa cells expressing wild-type or mutant PQBP1 cDNA. We showed that these different approaches were efficient to prove a functional effect of variants in the C-terminal domain of the protein. In conclusion, our study provided information on the pathological mechanisms involved in Renpenning syndrome, but also allowed the identification of a biomarker of PQBP1 deficiency useful to test variant effect.
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Affiliation(s)
- Jérémie Courraud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Camille Engel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Angélique Quartier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Nathalie Drouot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Ursula Houessou
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Damien Plassard
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Arthur Sorlin
- National Center of Genetics, Laboratoire national de santé, Dudelange, Luxembourg
| | - Elise Brischoux-Boucher
- Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25056, Besançon, France
| | - Evan Gouy
- Genetics Department, University Hospital of Lyon, Bron, 69500, France
| | - Lionel Van Maldergem
- Centre de Génétique Humaine, CHU Besançon, Université de Franche-Comté, 25056, Besançon, France
| | - Massimiliano Rossi
- Genetics Department, University Hospital of Lyon, Bron, 69500, France
- Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France
| | - Gaetan Lesca
- Genetics Department, University Hospital of Lyon, Bron, 69500, France
- Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France
| | - Patrick Edery
- Genetics Department, University Hospital of Lyon, Bron, 69500, France
- Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France
| | - Audrey Putoux
- Genetics Department, University Hospital of Lyon, Bron, 69500, France
- Equipe GENDEV, CRNL, Inserm U1028, CNRS UMR 5292, UCB Lyon1, Illkirch, France
| | - Frederic Bilan
- Service de génétique médicale, CHU de Poitiers, 86 000, Poitiers, France
| | | | - Isis Atallah
- Department of Medical Genetics, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | | | - Jean-Louis Mandel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, 67 400, Illkirch, France
| | - Amélie Piton
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France.
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France.
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France.
- Université de Strasbourg, 67 400, Illkirch, France.
- Genetic diagnosis laboratory, Strasbourg University Hospital, 67 090, Strasbourg, France.
- Institut Universitaire de France, Paris, France.
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Abdelmaksoud NM, Sallam AAM, Abulsoud AI, El-Dakroury WA, Abdel Mageed SS, Al-Noshokaty TM, Elrebehy MA, Elshaer SS, Mahmoud NA, Fathi D, Rizk NI, Elballal MS, Mohammed OA, Abdel-Reheim MA, Zaki MB, Saber S, Doghish AS. Unraveling the role of miRNAs in the diagnosis, progression, and therapeutic intervention of Alzheimer's disease. Pathol Res Pract 2024; 253:155007. [PMID: 38061270 DOI: 10.1016/j.prp.2023.155007] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 01/24/2024]
Abstract
Alzheimer's disease (AD) is a multifaceted, advancing neurodegenerative illness that is responsible for most cases of neurological impairment and dementia in the aged population. As the disease progresses, affected individuals may experience cognitive decline, linguistic problems, affective instability, and behavioral changes. The intricate nature of AD reflects the altered molecular mechanisms participating in the affected human brain. MicroRNAs (miRNAs, miR) are essential for the intricate control of gene expression in neurobiology. miRNAs exert their influence by modulating the transcriptome of brain cells, which typically exhibit substantial genetic activity, encompassing gene transcription and mRNA production. Presently, comprehensive studies are being conducted on AD to identify miRNA-based signatures that are indicative of the disease pathophysiology. These findings can contribute to the advancement of our understanding of the mechanisms underlying this disorder and can inform the development of therapeutic interventions based on miRNA and related RNA molecules. Therefore, this comprehensive review provides a detailed holistic analysis of the latest advances discussing the emerging role of miRNAs in the progression of AD and their possible application as potential biomarkers and targets for therapeutic interventions in future studies.
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Affiliation(s)
| | - Al-Aliaa M Sallam
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Ahmed I Abulsoud
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
| | - Walaa A El-Dakroury
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Sherif S Abdel Mageed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Tohada M Al-Noshokaty
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mahmoud A Elrebehy
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Shereen Saeid Elshaer
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt; Department of Biochemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Naira Ali Mahmoud
- Microbiology and Immunology Department, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Doaa Fathi
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Nehal I Rizk
- Biochemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo 11785, Egypt
| | - Mohammed S Elballal
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt
| | - Osama A Mohammed
- Department of Pharmacology, College of Medicine, University of Bisha, Bisha 61922, Saudi Arabia
| | - Mustafa Ahmed Abdel-Reheim
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni, Suef 62521, Egypt.
| | - Mohamed Bakr Zaki
- Department of Biochemistry, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt
| | - Sameh Saber
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt
| | - Ahmed S Doghish
- Department of Biochemistry, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr City, Cairo 11829, Egypt; Biochemistry and Molecular Biology Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11231, Cairo, Egypt.
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8
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Bassett C, Triplett H, Lott K, Howard KM, Kingsley K. Differential Expression of MicroRNA (MiR-27, MiR-145) among Dental Pulp Stem Cells (DPSCs) Following Neurogenic Differentiation Stimuli. Biomedicines 2023; 11:3003. [PMID: 38002003 PMCID: PMC10669296 DOI: 10.3390/biomedicines11113003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/03/2023] [Accepted: 11/07/2023] [Indexed: 11/26/2023] Open
Abstract
This study sought to evaluate the expression of previously identified microRNAs known to regulate neuronal differentiation in mesenchymal stem cells (MSCs), including miR-27, miR-125, miR-128, miR-135, miR-140, miR-145, miR-218 and miR-410, among dental pulp stem cells (DPSCs) under conditions demonstrated to induce neuronal differentiation. Using an approved protocol, n = 12 DPSCs were identified from an existing biorepository and treated with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF), which were previously demonstrated to induce neural differentiation markers including Sox1, Pax6 and NFM among these DPSCs. This study revealed that some microRNAs involved in the neuronal differentiation of MSCs were also differentially expressed among the DPSCs, including miR-27 and miR-145. In addition, this study also revealed that administration of bFGF and EGF was sufficient to modulate miR-27 and miR-145 expression in all of the stimulus-responsive DPSCs but not among all of the non-responsive DPSCs-suggesting that further investigation of the downstream targets of these microRNAs may be needed to fully evaluate and understand these observations.
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Affiliation(s)
- Charlton Bassett
- School of Medicine, University of Nevada, Las Vegas 1700 West Charleston Boulevard, Las Vegas, NV 89106, USA; (C.B.); (H.T.); (K.L.)
| | - Hunter Triplett
- School of Medicine, University of Nevada, Las Vegas 1700 West Charleston Boulevard, Las Vegas, NV 89106, USA; (C.B.); (H.T.); (K.L.)
| | - Keegan Lott
- School of Medicine, University of Nevada, Las Vegas 1700 West Charleston Boulevard, Las Vegas, NV 89106, USA; (C.B.); (H.T.); (K.L.)
| | - Katherine M. Howard
- School of Dental Medicine, University of Nevada, Las Vegas 1001 Shadow Lane, Las Vegas, NV 89106, USA;
| | - Karl Kingsley
- School of Dental Medicine, University of Nevada, Las Vegas 1001 Shadow Lane, Las Vegas, NV 89106, USA;
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9
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Hou KC, Tsai MH, Akbarian S, Huang HS. Mir125b-1 is Not Imprinted in Human Brain and Shows Developmental Expression Changes in Mouse Brain. Neuroscience 2023; 529:99-106. [PMID: 37598835 DOI: 10.1016/j.neuroscience.2023.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/05/2023] [Accepted: 08/07/2023] [Indexed: 08/22/2023]
Abstract
Genomic imprinting is a predominantly brain and placenta-specific epigenetic process that contributes to parent-of-origin-specific gene expression. While microRNAs are highly expressed in the brain, their imprinting status in this tissue remains poorly studied. Previous research demonstrated that Mir125b-2 is imprinted in the human brain and regulates hippocampal circuits and functions in mice. However, the imprinting status of another isoform of miR125b, Mir125b-1, in the human brain, as well as its spatiotemporal expression patterns in mice, have not been elucidated. Here, we show MIR125B1 is not imprinted in the human brain. Moreover, miR-125b-1 was highly expressed in the brains of mice. Furthermore, miR-125b-1 was down-regulated during brain development in mice. Specifically, miR-125b-1 displayed preferential expression in the olfactory bulb, thalamus, and hypothalamus of the mouse brain. Notably, miR-125b-1 was enriched in GABAergic neurons, particularly somatostatin-expressing GABAergic neurons, compared with glutamatergic neurons. Taken together, our findings provide the imprinting status and comprehensive spatiotemporal expression profiling of Mir125b-1 in the brain.
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Affiliation(s)
- Kuan-Chu Hou
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Meng-Han Tsai
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan
| | - Schahram Akbarian
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Hsien-Sung Huang
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
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10
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Freiría-Martínez L, Iglesias-Martínez-Almeida M, Rodríguez-Jamardo C, Rivera-Baltanás T, Comís-Tuche M, Rodrígues-Amorím D, Fernández-Palleiro P, Blanco-Formoso M, Diz-Chaves Y, González-Freiria N, Suárez-Albo M, Martín-Forero-Maestre M, Durán Fernández-Feijoo C, Fernández-Lorenzo JR, Concheiro Guisán A, Olivares JM, Spuch C. Human Breast Milk microRNAs, Potential Players in the Regulation of Nervous System. Nutrients 2023; 15:3284. [PMID: 37513702 PMCID: PMC10384760 DOI: 10.3390/nu15143284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/12/2023] [Accepted: 07/15/2023] [Indexed: 07/30/2023] Open
Abstract
Human milk is the biological fluid with the highest exosome amount and is rich in microRNAs (miRNAs). These are key regulators of gene expression networks in both normal physiologic and disease contexts, miRNAs can influence many biological processes and have also shown promise as biomarkers for disease. One of the key aspects in the regeneration of the nervous system is that there are practically no molecules that can be used as potential drugs. In the first weeks of lactation, we know that human breast milk must contain the mechanisms to transmit molecular and biological information for brain development. For this reason, our objective is to identify new modulators of the nervous system that can be used to investigate neurodevelopmental functions based on miRNAs. To do this, we collected human breast milk samples according to the time of delivery and milk states: mature milk and colostrum at term; moderate and very preterm mature milk and colostrum; and late preterm mature milk. We extracted exosomes and miRNAs and realized the miRNA functional assays and target prediction. Our results demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function. We found 132 different miRNAs were identified across all samples. Sixty-nine miRNAs had significant differential expression after paired group comparison. These miRNAs are implicated in gene regulation of dopaminergic/glutamatergic synapses and neurotransmitter secretion and are related to the biological process that regulates neuron projection morphogenesis and synaptic vesicle transport. We observed differences according to the delivery time and with less clarity according to the milk type. Our data demonstrate that miRNAs are abundant in human milk and likely play significant roles in neurodevelopment and normal function.
