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Denizci E, Altun G, Kaplan S. Morphological evidence for the potential protective effects of curcumin and Garcinia kola against diabetes in the rat hippocampus. Brain Res 2024; 1839:149020. [PMID: 38788929 DOI: 10.1016/j.brainres.2024.149020] [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: 04/11/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/26/2024]
Abstract
This research investigated the effects of sciatic nerve transection and diabetes on the hippocampus, and the protective effects of Garcinia kola and curcumin. Thirty-five adults male Wistar albino rats were divided into five groups: a control group (Cont), a transected group (Sham group), a transected + diabetes mellitus group (DM), a transected + diabetes mellitus + Garcinia kola group (DM + GK), and a transected + DM + curcumin group (DM + Cur), each containing seven animals. The experimental diabetes model was created with the intraperitoneal injection of a single dose of streptozotocin. No procedure was applied to the Cont group, while sciatic nerve transection was performed on the other groups. Garcinia kola was administered to the rats in DM + GK, and curcumin to those in DM + Cur. Cardiac perfusion was performed at the end of the experimental period. Brain tissues were dissected for stereological, histopathological, and immunohistochemical evaluations. The volume ratios of hippocampal layers to the entire hippocampus volume were compared between the groups. Anti-S100, anti-caspase 3, and anti-SOX 2 antibodies were used for immunohistochemical analysis. No statistically significant difference was observed in the volume ratios of the four hippocampal layers. However, the volume ratio of the stratum lucidum was higher in the Sham, DM, and DM + Cur groups compared to the Cont group. While curcumin exhibited a protective effect on hippocampal tissue following diabetes induction, Garcinia kola had only a weak protective effect. Increased cell density and nuclear deterioration due to diabetes and nerve transection can be partially ameliorated by treatment with Garcinia kola and curcumin.
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Affiliation(s)
- Eda Denizci
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Gamze Altun
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Süleyman Kaplan
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey; Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania.
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Kurtova AI, Finoshin AD, Aparina MS, Gazizova GR, Kozlova OS, Voronova SN, Shagimardanova EI, Ivashkin EG, Voronezhskaya EE. Expanded expression of pro-neurogenic factor SoxB1 during larval development of gastropod Lymnaea stagnalis suggests preadaptation to prolonged neurogenesis in Mollusca. Front Neurosci 2024; 18:1346610. [PMID: 38638695 PMCID: PMC11024475 DOI: 10.3389/fnins.2024.1346610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 03/01/2024] [Indexed: 04/20/2024] Open
Abstract
Introduction The remarkable diversity observed in the structure and development of the molluscan nervous system raises intriguing questions regarding the molecular mechanisms underlying neurogenesis in Mollusca. The expression of SoxB family transcription factors plays a pivotal role in neuronal development, thereby offering valuable insights into the strategies of neurogenesis. Methods In this study, we conducted gene expression analysis focusing on SoxB-family transcription factors during early neurogenesis in the gastropod Lymnaea stagnalis. We employed a combination of hybridization chain reaction in situ hybridization (HCR-ISH), immunocytochemistry, confocal microscopy, and cell proliferation assays to investigate the spatial and temporal expression patterns of LsSoxB1 and LsSoxB2 from the gastrula stage to hatching, with particular attention to the formation of central ring ganglia. Results Our investigation reveals that LsSoxB1 demonstrates expanded ectodermal expression from the gastrula to the hatching stage, whereas expression of LsSoxB2 in the ectoderm ceases by the veliger stage. LsSoxB1 is expressed in the ectoderm of the head, foot, and visceral complex, as well as in forming ganglia and sensory cells. Conversely, LsSoxB2 is mostly restricted to the subepithelial layer and forming ganglia cells during metamorphosis. Proliferation assays indicate a uniform distribution of dividing cells in the ectoderm across all developmental stages, suggesting the absence of distinct neurogenic zones with increased proliferation in gastropods. Discussion Our findings reveal a spatially and temporally extended pattern of SoxB1 expression in a gastropod representative compared to other lophotrochozoan species. This prolonged and widespread expression of SoxB genes may be interpreted as a form of transcriptional neoteny, representing a preadaptation to prolonged neurogenesis. Consequently, it could contribute to the diversification of nervous systems in gastropods and lead to an increase in the complexity of the central nervous system in Mollusca.