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Affiliation(s)
- Luis Freiría-Martínez
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Marta Iglesias-Martínez-Almeida
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Cynthia Rodríguez-Jamardo
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Tania Rivera-Baltanás
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
| | - María Comís-Tuche
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Department of Functional Biology and Health Sciences, Campus Lagoas Marcosende, Universidade de Vigo, 36310 Vigo, Spain
| | - Daniela Rodrígues-Amorím
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Patricia Fernández-Palleiro
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
| | - María Blanco-Formoso
- Department of Physical Chemistry, Singular Center for Biomedical Research (CINBIO), Universidade de Vigo, 36310 Vigo, Spain
| | - Yolanda Diz-Chaves
- Laboratory of Endocrinology, Singular Center for Biomedical Research (CINBIO), Universidade de Vigo, 36310 Vigo, Spain
| | | | - María Suárez-Albo
- Neonatal Intensive Care Unit, Alvaro Cunqueiro Hospital, 36312 Vigo, Spain
| | | | | | | | | | - Jose Manuel Olivares
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- CIBERSAM (Network Biomedical Research Center on Mental Health), 28029 Madrid, Spain
| | - Carlos Spuch
- Translational Neuroscience Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO (Servizo Galego de Saúde-Universidade de Vigo), 36312 Vigo, Spain
- CIBERSAM (Network Biomedical Research Center on Mental Health), 28029 Madrid, Spain
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11
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Pielok A, Kępska M, Steczkiewicz Z, Grobosz S, Bourebaba L, Marycz K. Equine Hoof Progenitor Cells Display Increased Mitochondrial Metabolism and Adaptive Potential to a Highly Pro-Inflammatory Microenvironment. Int J Mol Sci 2023; 24:11446. [PMID: 37511204 PMCID: PMC10379971 DOI: 10.3390/ijms241411446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/30/2023] Open
Abstract
Medicinal signaling cells (MSC) exhibit distinct molecular signatures and biological abilities, depending on the type of tissue they originate from. Recently, we isolated and described a new population of stem cells residing in the coronary corium, equine hoof progenitor cells (HPCs), which could be a new promising cell pool for the treatment of laminitis. Therefore, this study aimed to compare native populations of HPCs to well-established adipose-derived stem cells (ASCs) in standard culture conditions and in a pro-inflammatory milieu to mimic a laminitis condition. ASCs and HPCs were either cultured in standard conditions or subjected to priming with a cytokines cocktail mixture. The cells were harvested and analyzed for expression of key markers for phenotype, mitochondrial metabolism, oxidative stress, apoptosis, and immunomodulation using RT-qPCR. The morphology and migration were assessed based on fluorescent staining. Microcapillary cytometry analyses were performed to assess the distribution in the cell cycle, mitochondrial membrane potential, and oxidative stress. Native HPCs exhibited a similar morphology to ASCs, but a different phenotype. The HPCs possessed lower migration capacity and distinct distribution across cell cycle phases. Native HPCs were characterized by different mitochondrial dynamics and oxidative stress levels. Under standard culture conditions, HPCs displayed different expression patterns of apoptotic and immunomodulatory markers than ASCs, as well as distinct miRNA expression. Interestingly, after priming with the cytokines cocktail mixture, HPCs exhibited different mitochondrial dynamics than ASCs; however, the apoptosis and immunomodulatory marker expression was similar in both populations. Native ASCs and HPCs exhibited different baseline expressions of markers involved in mitochondrial dynamics, the oxidative stress response, apoptosis and inflammation. When exposed to a pro-inflammatory microenvironment, ASCs and HPCs differed in the expression of mitochondrial condition markers and chosen miRNAs.
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Affiliation(s)
- Ariadna Pielok
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Martyna Kępska
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Zofia Steczkiewicz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Sylwia Grobosz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Lynda Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
| | - Krzysztof Marycz
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wroclaw University of Environmental and Life Sciences, Norwida 27B, 50-375 Wroclaw, Poland
- International Institute of Translational Medicine, Jesionowa 11, Malin, 55-114 Wisznia Mała, Poland
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12
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Sun H, Hobert O. Temporal transitions in the postembryonic nervous system of the nematode Caenorhabditis elegans: Recent insights and open questions. Semin Cell Dev Biol 2023; 142:67-80. [PMID: 35688774 DOI: 10.1016/j.semcdb.2022.05.029] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 05/27/2022] [Accepted: 05/27/2022] [Indexed: 10/18/2022]
Abstract
After the generation, differentiation and integration into functional circuitry, post-mitotic neurons continue to change certain phenotypic properties throughout postnatal juvenile stages until an animal has reached a fully mature state in adulthood. We will discuss such changes in the context of the nervous system of the nematode C. elegans, focusing on recent descriptions of anatomical and molecular changes that accompany postembryonic maturation of neurons. We summarize the characterization of genetic timer mechanisms that control these temporal transitions or maturational changes, and discuss that many but not all of these transitions relate to sexual maturation of the animal. We describe how temporal, spatial and sex-determination pathways are intertwined to sculpt the emergence of cell-type specific maturation events. Finally, we lay out several unresolved questions that should be addressed to move the field forward, both in C. elegans and in vertebrates.
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Affiliation(s)
- Haosheng Sun
- Department of Cell, Developmental, and Integrative Biology. University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Oliver Hobert
- Department of Biological Sciences, Columbia University, New York, USA
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13
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Grochowska MM, Ferraro F, Mascaro AC, Natale D, Winkelaar A, Boumeester V, Breedveld GJ, Bonifati V, Mandemakers W. deCLUTTER2+ - a pipeline to analyze calcium traces in a stem cell model for ventral midbrain patterned astrocytes. Dis Model Mech 2023; 16:dmm049980. [PMID: 37260295 PMCID: PMC10309582 DOI: 10.1242/dmm.049980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 05/19/2023] [Indexed: 06/02/2023] Open
Abstract
Astrocytes are the most populous cell type of the human central nervous system and are essential for physiological brain function. Increasing evidence suggests multiple roles for astrocytes in Parkinson's disease, nudging a shift in the research focus, which historically pivoted around ventral midbrain dopaminergic neurons (vmDANs). Studying human astrocytes and other cell types in vivo remains challenging. However, in vitro-reprogrammed human stem cell-based models provide a promising alternative. Here, we describe a novel protocol for astrocyte differentiation from human stem cell-derived vmDAN-generating progenitors. This protocol simulates the regionalization, gliogenic switch, radial migration and final differentiation that occur in the developing human brain. We characterized the morphological, molecular and functional features of these ventral midbrain patterned astrocytes with a broad palette of techniques and identified novel candidate midbrain-astrocyte specific markers. In addition, we developed a new pipeline for calcium imaging data analysis called deCLUTTER2+ (deconvolution of Ca2+ fluorescent patterns) that can be used to discover spontaneous or cue-dependent patterns of Ca2+ transients. Altogether, our protocol enables the characterization of the functional properties of human ventral midbrain patterned astrocytes under physiological conditions and in disease.
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Affiliation(s)
- Martyna M. Grochowska
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Federico Ferraro
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Ana Carreras Mascaro
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Domenico Natale
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Amber Winkelaar
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Valerie Boumeester
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Guido J. Breedveld
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Vincenzo Bonifati
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
| | - Wim Mandemakers
- Erasmus MC, University Medical Center Rotterdam, Department of Clinical Genetics, P.O. Box 2040, 3000 CA Rotterdam, Netherlands
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14
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Bergamelli M, Martin H, Aubert Y, Mansuy JM, Marcellin M, Burlet-Schiltz O, Hurbain I, Raposo G, Izopet J, Fournier T, Benchoua A, Bénard M, Groussolles M, Cartron G, Tanguy Le Gac Y, Moinard N, D’Angelo G, Malnou CE. Human Cytomegalovirus Modifies Placental Small Extracellular Vesicle Composition to Enhance Infection of Fetal Neural Cells In Vitro. Viruses 2022; 14:v14092030. [PMID: 36146834 PMCID: PMC9501265 DOI: 10.3390/v14092030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 08/31/2022] [Accepted: 09/06/2022] [Indexed: 11/29/2022] Open
Abstract
Although placental small extracellular vesicles (sEVs) are extensively studied in the context of pregnancy, little is known about their role during viral congenital infection, especially at the beginning of pregnancy. In this study, we examined the consequences of human cytomegalovirus (hCMV) infection on sEVs production, composition, and function using an immortalized human cytotrophoblast cell line derived from first trimester placenta. By combining complementary approaches of biochemistry, electron microscopy, and quantitative proteomic analysis, we showed that hCMV infection increases the yield of sEVs produced by cytotrophoblasts and modifies their protein content towards a potential proviral phenotype. We further demonstrate that sEVs secreted by hCMV-infected cytotrophoblasts potentiate infection in naive recipient cells of fetal origin, including human neural stem cells. Importantly, these functional consequences are also observed with sEVs prepared from an ex vivo model of infected histocultures from early placenta. Based on these findings, we propose that placental sEVs could be important actors favoring viral dissemination to the fetal brain during hCMV congenital infection.
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Affiliation(s)
- Mathilde Bergamelli
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
| | - Hélène Martin
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
| | - Yann Aubert
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
| | - Jean-Michel Mansuy
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, Toulouse, France
| | - Marlène Marcellin
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Infrastructure nationale de protéomique, ProFI, FR 2048, Toulouse, France
| | - Odile Burlet-Schiltz
- Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France
- Infrastructure nationale de protéomique, ProFI, FR 2048, Toulouse, France
| | - Ilse Hurbain
- Institut Curie, CNRS UMR144, Structure et Compartiments Membranaires, Université Paris Sciences et Lettres, Paris, France
- Institut Curie, CNRS UMR144, Plateforme d’imagerie cellulaire et tissulaire (PICT-IBiSA), Université Paris Sciences et Lettres, Paris, France
| | - Graça Raposo
- Institut Curie, CNRS UMR144, Structure et Compartiments Membranaires, Université Paris Sciences et Lettres, Paris, France
- Institut Curie, CNRS UMR144, Plateforme d’imagerie cellulaire et tissulaire (PICT-IBiSA), Université Paris Sciences et Lettres, Paris, France
| | - Jacques Izopet
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
- CHU Toulouse, Hôpital Purpan, Laboratoire de Virologie, Toulouse, France
| | | | - Alexandra Benchoua
- Neuroplasticity and Therapeutics, CECS, I-STEM, AFM- Téléthon, Corbeil-Essonnes, France
| | - Mélinda Bénard
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
- CHU Toulouse, Hôpital des Enfants, Service de Néonatalogie, Toulouse, France
| | - Marion Groussolles
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
- CHU Toulouse, Hôpital Paule de Viguier, Service de Diagnostic Prénatal, Toulouse, France
- Equipe SPHERE Epidémiologie et Analyses en Santé Publique: Risques, Maladies chroniques et handicaps, Université de Toulouse, INSERM UMR1027, UPS, Toulouse, France
| | - Géraldine Cartron
- CHU Toulouse, Hôpital Paule de Viguier, Service de Gynécologie Obstétrique, Toulouse, France
| | - Yann Tanguy Le Gac
- CHU Toulouse, Hôpital Paule de Viguier, Service de Gynécologie Obstétrique, Toulouse, France
| | - Nathalie Moinard
- Développement Embryonnaire, Fertilité, Environnement (DEFE), INSERM UMR 1203, Université de Toulouse et Université de Montpellier, France
- CECOS, Service médecine de la reproduction, CHU Toulouse, Hôpital Paule de Viguier, Toulouse, France
| | - Gisela D’Angelo
- Institut Curie, CNRS UMR144, Structure et Compartiments Membranaires, Université Paris Sciences et Lettres, Paris, France
| | - Cécile E. Malnou
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université de Toulouse, INSERM, CNRS, UPS, Toulouse, France
- Correspondence:
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15
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Pakravan K, Razmara E, Mahmud Hussen B, Sattarikia F, Sadeghizadeh M, Babashah S. SMAD4 contributes to chondrocyte and osteocyte development. J Cell Mol Med 2022; 26:1-15. [PMID: 34841647 PMCID: PMC8742202 DOI: 10.1111/jcmm.17080] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/25/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Different cellular and molecular mechanisms contribute to chondrocyte and osteocyte development. Although vital roles of the mothers against decapentaplegic homolog 4 (also called 'SMAD4') have been discussed in different cancers and stem cell-related studies, there are a few reviews summarizing the roles of this protein in the skeletal development and bone homeostasis. In order to fill this gap, we discuss the critical roles of SMAD4 in the skeletal development. To this end, we review the different signalling pathways and also how SMAD4 defines stem cell features. We also elaborate how the epigenetic factors-ie DNA methylation, histone modifications and noncoding RNAs-make a contribution to the chondrocyte and osteocyte development. To better grasp the important roles of SMAD4 in the cartilage and bone development, we also review the genotype-phenotype correlation in animal models. This review helps us to understand the importance of the SMAD4 in the chondrocyte and bone development and the potential applications for therapeutic goals.