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Affiliation(s)
- Anastasia I. Kurtova
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Alexander D. Finoshin
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Margarita S. Aparina
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
- Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, Russia
| | - Guzel R. Gazizova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Olga S. Kozlova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Svetlana N. Voronova
- Koltsov Institute of Developmental Biology, Russian Academy of Sciences, Moscow, Russia
| | - Elena I. Shagimardanova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
- Life Improvement by Future Technologies Center “LIFT”, Moscow, Russia
- Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Evgeny G. Ivashkin
- Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences, Moscow, Russia
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Singleton KS, Silva-Rodriguez P, Cunningham DD, Silva EM. Xenopus Sox11 Partner Proteins and Functional Domains in Neurogenesis. Genes (Basel) 2024; 15:243. [PMID: 38397232 PMCID: PMC10887758 DOI: 10.3390/genes15020243] [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: 12/19/2023] [Revised: 02/03/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Sox11, a member of the SoxC family of transcription factors, has distinct functions at different times in neural development. Studies in mouse, frog, chick, and zebrafish show that Sox11 promotes neural fate, neural differentiation, and neuron maturation in the central nervous system. These diverse roles are controlled in part by spatial and temporal-specific protein interactions. However, the partner proteins and Sox11-interaction domains underlying these diverse functions are not well defined. Here, we identify partner proteins and the domains of Xenopus laevis Sox11 required for protein interaction and function during neurogenesis. Our data show that Sox11 co-localizes and interacts with Pou3f2 and Neurog2 in the anterior neural plate and in early neurons, respectively. We also demonstrate that Sox11 does not interact with Neurog1, a high-affinity partner of Sox11 in the mouse cortex, suggesting that Sox11 has species-specific partner proteins. Additionally, we determined that the N-terminus including the HMG domain of Sox11 is necessary for interaction with Pou3f2 and Neurog2, and we established a novel role for the N-terminal 46 amino acids in the specification of placodal progenitors. This is the first identification of partner proteins for Sox11 and of domains required for partner-protein interactions and distinct roles in neurogenesis.
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Affiliation(s)
- Kaela S. Singleton
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 200057, USA
| | - Pablo Silva-Rodriguez
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
| | - Doreen D. Cunningham
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
| | - Elena M. Silva
- Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 200057, USA
- Department of Biology, Georgetown University, Washington, DC 20057, USA; (P.S.-R.); (D.D.C.)
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Diawara M, Martin LJ. Regulatory mechanisms of SoxD transcription factors and their influences on male fertility. Reprod Biol 2023; 23:100823. [PMID: 37979495 DOI: 10.1016/j.repbio.2023.100823] [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: 09/22/2023] [Revised: 10/31/2023] [Accepted: 11/01/2023] [Indexed: 11/20/2023]
Abstract
Members of the SRY-related box (SOX) subfamily D (SoxD) of transcription factors are well conserved among vertebrate species and play important roles in different stages of male reproductive development. In mammals, the SoxD subfamily contains three members: SOX5, SOX6 and SOX13. Here, we describe their implications in testicular development and spermatogenesis, contributing to fertility. We also cover the mechanisms of action of SoxD transcription factors in gene regulation throughout male development. The specificity of activation of target genes by SoxD members depends, in part, on their post-translational modifications and interactions with other partners. Sperm production in adult males requires the coordination in the regulation of gene expression by different members of the SoxD subfamily of transcription factors in the testis. Specifically, the regulation of genes promoting adequate spermatogenesis by SoxD members is discussed in comparison between species.
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Affiliation(s)
- Mariama Diawara
- Biology Department, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada
| | - Luc J Martin
- Biology Department, Université de Moncton, Moncton, New Brunswick E1A 3E9, Canada.
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Akalın SA, Öcal E, Deveci E. Role of SOX9 and Hif-1α expression in placentas of patients with HELLP. Acta Cir Bras 2023; 38:e388023. [PMID: 37878989 PMCID: PMC10592703 DOI: 10.1590/acb388023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 08/13/2023] [Indexed: 10/27/2023] Open
Abstract
PURPOSE In this study, we investigated the immunohistochemical staining of SRY-box transcription factor 9 (SOX9) and Hif-1α expression in placentas of pregnant woman with hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. METHODS Placentas of 20 normotensive and 20 women with HELLP syndrome were processed for routine histological tissue processing. The biochemical and clinical parameters of patients were recorded. Placentas were stained with hematoxylin-eosin and SOX9 and Hif-1α immunostaining. RESULTS Normotensive placentas showed normal histology of placenta, however placentas of HELLP syndrome showed intense thrombosis, thinning of the villi membrane and vascular dilatation. In placentas of normotensive patients, SOX9 reaction was immunohistochemically negative, however placentas of HELLP group showed SOX9 expression in decidual cells, and syncytial regions of floating villi and inflammatory cells. In placentas of normotensive patients, Hif-1α reaction was mainly negative in vessels and connective tissue cells. Placentas of HELLP group showed increased Hif-1α expression in decidual cell and especially inflammatory cells in the maternal region. CONCLUSIONS Hif-1α and SOX9 proteins can be used as a marker to show severity of preeclampsia and regulation of cell proliferation and angiogenesis during placental development.
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Affiliation(s)
- Senem Alkan Akalın
- Private Medical Practice – Department of Gynecology and Obstetrics – Bursa – Turkey
| | - Ece Öcal
- Private Medical Practice – Department of Perinatology – Diyarbakir – Turkey
| | - Engin Deveci
- Dicle University – Medical School – Department of Histology and Embryology – Diyarbakir – Turkey
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Yokoi A, Nakamura Y, Hashimura M, Oguri Y, Matsumoto T, Nakagawa M, Ishibashi Y, Ito T, Ohhigata K, Harada Y, Fukagawa N, Saegusa M. Anaplastic lymphoma kinase overexpression enhances aggressive phenotypic characteristics of endometrial carcinoma. BMC Cancer 2023; 23:765. [PMID: 37592266 PMCID: PMC10436652 DOI: 10.1186/s12885-023-11144-2] [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: 10/25/2022] [Accepted: 07/02/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Although anaplastic lymphoma kinase (ALK) is overexpressed in several primary solid tumor types, its role in endometrial carcinoma (Em Ca) remains unclear. METHODS We evaluated expression of ALK and its related molecules in clinical samples consisting of 168 Em Ca tissues. We also used Em Ca cell lines to evaluate the functional role of ALK. RESULTS Cytoplasmic ALK immunoreactivity in the absence of chromosomal rearrangement was positively correlated with ALK mRNA expression, and was significantly higher in Grade (G) 3 Em Ca than in G1 or G2 tumors. ALK immunoreactivity was also significantly associated with expression of cancer stem cell (CSC)-related molecules (cytoplasmic CD133, ALDH1, Sox2) and neuroendocrine markers (CD56 and synaptophysin). Although the proliferative index was significantly higher in ALK-positive Em Ca when compared to ALK- negative malignancies, there was no association between ALK expression and other clinicopathological factors in this disease. In Em Ca cell lines, full-length ALK overexpression increased proliferation, decreased susceptibility to apoptosis, enhanced cancer stem cell features, and accelerated cell mobility, whereas these phenotypes were abrogated in ALK-knockdown cells. Finally, patients with tumors harboring either wild-type ALK or high ALK mRNA expression had a poorer prognosis than those with either mutant ALK or low ALK mRNA expression. CONCLUSION Full-length ALK overexpression occurs in a subset of Em Ca, particularly in G3 tumors, and contributes to the establishment and maintenance of aggressive phenotypic characteristics through modulation of several biological processes.
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Affiliation(s)
- Ako Yokoi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yusaku Nakamura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Toshihide Matsumoto
- Department of Pathology, Kitasato University School of Allied Health Science, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Mayu Nakagawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Yu Ishibashi
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Takashi Ito
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Kensuke Ohhigata
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Youhei Harada
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Naomi Fukagawa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan.
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Wang X, Liu D, Luo J, Kong D, Zhang Y. Exploring the Role of Enhancer-Mediated Transcriptional Regulation in Precision Biology. Int J Mol Sci 2023; 24:10843. [PMID: 37446021 PMCID: PMC10342031 DOI: 10.3390/ijms241310843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 06/18/2023] [Accepted: 06/25/2023] [Indexed: 07/15/2023] Open
Abstract
The emergence of precision biology has been driven by the development of advanced technologies and techniques in high-resolution biological research systems. Enhancer-mediated transcriptional regulation, a complex network of gene expression and regulation in eukaryotes, has attracted significant attention as a promising avenue for investigating the underlying mechanisms of biological processes and diseases. To address biological problems with precision, large amounts of data, functional information, and research on the mechanisms of action of biological molecules is required to address biological problems with precision. Enhancers, including typical enhancers and super enhancers, play a crucial role in gene expression and regulation within this network. The identification and targeting of disease-associated enhancers hold the potential to advance precision medicine. In this review, we present the concepts, progress, importance, and challenges in precision biology, transcription regulation, and enhancers. Furthermore, we propose a model of transcriptional regulation for multi-enhancers and provide examples of their mechanisms in mammalian cells, thereby enhancing our understanding of how enhancers achieve precise regulation of gene expression in life processes. Precision biology holds promise in providing new tools and platforms for discovering insights into gene expression and disease occurrence, ultimately benefiting individuals and society as a whole.
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Affiliation(s)
- Xueyan Wang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China;
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; (D.L.); (J.L.); (D.K.)
| | - Danli Liu
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; (D.L.); (J.L.); (D.K.)
| | - Jing Luo
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; (D.L.); (J.L.); (D.K.)
| | - Dashuai Kong
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; (D.L.); (J.L.); (D.K.)
| | - Yubo Zhang
- College of Life Science and Technology, Huazhong Agricultural University, Wuhan 430070, China;
- Shenzhen Branch, Guangdong Laboratory of Lingnan Modern Agriculture, Key Laboratory of Livestock and Poultry Multi-Omics of MARA, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518120, China; (D.L.); (J.L.); (D.K.)