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Affiliation(s)
- Katayoon Pakravan
- Department of Molecular GeneticsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Ehsan Razmara
- Department of Medical GeneticsFaculty of Medical SciencesTarbiat Modares UniversityTehranIran
| | - Bashdar Mahmud Hussen
- Department of PharmacognosyCollege of PharmacyHawler Medical UniversityKurdistan RegionIraq
| | - Fatemeh Sattarikia
- Department of Molecular GeneticsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Majid Sadeghizadeh
- Department of Molecular GeneticsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
| | - Sadegh Babashah
- Department of Molecular GeneticsFaculty of Biological SciencesTarbiat Modares UniversityTehranIran
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16
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Soni N, Gupta S, Rawat S, Krishnakumar V, Mohanty S, Banerjee A. MicroRNA-Enriched Exosomes from Different Sources of Mesenchymal Stem Cells Can Differentially Modulate Functions of Immune Cells and Neurogenesis. Biomedicines 2021; 10:biomedicines10010069. [PMID: 35052749 PMCID: PMC8772751 DOI: 10.3390/biomedicines10010069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 01/10/2023] Open
Abstract
Adult Mesenchymal stem cells-derived exosomes carry several biologically active molecules that play prominent roles in controlling disease manifestations. The content of these exosomes, their functions, and effect on the immune cells may differ depending on their tissue sources. Therefore, in this study, we purified the exosomes from three different sources and, using the RNA-Seq approach, highly abundant microRNAs were identified and compared between exosomes and parental cells. The effects of exosomes on different immune cells were studied in vitro by incubating exosomes with PBMC and neutrophils and assessing their functions. The expression levels of several miRNAs varied within the different MSCs and exosomes. Additionally, the expression profile of most of the miRNAs was not similar to that of their respective sources. Exosomes isolated from different sources had different abilities to induce the process of neurogenesis and angiogenesis. Moreover, these exosomes demonstrated their varying effect on PBMC proliferation, neutrophil survival, and NET formation, highlighting their versatility and broad interaction with immune cells. The knowledge gained from this study will improve our understanding of the miRNA landscape of exosomes from hMSCs and provide a resource for further improving our understanding of exosome cargo and their interaction with immune cells.
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Affiliation(s)
- Naina Soni
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Suchi Gupta
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Surender Rawat
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Vishnu Krishnakumar
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Sujata Mohanty
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
- Correspondence: (S.M.); (A.B.)
| | - Arup Banerjee
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
- Correspondence: (S.M.); (A.B.)
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17
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Prodromidou K, Matsas R. Evolving features of human cortical development and the emerging roles of non-coding RNAs in neural progenitor cell diversity and function. Cell Mol Life Sci 2021; 79:56. [PMID: 34921638 PMCID: PMC11071749 DOI: 10.1007/s00018-021-04063-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 11/25/2021] [Accepted: 11/26/2021] [Indexed: 10/19/2022]
Abstract
The human cerebral cortex is a uniquely complex structure encompassing an unparalleled diversity of neuronal types and subtypes. These arise during development through a series of evolutionary conserved processes, such as progenitor cell proliferation, migration and differentiation, incorporating human-associated adaptations including a protracted neurogenesis and the emergence of novel highly heterogeneous progenitor populations. Disentangling the unique features of human cortical development involves elucidation of the intricate developmental cell transitions orchestrated by progressive molecular events. Crucially, developmental timing controls the fine balance between cell cycle progression/exit and the neurogenic competence of precursor cells, which undergo morphological transitions coupled to transcriptome-defined temporal states. Recent advances in bulk and single-cell transcriptomic technologies suggest that alongside protein-coding genes, non-coding RNAs exert important regulatory roles in these processes. Interestingly, a considerable number of novel long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have appeared in human and non-human primates suggesting an evolutionary role in shaping cortical development. Here, we present an overview of human cortical development and highlight the marked diversification and complexity of human neuronal progenitors. We further discuss how lncRNAs and miRNAs constitute critical components of the extended epigenetic regulatory network defining intermediate states of progenitors and controlling cell cycle dynamics and fate choices with spatiotemporal precision, during human neurodevelopment.
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Affiliation(s)
- Kanella Prodromidou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521, Athens, Greece.
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, 127 Vasilissis Sofias Avenue, 11521, Athens, Greece
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18
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Benchoua A, Lasbareilles M, Tournois J. Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders. Cells 2021; 10:cells10123290. [PMID: 34943799 PMCID: PMC8699352 DOI: 10.3390/cells10123290] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/19/2021] [Accepted: 11/23/2021] [Indexed: 02/07/2023] Open
Abstract
One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders.
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Affiliation(s)
- Alexandra Benchoua
- Neuroplasticity and Therapeutics, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- High Throughput Screening Platform, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- Correspondence:
| | - Marie Lasbareilles
- Neuroplasticity and Therapeutics, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
- UEVE UMR 861, I-STEM, AFM, 91100 Corbeil-Essonnes, France
| | - Johana Tournois
- High Throughput Screening Platform, CECS, I-STEM, AFM, 91100 Corbeil-Essonnes, France;
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19
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Pourtoy-Brasselet S, Sciauvaud A, Boza-Moran MG, Cailleret M, Jarrige M, Polvèche H, Polentes J, Chevet E, Martinat C, Peschanski M, Aubry L. Human iPSC-derived neurons reveal early developmental alteration of neurite outgrowth in the late-occurring neurodegenerative Wolfram syndrome. Am J Hum Genet 2021; 108:2171-2185. [PMID: 34699745 DOI: 10.1016/j.ajhg.2021.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 09/30/2021] [Indexed: 11/18/2022] Open
Abstract
Recent studies indicate that neurodegenerative processes that appear during childhood and adolescence in individuals with Wolfram syndrome (WS) occur in addition to early brain development alteration, which is clinically silent. Underlying pathological mechanisms are still unknown. We have used induced pluripotent stem cell-derived neural cells from individuals affected by WS in order to reveal their phenotypic and molecular correlates. We have observed that a subpopulation of Wolfram neurons displayed aberrant neurite outgrowth associated with altered expression of axon guidance genes. Selective inhibition of the ATF6α arm of the unfolded protein response prevented the altered phenotype, although acute endoplasmic reticulum stress response-which is activated in late Wolfram degenerative processes-was not detected. Among the drugs currently tried in individuals with WS, valproic acid was the one that prevented the pathological phenotypes. These results suggest that early defects in axon guidance may contribute to the loss of neurons in individuals with WS.
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Affiliation(s)
| | - Axel Sciauvaud
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France
| | - Maria-Gabriela Boza-Moran
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France
| | - Michel Cailleret
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France
| | - Margot Jarrige
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France; CECS/AFM, I-STEM, Corbeil-Essonnes 91100, France
| | | | | | - Eric Chevet
- INSERM U1242, Université Rennes 1, Rennes 35000, France; Centre de Lutte Contre le Cancer Eugène Marquis, Rennes 35000, France
| | - Cécile Martinat
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France
| | - Marc Peschanski
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France; CECS/AFM, I-STEM, Corbeil-Essonnes 91100, France
| | - Laetitia Aubry
- INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France.
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20
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Afshari A, Yaghobi R, Rezaei G. Inter-regulatory role of microRNAs in interaction between viruses and stem cells. World J Stem Cells 2021; 13:985-1004. [PMID: 34567421 PMCID: PMC8422934 DOI: 10.4252/wjsc.v13.i8.985] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/11/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are well known for post-transcriptional regulatory ability over specific mRNA targets. miRNAs exhibit temporal or tissue-specific expression patterns and regulate the cell and tissue developmental pathways. They also have determinative roles in production and differentiation of multiple lineages of stem cells and might have therapeutic advantages. miRNAs are a part of some viruses' regulatory machinery, not a byproduct. The trace of miRNAs was detected in the genomes of viruses and regulation of cell reprograming and viral pathogenesis. Combination of inter-regulatory systems has been detected for miRNAs during viral infections in stem cells. Contraction between viruses and stem cells may be helpful in therapeutic tactics, pathogenesis, controlling viral infections and defining stem cell developmental strategies that is programmed by miRNAs as a tool. Therefore, in this review we intended to study the inter-regulatory role of miRNAs in the interaction between viruses and stem cells and tried to explain the advantages of miRNA regulatory potentials, which make a new landscape for future studies.
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Affiliation(s)
- Afsoon Afshari
- Shiraz Nephro-Urology Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
| | - Ramin Yaghobi
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran.
| | - Ghazal Rezaei
- Shiraz Transplant Research Center, Shiraz University of Medical Sciences, Shiraz 7193711351, Iran
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21
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Singh N. Role of mammalian long non-coding RNAs in normal and neuro oncological disorders. Genomics 2021; 113:3250-3273. [PMID: 34302945 DOI: 10.1016/j.ygeno.2021.07.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 07/10/2021] [Accepted: 07/14/2021] [Indexed: 12/09/2022]
Abstract
Long non-coding RNAs (lncRNAs) are expressed at lower levels than protein-coding genes but have a crucial role in gene regulation. LncRNA is distinct, they are being transcribed using RNA polymerase II, and their functionality depends on subcellular localization. Depending on their niche, they specifically interact with DNA, RNA, and proteins and modify chromatin function, regulate transcription at various stages, forms nuclear condensation bodies and nucleolar organization. lncRNAs may also change the stability and translation of cytoplasmic mRNAs and hamper signaling pathways. Thus, lncRNAs affect the physio-pathological states and lead to the development of various disorders, immune responses, and cancer. To date, ~40% of lncRNAs have been reported in the nervous system (NS) and are involved in the early development/differentiation of the NS to synaptogenesis. LncRNA expression patterns in the most common adult and pediatric tumor suggest them as potential biomarkers and provide a rationale for targeting them pharmaceutically. Here, we discuss the mechanisms of lncRNA synthesis, localization, and functions in transcriptional, post-transcriptional, and other forms of gene regulation, methods of lncRNA identification, and their potential therapeutic applications in neuro oncological disorders as explained by molecular mechanisms in other malignant disorders.
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Affiliation(s)
- Neetu Singh
- Molecular Biology Unit, Department of Centre for Advance Research, King George's Medical University, Lucknow, Uttar Pradesh 226 003, India.