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Fouani Y, Gholipour A, Oveisee M, Shahryari A, Saberi H, Mowla SJ, Malakootian M. Distinct gene expression patterns of SOX2 and SOX2OT variants in different types of brain tumours. J Genet 2023. [DOI: 10.1007/s12041-023-01423-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
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SOX1 antibody-related paraneoplastic neurological syndromes: clinical correlates and assessment of laboratory diagnostic techniques. J Neurol 2023; 270:1691-1701. [PMID: 36512064 DOI: 10.1007/s00415-022-11523-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/06/2022] [Accepted: 12/07/2022] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs. METHODS Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence). RESULTS Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0-90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive "antigenic-specific test + immunofluorescence" and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p < 0.001). CONCLUSION SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses.
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Wang Y, Xu X, Lin L. Prucalopride might improve intestinal motility by promoting the regeneration of the enteric nervous system in diabetic rats. Int J Mol Med 2022; 50:87. [PMID: 35543167 PMCID: PMC9162040 DOI: 10.3892/ijmm.2022.5143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 05/07/2021] [Indexed: 11/14/2022] Open
Abstract
The present study aimed to investigate whether prucalopride, as a 5-hydroxytryptamine 4 (5-HT4) receptor agonist, improved intestinal motility by promoting the regeneration of the enteric nervous system (ENS) in rats with diabetes mellitus (DM). A rat model of DM was established using an intraperitoneal injection of streptozotocin. The rats were randomly divided into four groups of 6 rats/group: Control, DM (DM model), DM + A (5 µg/kg prucalopride) and DM + B (10 µg/kg prucalopride). The rats in the Control group were given an equal volume of citric acid solvent. After successful model establishment, high blood glucose levels were maintained for 2 weeks before administration of prucalopride. The colonic transit time was measured using the glass bead discharge method. It was revealed that the colonic transit time of diabetic rats was the longest, and this was significantly shortened in the DM + B group. Subsequently, the colons were collected. The expression levels of Nestin, glial fibrillary acidic protein (GFAP), SOX10, RNA-binding protein human antigen D (HuD) and ubiquitin thiolesterase (PGP9.5) were determined via immunohistochemical analysis. Immunofluorescence double staining of 5-HT4 + Nestin and Ki67 + Nestin was performed. The 5-HT level was measured using ELISA. Compared with that in the control group, Nestin expression was significantly increased in the DM and DM + A groups, and it was concentrated in columnar epithelial cells and the mesenchyme. Furthermore, the expression levels of Nestin in the DM + A group were higher than those in the DM group. No difference was observed in the expression levels of Nestin between the DM + B group and the Control group. The expression levels of 5-HT protein were highest in the Control group; however, the expression levels of 5-HT protein in the DM group, DM + A group and DM + B group exhibited an increasing trend. Similar trends in the expression of 5-HT4 and Nestin were not observed; however, similar trends in the expression of Nestin and Ki67 were observed. The expression levels of GFAP, SOX10, PGP9.5 and Ki67 in the DM + A and DM + B groups were higher compared with those in the DM group. In the DM + A group, HuD expression was decreased compared with that in the Control group but it was markedly higher compared with that in the DM group. In conclusion, prucalopride may improve intestinal motility by promoting ENS regeneration in rats with DM.
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Affiliation(s)
- Yun Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Xinyu Xu
- Department of Spleen and Stomach Disease, Nanjing Integrated Traditional Chinese and Western Medicine Hospital, Nanjing, Jiangsu 210014, P.R. China
| | - Lin Lin
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Kant Tripathi S, Kumar Sahoo R, Kumar Biswal B. SOX9 as an emerging target for anticancer drugs and a prognostic biomarker for cancer drug resistance. Drug Discov Today 2022; 27:2541-2550. [DOI: 10.1016/j.drudis.2022.05.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 05/16/2022] [Accepted: 05/24/2022] [Indexed: 12/23/2022]
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Pavlova A, Harrisson KA, Turakulov R, Lee YP, Ingram BA, Gilligan D, Sunnucks P, Gan HM. Labile sex chromosomes in the Australian freshwater fish family Percichthyidae. Mol Ecol Resour 2021; 22:1639-1655. [PMID: 34863023 DOI: 10.1111/1755-0998.13569] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 12/01/2022]
Abstract
Sex-specific ecology has management implications, but rapid sex-chromosome turnover in fishes hinders sex-marker development for monomorphic species. We used annotated genomes and reduced-representation sequencing data for two Australian percichthyids, Macquarie perch Macquaria australasica and golden perch M. ambigua, and whole genome resequencing for 50 Macquarie perch of each sex, to identify sex-linked loci and develop an affordable sexing assay. In silico pool-seq tests of 1,492,004 Macquarie perch SNPs revealed that a 275-kb scaffold was enriched for gametologous loci. Within this scaffold, 22 loci were sex-linked in a predominantly XY system, with females being homozygous for the X-linked allele at all 22, and males having the Y-linked allele at >7. Seven XY-gametologous loci (all males, but no females, are heterozygous or homozygous for the male-specific allele) were within a 146-bp region. A PCR-RFLP sexing assay targeting one Y-linked SNP, tested in 66 known-sex Macquarie perch and two of each sex of three confamilial species, plus amplicon sequencing of 400 bp encompassing the 146-bp region, revealed that the few sex-linked positions differ between species and between Macquarie perch populations. This indicates sex-chromosome lability in Percichthyidae, supported by nonhomologous scaffolds containing sex-linked loci for Macquarie- and golden perches. The present resources facilitate genomic research in Percichthyidae, including formulation of hypotheses about candidate genes of interest such as transcription factor SOX1b that occurs in the 275-kb scaffold ~38 kb downstream of the 146-bp region containing seven XY-gametologous loci. Sex-linked markers will be useful for determining genetic sex in some populations and studying sex chromosome turnover.
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Affiliation(s)
- Alexandra Pavlova
- School of Biological Sciences, Monash University, Clayton, Vic., Australia
| | - Katherine A Harrisson
- Department of Ecology, Environment & Evolution, La Trobe University, Bundoora, Vic., Australia.,Department of Environment, Land, Water and Planning, Arthur Rylah Institute for Environmental Research, Heidelberg, Vic., Australia
| | - Rustam Turakulov
- Division of Ecology and Evolution, RSB, Australian National University, Acton, ACT, Australia
| | - Yin Peng Lee
- School of Life and Environmental Sciences, Deakin University, Geelong, Vic., Australia.,Deakin Genomics Centre, Deakin University, Geelong, Vic., Australia
| | | | - Dean Gilligan
- Freshwater Ecosystems Research, New South Wales Department of Primary Industries - Fisheries, Batemans Bay, NSW, Australia
| | - Paul Sunnucks
- School of Biological Sciences, Monash University, Clayton, Vic., Australia
| | - Han Ming Gan
- School of Life and Environmental Sciences, Deakin University, Geelong, Vic., Australia.,Deakin Genomics Centre, Deakin University, Geelong, Vic., Australia.,GeneSEQ Sdn Bhd, Rawang, Malaysia
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13
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Segura-Bautista D, Maya-Nunez G, Aguilar-Rojas A, Huerta-Reyes M, Pérez-Solis MA. Contribution of Stemness-linked Transcription Regulators to the Progression of Breast Cancer. Curr Mol Med 2021; 22:766-778. [PMID: 34819003 DOI: 10.2174/1566524021666211124154803] [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: 01/15/2021] [Revised: 05/05/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022]
Abstract
Although there are currently several factors that allow measuring the risk of having breast cancer or predicting its progression, the underlying causes of this malignancy have remained unknown. Several molecular studies have described some mechanisms involved in the progress of breast cancer. These have helped in identifying new targets with therapeutic potential. However, despite the therapeutic strategies implemented from the advances achieved in breast cancer research, a large percentage of patients with breast cancer die due to the spread of malignant cells to other tissues or organs, such as bones and lungs. Therefore, determining the processes that promote the migration of malignant cells remains one of the greatest challenges for oncological research. Several research groups have reported evidence on how the dedifferentiation of tumor cells leads to the acquisition of stemness characteristics, such as invasion, metastasis, the capability to evade the immunological response, and resistance to several cytotoxic drugs. These phenotypic changes have been associated with a complex reprogramming of gene expression in tumor cells during the Epithelial-Mesenchymal Transition (EMT). Considering the determining role that the transcriptional regulation plays in the expression of the specific characteristics and attributes of breast cancer during ETM, in the present work, we reviewed and analyzed several transcriptional mechanisms that support the mesenchymal phenotype. In the same way, we established the importance of transcription factors with a therapeutic perspective in the progress of breast cancer.