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22
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Dasgupta S, Dunham CL, Truong L, Simonich MT, Sullivan CM, Tanguay RL. Phenotypically Anchored mRNA and miRNA Expression Profiling in Zebrafish Reveals Flame Retardant Chemical Toxicity Networks. Front Cell Dev Biol 2021; 9:663032. [PMID: 33898466 PMCID: PMC8063052 DOI: 10.3389/fcell.2021.663032] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/03/2021] [Indexed: 01/24/2023] Open
Abstract
The ubiquitous use of flame retardant chemicals (FRCs) in the manufacture of many consumer products leads to inevitable environmental releases and human exposures. Studying toxic effects of FRCs as a group is challenging since they widely differ in physicochemical properties. We previously used zebrafish as a model to screen 61 representative FRCs and showed that many induced behavioral and teratogenic effects, with aryl phosphates identified as the most active. In this study, we selected 10 FRCs belonging to diverse physicochemical classes and zebrafish toxicity profiles to identify the gene expression responses following exposures. For each FRC, we executed paired mRNA-micro-RNA (miR) sequencing, which enabled us to study mRNA expression patterns and investigate the role of miRs as posttranscriptional regulators of gene expression. We found widespread disruption of mRNA and miR expression across several FRCs. Neurodevelopment was a key disrupted biological process across multiple FRCs and was corroborated by behavioral deficits. Several mRNAs (e.g., osbpl2a) and miRs (e.g., mir-125b-5p), showed differential expression common to multiple FRCs (10 and 7 respectively). These common miRs were also predicted to regulate a network of differentially expressed genes with diverse functions, including apoptosis, neurodevelopment, lipid regulation and inflammation. Commonly disrupted transcription factors (TFs) such as retinoic acid receptor, retinoid X receptor, and vitamin D regulator were predicted to regulate a wide network of differentially expressed mRNAs across a majority of the FRCs. Many of the differential mRNA-TF and mRNA-miR pairs were predicted to play important roles in development as well as cancer signaling. Specific comparisons between TBBPA and its derivative TBBPA-DBPE showed contrasting gene expression patterns that corroborated with their phenotypic profiles. The newer generation FRCs such as IPP and TCEP produced distinct gene expression changes compared to the legacy FRC BDE-47. Our study is the first to establish a mRNA-miR-TF regulatory network across a large group of structurally diverse FRCs and diverse phenotypic responses. The purpose was to discover common and unique biological targets that will help us understand mechanisms of action for these important chemicals and establish this approach as an important tool for better understanding toxic effects of environmental contaminants.
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Affiliation(s)
- Subham Dasgupta
- The Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Cheryl L. Dunham
- The Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Lisa Truong
- The Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Michael T. Simonich
- The Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
| | - Christopher M. Sullivan
- Center for Genome Research and Computing, Oregon State University, Corvallis, OR, United States
| | - Robyn L. Tanguay
- The Sinnhuber Aquatic Research Laboratory, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, United States
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23
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Copeland J, Simoes-Costa M. Post-transcriptional tuning of FGF signaling mediates neural crest induction. Proc Natl Acad Sci U S A 2020; 117:33305-33316. [PMID: 33376218 PMCID: PMC7777031 DOI: 10.1073/pnas.2009997117] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Ectodermal patterning is required for the establishment of multiple components of the vertebrate body plan. Previous studies have demonstrated that precise combinations of extracellular signals induce distinct ectodermal cell populations, such as the neural crest and the neural plate. Yet, we still lack understanding of how the response to inductive signals is modulated to generate the proper transcriptional output in target cells. Here we show that posttranscriptional attenuation of fibroblast growth factor (FGF) signaling is essential for the establishment of the neural crest territory. We found that neural crest progenitors display elevated expression of DICER, which promotes enhanced maturation of a set of cell-type-specific miRNAs. These miRNAs collectively target components of the FGF signaling pathway, a central player in the process of neural induction in amniotes. Inactivation of this posttranscriptional circuit results in a fate switch, in which neural crest cells are converted into progenitors of the central nervous system. Thus, the posttranscriptional attenuation of signaling systems is a prerequisite for proper segregation of ectodermal cell types. These findings demonstrate how posttranscriptional repression may alter the activity of signaling systems to generate distinct spatial domains of progenitor cells.
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Affiliation(s)
- Jacqueline Copeland
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850
| | - Marcos Simoes-Costa
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14850
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24
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Lai Y, Jin Q, Zhu F. Differential expression of microRNAs in mud crab Scylla paramamosain in response to white spot syndrome virus (WSSV) infection. FISH & SHELLFISH IMMUNOLOGY 2020; 105:1-7. [PMID: 32619629 DOI: 10.1016/j.fsi.2020.06.055] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/27/2020] [Accepted: 06/28/2020] [Indexed: 06/11/2023]
Abstract
Till date numerous microRNAs (miRNAs) have been discovered from various organisms, including fish, shellfish and crustaceans. The miRNAs are known to regulate immune functions in crustaceans, but little is known about the role of miRNAs against viral infection in crab. We performed small RNA sequencing to characterize the differentially expressed miRNAs in WSSV infected Scylla paramamosain, in comparison to that in uninfected crab, at 2 h and 12 h post infection. In total, 24 host miRNAs were up-regulated and 25 host miRNAs were down-regulated in response to WSSV infection at 2 h post infection. And 27 host miRNAs were up-regulated and 30 host miRNAs were down-regulated in response to WSSV infection at 12 h post infection. Further, the gene ontology analysis revealed that many signaling pathways were mediated by these miRNAs. The integral component of membrane is the most important biological process and endocytosis pathway is the most important pathway, which indicates that endocytosis is very important for WSSV infection. This study is one important attempt at characterizing crab miRNAs that response to WSSV infection, and will help unravel the miRNA pathways involved in antiviral immunity of crab.
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Affiliation(s)
- Yongyong Lai
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang Agriculture and Forestry University, Hangzhou, 311300, China
| | - Qingri Jin
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang Agriculture and Forestry University, Hangzhou, 311300, China
| | - Fei Zhu
- Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, College of Animal Science and Technology, College of Veterinary Medicine, Zhejiang Agriculture and Forestry University, Hangzhou, 311300, China.
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25
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Le Gall L, Anakor E, Connolly O, Vijayakumar UG, Duddy WJ, Duguez S. Molecular and Cellular Mechanisms Affected in ALS. J Pers Med 2020; 10:E101. [PMID: 32854276 PMCID: PMC7564998 DOI: 10.3390/jpm10030101] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 08/17/2020] [Accepted: 08/22/2020] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.
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Affiliation(s)
- Laura Le Gall
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
- NIHR Biomedical Research Centre, University College London, Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust, London WC1N 1EH, UK
| | - Ekene Anakor
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Owen Connolly
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Udaya Geetha Vijayakumar
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - William J. Duddy
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
| | - Stephanie Duguez
- Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Derry-Londonderry BT47, UK; (L.L.G.); (E.A.); (O.C.); (U.G.V.); (W.J.D.)
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Vasu MM, Sumitha PS, Rahna P, Thanseem I, Anitha A. microRNAs in Autism Spectrum Disorders. Curr Pharm Des 2020; 25:4368-4378. [PMID: 31692427 DOI: 10.2174/1381612825666191105120901] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2019] [Accepted: 10/31/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Efforts to unravel the extensive impact of the non-coding elements of the human genome on cell homeostasis and pathological processes have gained momentum over the last couple of decades. miRNAs refer to short, often 18-25 nucleotides long, non-coding RNA molecules which can regulate gene expression. Each miRNA can regulate several mRNAs. METHODS This article reviews the literature on the roles of miRNAs in autism. RESULTS Considering the fact that ~ 1% of the human DNA encodes different families of miRNAs, their overall impact as critical regulators of gene expression in the mammalian brain should be immense. Though the autism spectrum disorders (ASDs) are predominantly genetic in nature and several candidate genes are already identified, the highly heterogeneous and multifactorial nature of the disorder makes it difficult to identify common genetic risk factors. Several studies have suggested that the environmental factors may interact with the genetic factors to increase the risk. miRNAs could possibly be one of those factors which explain this link between genetics and the environment. CONCLUSION In the present review, we have summarized our current knowledge on miRNAs and their complex roles in ASD, and also on their therapeutic applications.
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Affiliation(s)
- Mahesh Mundalil Vasu
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Puthiripadath S Sumitha
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Parakkal Rahna
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Ismail Thanseem
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
| | - Ayyappan Anitha
- Department of Neurogenetics, Institute for Communicative and Cognitive Neurosciences (ICCONS), Kavalappara, Shoranur, Palakkad - 679 523, Kerala, India
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27
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Laneve P, Caffarelli E. The Non-coding Side of Medulloblastoma. Front Cell Dev Biol 2020; 8:275. [PMID: 32528946 PMCID: PMC7266940 DOI: 10.3389/fcell.2020.00275] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 03/31/2020] [Indexed: 12/18/2022] Open
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor and a primary cause of cancer-related death in children. Until a few years ago, only clinical and histological features were exploited for MB pathological classification and outcome prognosis. In the past decade, the advancement of high-throughput molecular analyses that integrate genetic, epigenetic, and expression data, together with the availability of increasing wealth of patient samples, revealed the existence of four molecularly distinct MB subgroups. Their further classification into 12 subtypes not only reduced the well-characterized intertumoral heterogeneity, but also provided new opportunities for the design of targets for precision oncology. Moreover, the identification of tumorigenic and self-renewing subpopulations of cancer stem cells in MB has increased our knowledge of its biology. Despite these advancements, the origin of MB is still debated, and its molecular bases are poorly characterized. A major goal in the field is to identify the key genes that drive tumor growth and the mechanisms through which they are able to promote tumorigenesis. So far, only protein-coding genes acting as oncogenic drivers have been characterized in each MB subgroup. The contribution of the non-coding side of the genome, which produces a plethora of transcripts that control fundamental biological processes, as the cell choice between proliferation and differentiation, is still unappreciated. This review wants to fill this major gap by summarizing the recent findings on the impact of non-coding RNAs in MB initiation and progression. Furthermore, their potential role as specific MB biomarkers and novel therapeutic targets is also highlighted.
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Affiliation(s)
- Pietro Laneve
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Elisa Caffarelli
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
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28
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Prodromidou K, Vlachos IS, Gaitanou M, Kouroupi G, Hatzigeorgiou AG, Matsas R. MicroRNA-934 is a novel primate-specific small non-coding RNA with neurogenic function during early development. eLife 2020; 9:e50561. [PMID: 32459171 PMCID: PMC7295570 DOI: 10.7554/elife.50561] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 05/21/2020] [Indexed: 12/12/2022] Open
Abstract
Integrating differential RNA and miRNA expression during neuronal lineage induction of human embryonic stem cells we identified miR-934, a primate-specific miRNA that displays a stage-specific expression pattern during progenitor expansion and early neuron generation. We demonstrate the biological relevance of this finding by comparison with data from early to mid-gestation human cortical tissue. Further we find that miR-934 directly controls progenitor to neuroblast transition and impacts on neurite growth of newborn neurons. In agreement, miR-934 targets are involved in progenitor proliferation and neuronal differentiation whilst miR-934 inhibition results in profound global transcriptome changes associated with neurogenesis, axonogenesis, neuronal migration and neurotransmission. Interestingly, miR-934 inhibition affects the expression of genes associated with the subplate zone, a transient compartment most prominent in primates that emerges during early corticogenesis. Our data suggest that mir-934 is a novel regulator of early human neurogenesis with potential implications for a species-specific evolutionary role in brain function.