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Affiliation(s)
- David Segura-Bautista
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Guadalupe Maya-Nunez
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Arturo Aguilar-Rojas
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Maira Huerta-Reyes
- Medical Research Unit in Nephrological Diseases, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City. Mexico
| | - Marco Allan Pérez-Solis
- Medical Research Unit in Reproductive Medicine, UMAE Hospital de Gineco Obstetricia no. 4 'Luis Castelazo-Ayala', Instituto Mexicano del Seguro Social, Mexico City. Mexico
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14
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OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human. Nat Commun 2021; 12:5123. [PMID: 34446700 PMCID: PMC8390644 DOI: 10.1038/s41467-021-25107-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their interactome in human ESCs (hESCs) has not to date been explored. Here we mapped the OCT4 interactomes in naïve and primed hESCs, revealing extensive connections to mammalian ATP-dependent nucleosome remodeling complexes. In naïve hESCs, OCT4 is associated with both BRG1 and BRM, the two paralog ATPases of the BAF complex. Genome-wide location analyses and genetic studies reveal that these two enzymes cooperate in a functionally redundant manner in the transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs, OCT4 cooperates with BRG1 and SOX2 to promote chromatin accessibility at ectodermal genes. This work reveals how a common transcription factor utilizes differential BAF complexes to control distinct transcriptional programs in naïve and primed hESCs. Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.
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15
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Anaplastic Lymphoma Kinase Overexpression Is Associated with Aggressive Phenotypic Characteristics of Ovarian High-Grade Serous Carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:1837-1850. [PMID: 34214505 DOI: 10.1016/j.ajpath.2021.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/14/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
Deregulated full-length anaplastic lymphoma kinase (ALK) overexpression has been found in some primary solid tumors, but little is known about its role in ovarian high-grade serous carcinoma (HGSC). Herein, we focused on the functional roles of ALK in HGSC. Cytoplasmic ALK immunoreactivity without chromosomal rearrangement and gene mutations was significantly higher in HGSC compared with non-HGSC type ovarian carcinomas, and was significantly associated with several unfavorable clinicopathologic factors and poor prognosis. HGSC cell lines stably overexpressing ALK exhibited increased cell proliferation, enhanced cancer stem cell features, and accelerated cell mobility, whereas these phenotypes were abrogated in ALK-knockdown cells. Expression of the nervous system-associated gene, ELAVL3, and the corresponding protein (commonly known as HuC) was significantly increased in cells overexpressing ALK. There was increased expression of Sox2 and Sox3 (genes associated with the neural progenitor population) in ALK-overexpressing but not ALK-knockdown cells. Furthermore, overexpression of Sox2 or Sox3 enhanced both ALK and ELAVL3 promoter activities, suggesting the existence of ALK/Sox/HuC signaling loops. Finally, ALK overexpression was due to increased expression of neuroendocrine markers, including synaptophysin, CD56, and BCL2, in HGSC tissues. These findings suggest that overexpression of full-length ALK may influence the biological behavior of HGSC through cooperation with ELAVL3 and Sox factors, leading to establishment and maintenance of the aggressive phenotypic characteristics of HGSC.
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Kattupalli D, Barbadikar KM, Balija V, Ballichatla S, R A, Padmakumari AP, Saxena S, Gaikwad K, Yerram S, Kokku P, Madhav MS. The Draft Genome of Yellow Stem Borer, an Agriculturally Important Pest, Provides Molecular Insights into Its Biology, Development and Specificity Towards Rice for Infestation. INSECTS 2021; 12:insects12060563. [PMID: 34205299 PMCID: PMC8234988 DOI: 10.3390/insects12060563] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/20/2021] [Accepted: 05/23/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary Yellow stem borer (YSB), is the most destructive and widely occurring pest that attacks rice throughout the growing season. Rice (Oryza sativa L.) is a major staple cereal worldwide, providing essential caloric requirements for more than half of the world’s population. Annual losses to rice borers are approximately 5–10%, but losses in individual fields may reach up to 50–60%. The use of traditional pest management strategies in controlling YSB is somewhat challenging due to its unique internal feeding habit. Genome sequence information of economically important crop pests is important for designing or developing pest-resistant rice varieties. In an approach to achieve this, we present our first-ever study on the draft genome sequence of YSB. The information provided from our current study might be useful in developing genome-based approaches for the management of pest species. Abstract Yellow stem borer (YSB), Scirpophaga incertulas (Walker) (Lepidoptera: Crambidae), a major monophagous insect pest of rice, causes significant yield losses. The rice–YSB interaction is very dynamic, making it difficult for management. The development of resistant lines has been unsuccessful as there are no effective resistant sources in the germplasm. Genome information is necessary for a better understanding of interaction with rice in terms of its recognition, response, and infestation mechanism. The draft genome of YSB is predicted to have 46,057 genes with an estimated size of 308 Mb, being correlated with the flow cytometry analysis. The existence of complex metabolic mechanisms and genes related to specific behavior was identified, being conditioned by a higher level of regulation. We deciphered the possible visual, olfactory, and gustatory mechanisms responsible for its evolution as a monophagous pest. Comparative genomic analysis revealed that YSB is unique in the way it has evolved. The obvious presence of high-immunity-related genes, well-developed RNAi machinery, and diverse effectors provides a means for developing genomic tools for its management. The identified 21,696 SSR markers can be utilized for diversity analysis of populations across the rice-growing regions. We present the first draft genome of YSB. The information emanated paves a way for biologists to design novel pest management strategies as well as for the industry to design new classes of safer and specific insecticide molecules.