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Affiliation(s)
- Kanella Prodromidou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur InstituteAthensGreece
| | - Ioannis S Vlachos
- Department of Pathology, Beth Israel Deaconess Medical CenterBostonUnited States
- DIANA-Lab, Hellenic Pasteur InstituteAthensGreece
- Harvard Medical SchoolBostonUnited States
- Broad Institute of MIT and HarvardCambridgeUnited States
| | - Maria Gaitanou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur InstituteAthensGreece
| | - Georgia Kouroupi
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur InstituteAthensGreece
| | | | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur InstituteAthensGreece
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Du X, Li Q, Yang L, Liu L, Cao Q, Li Q. SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis. Cell Death Dis 2020; 11:373. [PMID: 32415058 PMCID: PMC7228950 DOI: 10.1038/s41419-020-2578-x] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/26/2020] [Accepted: 04/27/2020] [Indexed: 12/12/2022]
Abstract
The TGF-β and Wnt signaling pathways are interrelated in many cell types and tissues, and control cell functions in coordination. Here, we report that SMAD4, a downstream effector of the TGF-β signaling pathway, induces FZD4, a receptor of the Wnt signaling pathway, establishing a novel route of communication between these two pathways in granulosa cells (GCs). We found that SMAD4 is a strong inducer of FZD4, not only initiating FZD4 transcription but also activating FZD4-dependent Wnt signaling and GC apoptosis. Furthermore, we identified the direct and indirect mechanisms by which SMAD4 promotes expression of FZD4 in GCs. First, SMAD4 functions as a transcription factor to directly bind to the FZD4 promoter region to increase its transcriptional activity. Second, SMAD4 promotes production of SDNOR, a novel lncRNA that acts as a sponge for miR-29c, providing another mean to block miR-29c from degenerating FZD4 mRNA. Overall, our findings not only reveal a new channel of crosstalk between the TGF-β and Wnt signaling pathways, SMAD4–FZD4 axis, but also provide new insights into the regulatory network of GC apoptosis and follicular atresia. These RNA molecules, such as miR-29c and lnc-SDNOR, represent potential targets for treatment of reproductive diseases and improvement of female fertility.
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Affiliation(s)
- Xing Du
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Qiqi Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Liu Yang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Lu Liu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Qiuyu Cao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China
| | - Qifa Li
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
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Rai N, Singh AK, Singh SK, Gaurishankar B, Kamble SC, Mishra P, Kotiya D, Barik S, Atri N, Gautam V. Recent technological advancements in stem cell research for targeted therapeutics. Drug Deliv Transl Res 2020; 10:1147-1169. [DOI: 10.1007/s13346-020-00766-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Wang Y, Wang X, Jiang Y, Liu R, Cao D, Pan J, Luo Y. Identification of key miRNAs and genes for mouse retinal development using a linear model. Mol Med Rep 2020; 22:494-506. [PMID: 32319662 PMCID: PMC7248464 DOI: 10.3892/mmr.2020.11082] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 04/01/2020] [Indexed: 11/05/2022] Open
Abstract
MicroRNAs (miRNAs) are upstream regulators of gene expression and are involved in several biological processes. The purpose of the present study was to obtain a detailed spatiotemporal miRNA expression profile in mouse retina, to identify one or more miRNAs that are key to mouse retinal development and to investigate the roles and mechanisms of these miRNAs. The miRNA expression pattern of the developing mouse retina was acquired from Locked Nucleic Acid microarrays. Data were processed to identify differentially expressed miRNAs (DE‑miRNAs) using the linear model in Python 3.6. Following bioinformatics analysis and reverse transcription‑quantitative polymerase chain reaction validation, 8 miRNAs (miR‑9‑5p, miR‑130a‑3p, miR‑92a‑3p, miR‑20a‑5p, miR‑93‑5p, miR‑9‑3p, miR‑709 and miR‑124) were identified as key DE‑miRNAs with low variability during mouse retinal development. Gene Ontology analysis revealed that the target genes of the DE‑miRNAs were enriched in cellular metabolic processes. Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the target genes of the DE‑miRNAs were significantly enriched in PI3K/AKT/mTOR, class O of forkhead box transcription factors, mitogen‑activated protein kinase (MAPK), neurotrophin and transforming growth factor (TGF)‑β signaling, as well as focal adhesion and the axon guidance pathway. PI3K, AKT, PTEN, MAPK1, Son of Sevenless, sphingosine‑1‑phosphate receptor 1, BCL‑2L11, TGF‑β receptor type 1/2 and integrin α (ITGA)/ITGAB, which are key components of the aforementioned pathways and were revealed to be target genes of several of the DE‑miRNAs. The present study used a linear model to identify several DE‑miRNAs, as well as their target genes and associated pathways, which may serve crucial roles in mouse retinal development. Therefore, the results obtained in the present study may provide the groundwork for further experiments.
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Affiliation(s)
- Yishen Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Xiao Wang
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Yukang Jiang
- Department of Statistical Science, School of Mathematics, Southern China Research Center of Statistical Science, Sun Yat‑Sen University, Guangzhou, Guangdong 51027, P.R. China
| | - Ruyuan Liu
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Di Cao
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Jianying Pan
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
| | - Yan Luo
- State Key Laboratory of Ophthalmology, Image Reading Center, Zhongshan Ophthalmic Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
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Mattioli F, Hayot G, Drouot N, Isidor B, Courraud J, Hinckelmann MV, Mau-Them FT, Sellier C, Goldman A, Telegrafi A, Boughton A, Gamble C, Moutton S, Quartier A, Jean N, Van Ness P, Grotto S, Nambot S, Douglas G, Si YC, Chelly J, Shad Z, Kaplan E, Dineen R, Golzio C, Charlet-Berguerand N, Mandel JL, Piton A. De Novo Frameshift Variants in the Neuronal Splicing Factor NOVA2 Result in a Common C-Terminal Extension and Cause a Severe Form of Neurodevelopmental Disorder. Am J Hum Genet 2020; 106:438-452. [PMID: 32197073 DOI: 10.1016/j.ajhg.2020.02.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 02/18/2020] [Indexed: 12/13/2022] Open
Abstract
The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.
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Affiliation(s)
- Francesca Mattioli
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Gaelle Hayot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Nathalie Drouot
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Bertrand Isidor
- Service de Génétique Médicale, CHU de Nantes, Nantes 44093, France
| | - Jérémie Courraud
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Maria-Victoria Hinckelmann
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Frederic Tran Mau-Them
- Laboratoire de Génétique Moléculaire, UF Innovation en diagnostic génomique des maladies rares, Plateau Technique de Biologie, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France; INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France
| | - Chantal Sellier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Alica Goldman
- Department of Neurology, Neurophysiology Section, Baylor College of Medicine, Houston, TX 77030, USA
| | | | | | | | - Sebastien Moutton
- INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France; Centre de Génétique et Centre de référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France
| | - Angélique Quartier
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Nolwenn Jean
- INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France; Centre de Génétique et Centre de référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France
| | - Paul Van Ness
- Department of Neurology, Neurophysiology Section, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sarah Grotto
- Service de Génétique Médicale, AP-HP Robert-Debré, Paris 75019, France
| | - Sophie Nambot
- INSERM U1231, LNC UMR1231 GAD, Burgundy University, Dijon 21070, France; Centre de Génétique et Centre de référence "Anomalies du Développement et Syndromes Malformatifs," Hôpital d'Enfants, Centre Hospitalier Universitaire de Dijon, Dijon 21070, France
| | | | | | - Jamel Chelly
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France
| | - Zohra Shad
- Department of Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Elisabeth Kaplan
- Department of Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Richard Dineen
- Department of Genetics, University of Illinois College of Medicine, Chicago, IL 60607, USA
| | - Christelle Golzio
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Nicolas Charlet-Berguerand
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France
| | - Jean-Louis Mandel
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; University of Strasbourg Institute of Advanced Studies, Strasbourg 67000, France
| | - Amélie Piton
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67400, France; Centre National de la Recherche Scientifique, UMR7104, Illkirch 67400, France; Institut National de la Santé et de la Recherche Médicale, U964, Illkirch 67400, France; Université de Strasbourg, Illkirch 67400, France; Laboratory of Genetic Diagnostic, Hôpitaux Universitaires de Strasbourg, Strasbourg 67000, France.
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Giorgi Silveira R, Perelló Ferrúa C, do Amaral CC, Fernandez Garcia T, de Souza KB, Nedel F. MicroRNAs expressed in neuronal differentiation and their associated pathways: Systematic review and bioinformatics analysis. Brain Res Bull 2020; 157:140-148. [PMID: 31945407 DOI: 10.1016/j.brainresbull.2020.01.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 12/30/2019] [Accepted: 01/09/2020] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) plays an important role in the human brain from the embryonic period to adulthood. In this sense, they influence the development of neural stem cells (NSCs), regulating cellular differentiation and survival. Therefore, due to the importance of better comprehending the regulation of miRNAs in NSCs differentiation and the lack of studies that show the panorama of miRNAs and their signaling pathways studied until now we aimed to systematically review the literature to identify which miRNAs are currently being associated with neuronal differentiation and using bioinformatics analysis to identify their related pathways. A search was carried out in the following databases: Scientific Electronic Library Online (Scielo), National Library of Medicine National Institutes of Health (PubMed), Scopus, Web of Science and Science Direct, using the descriptors "(microRNA [MeSH])" and "(neurogenesis [MeSH])". From the articles found, two independent and previously calibrated reviewers, using the EndNote X7 (Thomson Reuters, New York, NY, US), selected those that concern miRNA in the development of NSCs, based on in vitro studies. After, bioinformatic analysis was performed using the software DIANA Tools, mirPath v.3. Subsequently, data was tabulated, analyzed and interpreted. Among the 106 miRNAs cited by included studies, 55 were up-regulated and 47 were down-regulated. The bioinformatics analysis revealed that among the up-regulated miRNAs there were 24 total and 6 union pathways, and 3 presented a statistically significant difference (p ≤ 0.05). Among the down-regulated miRNAs, 46 total and 13 union pathways were found, with 7 presenting a significant difference (p ≤ 0.05). The miR-125a-5p, miR-423-5p, miR-320 were the most frequently found miRNAs in the pathways determined by bioinformatics. In this study a panel of altered miRNAs in neuronal differentiation was created with their related pathways, which could be a step towards understanding the complex network of miRNAs in neuronal differentiation.
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Affiliation(s)
- Roberta Giorgi Silveira
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil
| | - Camila Perelló Ferrúa
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil
| | - Cainá Corrêa do Amaral
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil
| | - Tiago Fernandez Garcia
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil
| | - Karoline Brizola de Souza
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil
| | - Fernanda Nedel
- Graduate Program in Health and Behavior, Catholic University of Pelotas, Pelotas, RS, 96010-901, Brazil.
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Marangon D, Boda E, Parolisi R, Negri C, Giorgi C, Montarolo F, Perga S, Bertolotto A, Buffo A, Abbracchio MP, Lecca D. In vivo silencing of miR-125a-3p promotes myelin repair in models of white matter demyelination. Glia 2020; 68:2001-2014. [PMID: 32163190 DOI: 10.1002/glia.23819] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 02/13/2020] [Accepted: 03/02/2020] [Indexed: 12/18/2022]
Abstract
In the last decade, microRNAs have been increasingly recognized as key modulators of glial development. Recently, we identified miR-125a-3p as a new player in oligodendrocyte physiology, regulating in vitro differentiation of oligodendrocyte precursor cells (OPCs). Here, we show that miR-125a-3p is upregulated in active lesions of multiple sclerosis (MS) patients and in OPCs isolated from the spinal cord of chronic experimental autoimmune encephalomyelitis (EAE) mice, but not in those isolated from the spontaneously remyelinating corpus callosum of lysolecithin-treated mice. To test whether a sustained expression of miR-125a-3p in OPCs contribute to defective remyelination, we modulated miR-125a-3p expression in vivo and ex vivo after lysolecithin-induced demyelination. We found that lentiviral over-expression of miR-125a-3p impaired OPC maturation, whereas its downregulation accelerated remyelination. Transcriptome analysis and luciferase reporter assay revealed that these effects are partly mediated by the direct interaction of miR-125a-3p with Slc8a3, a sodium-calcium membrane transporter, and identified novel candidate targets, such as Gas7, that we demonstrated necessary to correctly address oligodendrocytes to terminal maturation. These findings show that miR-125a-3p upregulation negatively affects OPC maturation in vivo, suggest its role in the pathogenesis of demyelinating diseases and unveil new targets for future promyelinating protective interventions.
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Affiliation(s)
- Davide Marangon
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Enrica Boda
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Roberta Parolisi
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Camilla Negri
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Corinna Giorgi
- European Brain Research Institute Rita Levi-Montalcini, Rome, Italy
| | - Francesca Montarolo
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Simona Perga
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Antonio Bertolotto
- Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy.,Neurobiology Unit, Neurology-CReSM (Regional Referring Center of Multiple Sclerosis), AOU San Luigi Gonzaga, Orbassano, Italy
| | - Annalisa Buffo
- Department of Neuroscience Rita Levi Montalcini, University of Turin, Turin, Italy.,Neuroscience Institute Cavalieri Ottolenghi, Orbassano, Italy
| | - Maria P Abbracchio
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Davide Lecca
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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35
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Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome. Cells 2020; 9:cells9020289. [PMID: 31991700 PMCID: PMC7072127 DOI: 10.3390/cells9020289] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/06/2020] [Accepted: 01/22/2020] [Indexed: 01/01/2023] Open
Abstract
A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS.
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Nicolai S, Pieraccioli M, Smirnov A, Pitolli C, Anemona L, Mauriello A, Candi E, Annicchiarico-Petruzzelli M, Shi Y, Wang Y, Melino G, Raschellà G. ZNF281/Zfp281 is a target of miR-1 and counteracts muscle differentiation. Mol Oncol 2019; 14:294-308. [PMID: 31782884 PMCID: PMC6998661 DOI: 10.1002/1878-0261.12605] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/04/2019] [Accepted: 11/27/2019] [Indexed: 01/28/2023] Open
Abstract
Defects in achieving a fully differentiated state and aberrant expression of genes and microRNAs (miRs) involved in differentiation are common to virtually all tumor types. Here, we demonstrate that the zinc finger transcription factor ZNF281/Zfp281 is down‐regulated during epithelial, muscle, and granulocytic differentiation in vitro. The expression of this gene is absent in terminally differentiated human tissues, in contrast to the elevated expression in proliferating/differentiating ones. Analysis of the 3’UTR of ZNF281/Zfp281 revealed the presence of numerous previously undescribed miR binding sites that were proved to be functional for miR‐mediated post‐transcriptional regulation. Many of these miRs are involved in differentiation pathways of distinct cell lineages. Of interest, ZNF281/Zfp281 is able to inhibit muscle differentiation promoted by miR‐1, of which ZNF281/Zfp281 is a direct target. These data suggest that down‐regulation of ZNF281/Zfp281 during differentiation in various cell types may occur through specific miRs whose expression is tissue‐restricted. In addition, we found that in rhabdomyosarcoma and leiomyosarcoma tumors, the expression of ZNF281/Zfp281 is significantly higher compared with normal counterparts. We extended our analysis to other human soft tissue sarcomas, in which the expression of ZNF281 is associated with a worse prognosis. In summary, we highlight here a new role of ZNF281/Zfp281 in counteracting muscle differentiation; its down‐regulation is at least in part mediated by miR‐1. The elevated expression of ZNF281/Zfp281 in soft tissue sarcomas warrants further analysis for its possible exploitation as a prognostic marker in this class of tumors.
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Affiliation(s)
- Sara Nicolai
- Medical Research Council, Toxicology Unit, Department of Pathology, University of Cambridge, UK
| | - Marco Pieraccioli
- Department of Experimental Medicine, University of Rome Tor Vergata, Italy
| | - Artem Smirnov
- Department of Experimental Medicine, University of Rome Tor Vergata, Italy
| | - Consuelo Pitolli
- Medical Research Council, Toxicology Unit, Department of Pathology, University of Cambridge, UK
| | - Lucia Anemona
- Department of Experimental Medicine, University of Rome Tor Vergata, Italy
| | | | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, Italy.,Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy
| | | | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.,The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Gerry Melino
- Medical Research Council, Toxicology Unit, Department of Pathology, University of Cambridge, UK.,Department of Experimental Medicine, University of Rome Tor Vergata, Italy
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Prodromidou K, Matsas R. Species-Specific miRNAs in Human Brain Development and Disease. Front Cell Neurosci 2019; 13:559. [PMID: 31920559 PMCID: PMC6930153 DOI: 10.3389/fncel.2019.00559] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 12/04/2019] [Indexed: 12/20/2022] Open
Abstract
Identification of the unique features of human brain development and function can be critical towards the elucidation of intricate processes such as higher cognitive functions and human-specific pathologies like neuropsychiatric and behavioral disorders. The developing primate and human central nervous system (CNS) are distinguished by expanded progenitor zones and a protracted time course of neurogenesis, leading to the expansion in brain size, prominent gyral anatomy, distinctive synaptic properties, and complex neural circuits. Comparative genomic studies have revealed that adaptations of brain capacities may be partly explained by human-specific genetic changes that impact the function of proteins associated with neocortical expansion, synaptic function, and language development. However, the formation of complex gene networks may be most relevant for brain evolution. Indeed, recent studies identified distinct human-specific gene expression patterns across developmental time occurring in brain regions linked to cognition. Interestingly, such modules show species-specific divergence and are enriched in genes associated with neuronal development and synapse formation whilst also being implicated in neuropsychiatric diseases. microRNAs represent a powerful component of gene-regulatory networks by promoting spatiotemporal post-transcriptional control of gene expression in the human and primate brain. It has also been suggested that the divergence in miRNA expression plays an important role in shaping gene expression divergence among species. Primate-specific and human-specific miRNAs are principally involved in progenitor proliferation and neurogenic processes but also associate with human cognition, and neurological disorders. Human embryonic or induced pluripotent stem cells and brain organoids, permitting experimental access to neural cells and differentiation stages that are otherwise difficult or impossible to reach in humans, are an essential means for studying species-specific brain miRNAs. Single-cell sequencing approaches can further decode refined miRNA-mRNA interactions during developmental transitions. Elucidating species-specific miRNA regulation will shed new light into the mechanisms that control spatiotemporal events during human brain development and disease, an important step towards fostering novel, holistic and effective therapeutic approaches for neural disorders. In this review, we discuss species-specific regulation of miRNA function, its contribution to the evolving features of the human brain and in neurological disease, with respect also to future therapeutic approaches.
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Affiliation(s)
- Kanella Prodromidou
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece
| | - Rebecca Matsas
- Laboratory of Cellular and Molecular Neurobiology-Stem Cells, Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece
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microRNA: The Impact on Cancer Stemness and Therapeutic Resistance. Cells 2019; 9:cells9010008. [PMID: 31861404 PMCID: PMC7016867 DOI: 10.3390/cells9010008] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/12/2019] [Accepted: 12/16/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer ranks as the second leading cause of death worldwide, causing a large social and economic burden. However, most anti-cancer treatments face the problems of tumor recurrence and metastasis. Therefore, finding an effective cure for cancer needs to be solved urgently. Recently, the discovery of cancer stem cells (CSCs) provides a new orientation for cancer research and therapy. CSCs share main characteristics with stem cells and are able to generate an entire tumor. Besides, CSCs usually escape from current anti-cancer therapies, which is partly responsible for tumor recurrence and poor prognosis. microRNAs (miRNAs) belong to small noncoding RNA and regulate gene post-transcriptional expression. The dysregulation of miRNAs leads to plenty of diseases, including cancer. The aberrant miRNA expression in CSCs enhances stemness maintenance. In this review, we summarize the role of miRNAs on CSCs in the eight most common cancers, hoping to bridge the research of miRNAs and CSCs with clinical applications. We found that miRNAs can act as tumor promoter or suppressor. The dysregulation of miRNAs enhances cell stemness and contributes to tumor metastasis and therapeutic resistance via the formation of feedback loops and constitutive activation of carcinogenic signaling pathways. More importantly, some miRNAs may be potential targets for diagnosis, prognosis, and cancer treatments.
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Diana A, Gaido G, Murtas D. MicroRNA Signature in Human Normal and Tumoral Neural Stem Cells. Int J Mol Sci 2019; 20:ijms20174123. [PMID: 31450858 PMCID: PMC6747235 DOI: 10.3390/ijms20174123] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 08/16/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs, also called miRNAs or simply miR-, represent a unique class of non-coding RNAs that have gained exponential interest during recent years because of their determinant involvement in regulating the expression of several genes. Despite the increasing number of mature miRNAs recognized in the human species, only a limited proportion is engaged in the ontogeny of the central nervous system (CNS). miRNAs also play a pivotal role during the transition of normal neural stem cells (NSCs) into tumor-forming NSCs. More specifically, extensive studies have identified some shared miRNAs between NSCs and neural cancer stem cells (CSCs), namely miR-7, -124, -125, -181 and miR-9, -10, -130. In the context of NSCs, miRNAs are intercalated from embryonic stages throughout the differentiation pathway in order to achieve mature neuronal lineages. Within CSCs, under a different cellular context, miRNAs perform tumor suppressive or oncogenic functions that govern the homeostasis of brain tumors. This review will draw attention to the most characterizing studies dealing with miRNAs engaged in neurogenesis and in the tumoral neural stem cell context, offering the reader insight into the power of next generation miRNA-targeted therapies against brain malignances.
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Affiliation(s)
- Andrea Diana
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato (Cagliari), Italy.
| | - Giuseppe Gaido
- Department of Surgery, Cottolengo Mission Hospital Charia, 60200 Meru, Kenya
| | - Daniela Murtas
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato (Cagliari), Italy.