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Affiliation(s)
- Divya Kattupalli
- Biotechnology Section, Division of Crop Improvement, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (D.K.); (K.M.B.); (V.B.); (S.B.)
| | - Kalyani M. Barbadikar
- Biotechnology Section, Division of Crop Improvement, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (D.K.); (K.M.B.); (V.B.); (S.B.)
| | - Vishalakshi Balija
- Biotechnology Section, Division of Crop Improvement, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (D.K.); (K.M.B.); (V.B.); (S.B.)
| | - Suneel Ballichatla
- Biotechnology Section, Division of Crop Improvement, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (D.K.); (K.M.B.); (V.B.); (S.B.)
| | - Athulya R
- Entomology Section, Division of Crop Protection, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (A.R.); (A.P.P.); (S.Y.)
| | - Ayyagari Phani Padmakumari
- Entomology Section, Division of Crop Protection, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (A.R.); (A.P.P.); (S.Y.)
| | - Swati Saxena
- Genomics Lab, ICAR-National Institute of Plant Biotechnology, New Delhi 110012, India; (S.S.); (K.G.)
| | - Kishor Gaikwad
- Genomics Lab, ICAR-National Institute of Plant Biotechnology, New Delhi 110012, India; (S.S.); (K.G.)
| | - Sridhar Yerram
- Entomology Section, Division of Crop Protection, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (A.R.); (A.P.P.); (S.Y.)
| | - Premalatha Kokku
- Department of Chemistry, Osmania University, Hyderabad 500007, India;
| | - Maganti Sheshu Madhav
- Biotechnology Section, Division of Crop Improvement, ICAR-Indian Institute of Rice Research, Hyderabad 500030, India; (D.K.); (K.M.B.); (V.B.); (S.B.)
- Correspondence:
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Interplay between SOX9 transcription factor and microRNAs in cancer. Int J Biol Macromol 2021; 183:681-694. [PMID: 33957202 DOI: 10.1016/j.ijbiomac.2021.04.185] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/29/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023]
Abstract
SOX transcription factors are critical regulators of development, homeostasis and disease progression and their dysregulation is a common finding in various cancers. SOX9 belongs to SOXE family located on chromosome 17. MicroRNAs (miRNAs) possess the capacity of regulating different transcription factors in cancer cells by binding to 3'-UTR. Since miRNAs can affect differentiation, migration, proliferation and other physiological mechanisms, disturbances in their expression have been associated with cancer development. In this review, we evaluate the relationship between miRNAs and SOX9 in different cancers to reveal how this interaction can affect proliferation, metastasis and therapy response of cancer cells. The tumor-suppressor miRNAs can decrease the expression of SOX9 by binding to the 3'-UTR of mRNAs. Furthermore, the expression of downstream targets of SOX9, such as c-Myc, Wnt, PI3K/Akt can be affected by miRNAs. It is noteworthy that other non-coding RNAs including lncRNAs and circRNAs regulate miRNA/SOX9 expression to promote/inhibit cancer progression and malignancy. The pre-clinical findings can be applied as biomarkers for diagnosis and prognosis of cancer patients.
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Stevanovic M, Drakulic D, Lazic A, Ninkovic DS, Schwirtlich M, Mojsin M. SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis. Front Mol Neurosci 2021; 14:654031. [PMID: 33867936 PMCID: PMC8044450 DOI: 10.3389/fnmol.2021.654031] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
The SOX proteins belong to the superfamily of transcription factors (TFs) that display properties of both classical TFs and architectural components of chromatin. Since the cloning of the Sox/SOX genes, remarkable progress has been made in illuminating their roles as key players in the regulation of multiple developmental and physiological processes. SOX TFs govern diverse cellular processes during development, such as maintaining the pluripotency of stem cells, cell proliferation, cell fate decisions/germ layer formation as well as terminal cell differentiation into tissues and organs. However, their roles are not limited to development since SOX proteins influence survival, regeneration, cell death and control homeostasis in adult tissues. This review summarized current knowledge of the roles of SOX proteins in control of central nervous system development. Some SOX TFs suspend neural progenitors in proliferative, stem-like state and prevent their differentiation. SOX proteins function as pioneer factors that occupy silenced target genes and keep them in a poised state for activation at subsequent stages of differentiation. At appropriate stage of development, SOX members that maintain stemness are down-regulated in cells that are competent to differentiate, while other SOX members take over their functions and govern the process of differentiation. Distinct SOX members determine down-stream processes of neuronal and glial differentiation. Thus, sequentially acting SOX TFs orchestrate neural lineage development defining neuronal and glial phenotypes. In line with their crucial roles in the nervous system development, deregulation of specific SOX proteins activities is associated with neurodevelopmental disorders (NDDs). The overview of the current knowledge about the link between SOX gene variants and NDDs is presented. We outline the roles of SOX TFs in adult neurogenesis and brain homeostasis and discuss whether impaired adult neurogenesis, detected in neurodegenerative diseases, could be associated with deregulation of SOX proteins activities. We present the current data regarding the interaction between SOX proteins and signaling pathways and microRNAs that play roles in nervous system development. Finally, future research directions that will improve the knowledge about distinct and various roles of SOX TFs in health and diseases are presented and discussed.