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MicroRNA Profiling During Neural Differentiation of Induced Pluripotent Stem Cells. Int J Mol Sci 2019; 20:ijms20153651. [PMID: 31357387 PMCID: PMC6696086 DOI: 10.3390/ijms20153651] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/17/2019] [Accepted: 07/25/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNA) play an essential role in the regulation of gene expression and influence signaling networks responsible for several cellular processes like differentiation of pluripotent stem cells. Despite several studies on the neurogenesis process, no global analysis of microRNA expression during differentiation of induced pluripotent stem cells (iPSC) to neuronal stem cells (NSC) has been done. Therefore, we compared the profile of microRNA expression in iPSC lines and in NSC lines derived from them, using microarray-based analysis. Two different protocols for NSC formation were used: Direct and two-step via neural rosette formation. We confirmed the new associations of previously described miRNAs in regulation of NSC differentiation from iPSC. We discovered upregulation of miR-10 family, miR-30 family and miR-9 family and downregulation of miR-302 and miR-515 family expression. Moreover, we showed that miR-10 family play a crucial role in the negative regulation of genes expression belonging to signaling pathways involved in neural differentiation: WNT signaling pathway, focal adhesion, and signaling pathways regulating pluripotency of stem cells.
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Colasante G, Rubio A, Massimino L, Broccoli V. Direct Neuronal Reprogramming Reveals Unknown Functions for Known Transcription Factors. Front Neurosci 2019; 13:283. [PMID: 30971887 PMCID: PMC6445133 DOI: 10.3389/fnins.2019.00283] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/11/2019] [Indexed: 12/25/2022] Open
Abstract
In recent years, the need to derive sources of specialized cell types to be employed for cell replacement therapies and modeling studies has triggered a fast acceleration of novel cell reprogramming methods. In particular, in neuroscience, a number of protocols for the efficient differentiation of somatic or pluripotent stem cells have been established to obtain a renewable source of different neuronal cell types. Alternatively, several neuronal populations have been generated through direct reprogramming/transdifferentiation, which concerns the conversion of fully differentiated somatic cells into induced neurons. This is achieved through the forced expression of selected transcription factors (TFs) in the donor cell population. The reprogramming cocktail is chosen after an accurate screening process involving lists of TFs enriched into desired cell lineages. In some instances, this type of studies has revealed the crucial role of TFs whose function in the differentiation of a given specific cell type had been neglected or underestimated. Herein, we will speculate on how the in vitro studies have served to better understand physiological mechanisms of neuronal development in vivo.
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Affiliation(s)
- Gaia Colasante
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | - Alicia Rubio
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.,CNR Institute of Neuroscience, Milan, Italy
| | - Luca Massimino
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy
| | - Vania Broccoli
- Stem Cell and Neurogenesis Unit, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.,CNR Institute of Neuroscience, Milan, Italy
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Laneve P, Rea J, Caffarelli E. Long Noncoding RNAs: Emerging Players in Medulloblastoma. Front Pediatr 2019; 7:67. [PMID: 30923703 PMCID: PMC6426782 DOI: 10.3389/fped.2019.00067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 02/18/2019] [Indexed: 01/02/2023] Open
Abstract
Central Nervous System tumors are the leading cause of cancer-related death in children, and medulloblastoma has the highest incidence rate. The current therapies achieve a 5-year survival rate of 50-80%, but often inflict severe secondary effects demanding the urgent development of novel, effective, and less toxic therapeutic strategies. Historically identified on a histopathological basis, medulloblastoma was later classified into four major subgroups-namely WNT, SHH, Group 3, and Group 4-each characterized by distinct transcriptional profiles, copy-number aberrations, somatic mutations, and clinical outcomes. Additional complexity was recently provided by integrating gene- and non-gene-based data, which indicates that each subclass can be further subdivided into specific subtypes. These deeper classifications, while getting over the typical tumor heterogeneity, indicate that different forms of medulloblastoma hold different molecular drivers that can be successfully exploited for a greater diagnostic accuracy and for the development of novel, targeted treatments. Long noncoding RNAs are transcripts that lack coding potential and play relevant roles as regulators of gene expression in mammalian differentiation and developmental processes. Their cell type- and tissue-specificity, higher than mRNAs, make them more informative about cell- type identity than protein-coding genes. Remarkably, about 40% of long noncoding RNAs are expressed in the brain and their aberrant expression has been linked to neuro-oncological disorders. However, while their involvement in gliomas and neuroblastomas has been extensively studied, their role in medulloblastoma is still poorly explored. Here, we present an overview of current knowledge regarding the function played by long noncoding RNAs in medulloblastoma biology.
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Affiliation(s)
- Pietro Laneve
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
| | - Jessica Rea
- Department of Biology and Biotechnology, Sapienza University of Rome, Rome, Italy
| | - Elisa Caffarelli
- Institute of Molecular Biology and Pathology, National Research Council, Rome, Italy
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Zhou T, Wu N, Meng F, Venter J, Giang TK, Francis H, Kyritsi K, Wu C, Franchitto A, Alvaro D, Marzioni M, Onori P, Mancinelli R, Gaudio E, Glaser S, Alpini G. Knockout of secretin receptor reduces biliary damage and liver fibrosis in Mdr2 -/- mice by diminishing senescence of cholangiocytes. J Transl Med 2018; 98:1449-1464. [PMID: 29977037 PMCID: PMC6214714 DOI: 10.1038/s41374-018-0093-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 05/03/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023] Open
Abstract
Secretin receptor (SR), only expressed by cholangiocytes, plays a key role in the regulation of biliary damage and liver fibrosis. The aim of this study was to determine the effects of genetic depletion of SR in Mdr2-/- mice on intrahepatic biliary mass, liver fibrosis, senescence, and angiogenesis. 12 wk SR-/-, Mdr2-/-, and SR-/-/Mdr2-/- mice with corresponding wild-type mice were used for the in vivo studies. Immunohistochemistry or immunofluorescence was performed in liver sections for (i) biliary expression of SR; (ii) hematoxylin and eosin; (iii) intrahepatic biliary mass by CK-19; (iv) fibrosis by Col1a1 and α-SMA; (v) senescence by SA-β-gal and p16; and (vi) angiogenesis by VEGF-A and CD31. Secretin (Sct) and TGF-β1 levels were measured in serum and cholangiocyte supernatant by ELISA. In total liver, isolated cholangiocytes or HSCs, we evaluated the expression of fibrosis markers (FN-1 and Col1a1); senescence markers (p16 and CCL2); microRNA 125b and angiogenesis markers (VEGF-A, VEGFR-2, CD31, and vWF) by immunoblots and/or qPCR. In vitro, we measured the paracrine effect of cholangiocyte supernatant on the expression of senescent and fibrosis markers in human hepatic stellate cells (HHSteCs). The increased level of ductular reaction, fibrosis, and angiogenesis in Mdr2-/- mice was reduced in SR-/-/Mdr2-/- mice. Enhanced senescence levels in cholangiocytes from Mdr2-/- mice were reversed to normal in SR-/-/Mdr2-/- mice. However, senescence was decreased in HSCs from Mdr2-/- mice but returned to normal values in SR-/-/Mdr2-/- mice. In vitro treatment of HHSteCs with supernatant from cholangiocyte lacking SR (containing lower biliary levels of Sct-dependent TGF-β1) have decreased fibrotic reaction and increased cellular senescence. Sct-induced TGF-β1 secretion was mediated by microRNA 125b. Our data suggest that differential modulation of angiogenesis-dependent senescence of cholangiocytes and HSCs may be important for the treatment of liver fibrosis in cholangiopathies.
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Affiliation(s)
- Tianhao Zhou
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
| | - Nan Wu
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA
- Academic Research Integration, Baylor Scott & White Healthcare, Temple, TX, 76504, USA
| | - Julie Venter
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
| | - Thao K Giang
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
| | - Heather Francis
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
- Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA
| | - Konstantina Kyritsi
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA
| | - Chaodong Wu
- Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77840, USA
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy
- Eleonora Lorillard Spencer Cenci Foundation, Rome, Italy
| | - Domenico Alvaro
- Department of Medicine, Gastroenterology, Sapienza, Rome, Italy
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti - University Hospital, Ancona, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy
| | - Romina Mancinelli
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopaedics Sciences, Sapienza, Rome, Italy
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
- Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA.
| | - Gianfranco Alpini
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, TX, 76504, USA.
- Research, Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, TX, 76504, USA.
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Shen XB, Zhang SH, Li HY, Chi XD, Jiang L, Huang QL, Xu SH. Rs12976445 Polymorphism Is Associated with Post-Ablation Recurrence of Atrial Fibrillation by Modulating the Expression of MicroRNA-125a and Interleukin-6R. Med Sci Monit 2018; 24:6349-6358. [PMID: 30203815 PMCID: PMC6145598 DOI: 10.12659/msm.908555] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND This study aimed to identify the relationship between miR-125a polymorphism rs12976445 and the post-ablation recurrence of atrial fibrillation (AF), as well as to explore the underlying mechanism of miR-125a in AF recurrence. MATERIAL AND METHODS Microarray analysis was performed to search for miRNAs potentially involved in the regulation of AF recurrence, while real-time PCR (polymerase chain reaction) and Western blot analyses were carried out to study the expression of miR-125a (microRNA-125a), IL-6R (interleukin-6 receptor), and IL-16 (interleukin-16) in different experimental groups, so as to understand the regulatory relationships among miR-125a, IL-6R, and IL-16. Subsequently, a logistic regression analysis was utilized to investigate the survival status of recurrent AF in subjects harboring different genotypes of rs12976445. RESULTS The subjects in the GG and GC/CC groups of miR-125a polymorphism rs12976445 showed no obvious difference regarding all demographic characteristics that were collected in this study. In addition, 19 miRNAs were identified as potentially involved in the regulation of AF recurrence. Among these miRNAs, 6 were upregulated and 13 were downregulated in the group with early recurrence. According to real-time PCR results, the expression of miR-125a was dramatically upregulated in LRAF (late recurrence of atrial fibrillation) as well as in subjects harboring the GG genotype. On the contrary, the level of IL-6R mRNA was dramatically downregulated in LRAF and subjects harboring the GG genotype. Furthermore, IL-6R was confirmed as a candidate target of miR-125a by a luciferase reporter assay. CONCLUSIONS MicroRNA-125a polymorphism rs12976445 plays a role in AF recurrence via the regulation of IL-6R.
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Affiliation(s)
- Xue-Bin Shen
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Shao-Hong Zhang
- Department of Medical Laboratory Medicine, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Hai-Yang Li
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Xi-Di Chi
- Department of Medical Laboratory Medicine, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Ling Jiang
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Qi-Lei Huang
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
| | - Shang-Hua Xu
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University, Nanping, Fujian, China (mainland)
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Reza AMMT, Choi YJ, Han SG, Song H, Park C, Hong K, Kim JH. Roles of microRNAs in mammalian reproduction: from the commitment of germ cells to peri-implantation embryos. Biol Rev Camb Philos Soc 2018; 94:415-438. [PMID: 30151880 PMCID: PMC7379200 DOI: 10.1111/brv.12459] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 07/25/2018] [Accepted: 07/27/2018] [Indexed: 12/15/2022]
Abstract
MicroRNAs (miRNAs) are active regulators of numerous biological and physiological processes including most of the events of mammalian reproduction. Understanding the biological functions of miRNAs in the context of mammalian reproduction will allow a better and comparative understanding of fertility and sterility in male and female mammals. Herein, we summarize recent progress in miRNA‐mediated regulation of mammalian reproduction and highlight the significance of miRNAs in different aspects of mammalian reproduction including the biogenesis of germ cells, the functionality of reproductive organs, and the development of early embryos. Furthermore, we focus on the gene expression regulatory feedback loops involving hormones and miRNA expression to increase our understanding of germ cell commitment and the functioning of reproductive organs. Finally, we discuss the influence of miRNAs on male and female reproductive failure, and provide perspectives for future studies on this topic.
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Affiliation(s)
- Abu Musa Md Talimur Reza
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
| | - Yun-Jung Choi
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
| | - Sung Gu Han
- Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul, 05029, Republic of Korea
| | - Hyuk Song
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
| | - Chankyu Park
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
| | - Kwonho Hong
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
| | - Jin-Hoi Kim
- Department of Stem Cell and Regenerative Biotechnology, Humanized Pig Research Centre (SRC), Konkuk University, Seoul, 143-701, Republic of Korea
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Xiu L, Xing Q, Mao J, Sun H, Teng W, Shan Z. miRNA-125b-5p Suppresses Hypothyroidism Development by Targeting Signal Transducer and Activator of Transcription 3. Med Sci Monit 2018; 24:5041-5049. [PMID: 30027933 PMCID: PMC6067029 DOI: 10.12659/msm.907510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background A deficiency of maternal thyroid hormones (THs) during pregnancy has severe impacts on fetal brain development. Neural stem cells (NSCs) are major targets of THs and provided a powerful model to explore the underlying mechanism of THs during brain development. Although miRNA-125 might be associated with the NSCs differentiation, the relationship between miR-125 and hypothyroidism (HypoT) development remains unclear. Material/Methods In our study, we screened a differentially expressed gene miR-125b-5p from brain between euthyroid (EuT) and HypoT rats. In vitro, we employed anion exchange resin to remove THs to stimulate HypoT. QRT-PCR and Western blot were used to examine the expression of signal transducer and activator of transcription 3 (Stat3). The relationship between miR-125b-5p and Stat3 was detected via a dual-luciferase assay. Results QRT-PCR results showed that the level of miR-125b-5p in HypoT rat brains was significantly suppressed, suggesting some relationship between miR-125b-5p and HypoT. In C17.2, miR-125b-5p promoted cell differentiation into neurons by regulating the expression of tubulin beta chain 3 (TUBB3) and glial fibrillary acid protein (GFAP). QRT-PCR and Western blot results revealed that miR-125b-5p mimic modulated the contents of total Stat3 and p-Stat3. A dual-luciferase assay showed that miR-125b-5p negatively regulated the expression of Stat3 by binding with the first site in 3′ UTR of Stat3. Conclusions These results revealed Stat3 is a new target of miR-125b-5p and revealed the mechanism of miR-125b-5p suppressing HypoT development. These findings provide a new target for HypoT therapy.
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Affiliation(s)
- Liu Xiu
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland).,Shijiazhuang First Hospital, Shijiazhuang, Hebei, China (mainland)
| | - Qian Xing
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Jinyuan Mao
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Huakun Sun
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Weiping Teng
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
| | - Zhongyan Shan
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning, Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China (mainland)
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Lee YS, Jung WY, Heo H, Park MG, Oh SH, Park BG, Kim S. Exosome-Mediated Ultra-Effective Direct Conversion of Human Fibroblasts into Neural Progenitor-like Cells. ACS NANO 2018; 12:2531-2538. [PMID: 29462562 DOI: 10.1021/acsnano.7b08297] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Exosomes, naturally secreted nanoparticles, have been introduced as vehicles for horizontal transfer of genetic material. We induced autologous exosomes containing a cocktail of reprogramming factors ("reprosomes") to convert fibroblasts into neural progenitor cells (NPCs). The fibroblasts were treated with ultrasound and subsequently cultured in neural stem cell medium for 1 day to induce the release of reprosomes composed of reprogramming factors associated with chromatin remodeling and neural lineage-specific factors. After being treated with reprosomes, fibroblasts were converted into NPCs (rNPCs) with great efficiency via activation of chromatin remodeling, so quickly that only 5 days were required for the formation of 1500 spheroids showing an NPC-like phenotype. The rNPCs maintained self-renewal and proliferative properties for several weeks and successfully differentiated into neurons, astrocytes, and oligodendrocytes in vitro and in vivo. Reprosome-mediated cellular reprogramming is simple, safe, and efficient to produce autologous stem cells for clinical application.
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Affiliation(s)
- Yong Seung Lee
- Institute for Bio-Medical Convergence, College of Medicine , Catholic Kwandong University , Gangneung-si , Gangwon-do 270-701 , Republic of Korea
- Catholic Kwandong University International St. Mary's Hospital , Incheon Metropolitan City 404-834 , Republic of Korea
| | - Woon Yong Jung
- Department of Pathology , Catholic Kwandong University International St. Mary's Hospital , Incheon Metropolitan City 404-834 , Republic of Korea
| | - Hyejung Heo
- Institute for Bio-Medical Convergence, College of Medicine , Catholic Kwandong University , Gangneung-si , Gangwon-do 270-701 , Republic of Korea
- Catholic Kwandong University International St. Mary's Hospital , Incheon Metropolitan City 404-834 , Republic of Korea
| | - Min Geun Park
- Department of Surgery , Catholic Kwandong University International St. Mary's Hospital , Incheon Metropolitan City 404-834 , Republic of Korea
| | - Seung-Hun Oh
- Department of Neurology, CHA Bundang Medical Center , CHA University , Seongnam 13497 , Republic of Korea
| | - Byong-Gon Park
- Department of Physiology, College of Medicine , Catholic Kwandong University , Gangneung-si , Gangwon-do 270-701 , Republic of Korea
| | - Soonhag Kim
- Institute for Bio-Medical Convergence, College of Medicine , Catholic Kwandong University , Gangneung-si , Gangwon-do 270-701 , Republic of Korea
- Catholic Kwandong University International St. Mary's Hospital , Incheon Metropolitan City 404-834 , Republic of Korea
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48
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He H, Li W, Peng M, Qin J, Shi J, Li H, Tian M, Zhang X, Lv G, Jin G. MicroRNA expression profiles of neural stem cells following valproate inducement. J Cell Biochem 2018; 119:6204-6215. [PMID: 29575035 DOI: 10.1002/jcb.26831] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 02/28/2018] [Indexed: 12/18/2022]
Abstract
Neural stem cells (NSCs) possess self-renewal and multilineage differentiation ability, thus are considered to be a potential source for cell replacement therapy of many nervous system diseases, such as neurodegenerative diseases. Valproate (VPA), a member of histone deacetylase inhibitor family, is an epigenetic regulator and can promote NSCs to differentiate into neurons, nevertheless, the underlying mechanisms of the process remain unclear. MicroRNAs (miRNAs) exert a crucial part in the posttranscriptional regulation of gene expression. Epigenetic mechanisms involve in the regulation of miRNAs expression. Therefore we speculated that miRNAs may be important factors during the promotion of neuronal differentiation by VPA. Here, after selecting appropriate concentration and treatment time of VPA, we conducted microRNA arrays at 24 h on the treatment of 1 mM VPA or vehicle. After validation, we obtained 5 significantly upregulated miRNAs (miR-29a-5p, miR-674-5p, miR-155-5p, miR-652-3p, and miR-210-3p) in VPA group compared with control. We predicted the target genes of these miRNAs on the website. Through gene ontology (GO) and pathway analyses, we obtained preliminary comprehension of the function of these genes. The bioinformatics analyses indicated the involvement of them during neurogenesis. In addition, we observed high expression of miR-210-3p, miR-29a-5p, and miR-674-5p in central nervous system, which suggested that they were likely to play crucial roles in neuronal differentiation. We then defined the upregulation of Map2 by transfecting mimic of miR-674-5p, which indicated the promotion of miR-674-5p on NSCs differentiation. The present study explored the miRNAs potentially mediated the function of VPA on promoting NSCs to differentiate into neurons.
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Affiliation(s)
- Hui He
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Wen Li
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Min Peng
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Jianbing Qin
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Jinhong Shi
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Haoming Li
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Meiling Tian
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Xinhua Zhang
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China
| | - Guangming Lv
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China.,Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, PR China
| | - Guohua Jin
- Department of Human Anatomy, Medical School, Nantong University, Nantong, Jiangsu, PR China.,Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, PR China.,Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, PR China
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49
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Honda M, Nakashima K, Katada S. Epigenetic Regulation of Human Neural Stem Cell Differentiation. Results Probl Cell Differ 2018; 66:125-136. [PMID: 30209657 DOI: 10.1007/978-3-319-93485-3_5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emerging evidence has demonstrated that epigenetic programs influence many aspects of neural stem cell (NSC) behavior, including proliferation and differentiation. It is becoming apparent that epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNA expression, are spatiotemporally regulated and that these intracellular programs, in concert with extracellular signals, ensure appropriate gene activation. Here we summarize recent advances in understanding of the epigenetic regulation of human NSCs directly isolated from the brain or produced from pluripotent stem cells (embryonic and induced pluripotent stem cells, respectively).
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Affiliation(s)
- Mizuki Honda
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kinichi Nakashima
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sayako Katada
- Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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50
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Tanno B, Leonardi S, Babini G, Giardullo P, De Stefano I, Pasquali E, Saran A, Mancuso M. Nanog-driven cell-reprogramming and self-renewal maintenance in Ptch1 +/- granule cell precursors after radiation injury. Sci Rep 2017; 7:14238. [PMID: 29079783 PMCID: PMC5660207 DOI: 10.1038/s41598-017-14506-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 10/11/2017] [Indexed: 12/31/2022] Open
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor, comprising four distinct molecular variants, one of which characterized by activation of the Sonic Hedgehog (SHH) pathway, driving 25–30% of sporadic MB. SHH-dependent MBs arise from granule cell precursors (GCPs), are fatal in 40–70% of cases and radioresistance strongly contributes to poor prognosis and tumor recurrence. Patched1 heterozygous (Ptch1+/−) mice, carrying a germ-line heterozygous inactivating mutation in the Ptch1 gene, the Shh receptor and negative regulator of the pathway, are uniquely susceptible to MB development after radiation damage in neonatal cerebellum. Here, we irradiated ex-vivo GCPs isolated from cerebella of neonatal WT and Ptch1+/− mice. Our results highlight a less differentiated status of Ptch1-mutated cells after irradiation, influencing DNA damage response. Increased expression levels of pluripotency genes Nanog, Oct4 and Sal4, together with greater clonogenic potential, clearly suggest that radiation induces expansion of the stem-like cell compartment through cell-reprogramming and self-renewal maintenance, and that this mechanism is strongly dependent on Nanog. These results contribute to clarify the molecular mechanisms that control radiation-induced Shh-mediated tumorigenesis and may suggest Nanog as a potential target to inhibit for adjuvant radiotherapy in treatment of SHH-dependent MB.
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Affiliation(s)
- Barbara Tanno
- Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy
| | - Simona Leonardi
- Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy
| | | | - Paola Giardullo
- Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy.,Department of Sciences, Roma Tre University, Rome, Italy
| | - Ilaria De Stefano
- Department of Radiation Physics, Guglielmo Marconi University, Rome, Italy
| | - Emanuela Pasquali
- Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy
| | - Anna Saran
- Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy.
| | - Mariateresa Mancuso
- Laboratory of Biomedical Technologies, Italian National Agency for New Technologies, Energy and Sustainable Economic Development (ENEA), Rome, Italy.
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