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Affiliation(s)
- Milena Stevanovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia.,Faculty of Biology, University of Belgrade, Belgrade, Serbia.,Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Danijela Drakulic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Andrijana Lazic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Danijela Stanisavljevic Ninkovic
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Schwirtlich
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Mojsin
- Laboratory for Human Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
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20
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Jiang LL, Liu L. Effect of metformin on stem cells: Molecular mechanism and clinical prospect. World J Stem Cells 2020; 12:1455-1473. [PMID: 33505595 PMCID: PMC7789120 DOI: 10.4252/wjsc.v12.i12.1455] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 09/28/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023] Open
Abstract
Metformin is a first-line medication for type II diabetes. Numerous studies have shown that metformin not only has hypoglycemic effects, but also modulates many physiological and pathological processes ranging from aging and cancer to fracture healing. During these different physiological activities and pathological changes, stem cells usually play a core role. Thus, many studies have investigated the effects of metformin on stem cells. Metformin affects cell differentiation and has promising applications in stem cell medicine. It exerts anti-aging effects and can be applied to gerontology and regenerative medicine. The potential anti-cancer stem cell effect of metformin indicates that it can be an adjuvant therapy for cancers. Furthermore, metformin has beneficial effects against many other diseases including cardiovascular and autoimmune diseases. In this review, we summarize the effects of metformin on stem cells and provide an overview of its molecular mechanisms and clinical prospects.
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Affiliation(s)
- Lin-Li Jiang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei Liu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China.
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21
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Yu L, Peng F, Dong X, Chen Y, Sun D, Jiang S, Deng C. Sex-Determining Region Y Chromosome-Related High-Mobility-Group Box 10 in Cancer: A Potential Therapeutic Target. Front Cell Dev Biol 2020; 8:564740. [PMID: 33344444 PMCID: PMC7744619 DOI: 10.3389/fcell.2020.564740] [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: 05/22/2020] [Accepted: 11/17/2020] [Indexed: 01/20/2023] Open
Abstract
Sex-determining region Y-related high mobility group-box 10 (SOX10), a member of the SOX family, has recently been highlighted as an essential transcriptional factor involved in developmental biology. Recently, the functionality of SOX 10 has been increasingly revealed by researchers worldwide. It has been reported that SOX10 significantly regulates the proliferation, migration, and apoptosis of tumors and is closely associated with the progression of cancer. In this review, we first introduce the basic background of the SOX family and SOX10 and then discuss the pathophysiological roles of SOX10 in cancer. Besides, we enumerate the application of SOX10 in the pathological diagnosis and therapeutic potential of cancer. Eventually, we summarize the potential directions and perspectives of SOX10 in neoplastic theranostics. The information compiled herein may assist in additional studies and increase the potential of SOX10 as a therapeutic target for cancer.
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Affiliation(s)
- Liming Yu
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.,Department of Cardiovascular Surgery, General Hospital of Northern Theater Command, Shenyang, China
| | - Fan Peng
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Xue Dong
- Outpatient Department of Liaoning Military Region, General Hospital of Northern Theater Command, Shenyang, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dongdong Sun
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Shuai Jiang
- Department of Cardiology, Xijing Hopspital, The Airforce Military Medical University, Xi'an, China
| | - Chao Deng
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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22
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Huang YW, Lin CY, Chin YT, Kuo PJ, Wu Y, Weng IT, Chen TY, Wang HH, Huang HM, Hsiung CN, Lee SY. 2,3,5,4'-tetrahydroxystilbene-2-O-b-D-glucoside triggers the pluripotent-like possibility of dental pulp stem cells by activating the JAK2/STAT3 axis: Preliminary observations. J Dent Sci 2020; 16:599-607. [PMID: 33854708 PMCID: PMC8025197 DOI: 10.1016/j.jds.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/23/2020] [Indexed: 11/24/2022] Open
Abstract
Abstract Background/Purpose Although 2,3,5,4′-Tetrahydroxystilbene-2-O-beta-glucoside (THSG) reportedly has anti-inflammatory properties, its role in inducing the dedifferentiation of human dental pulp stem cells (DPSC) into pluripotent-like stem cells remains to be determined. The purpose of this study is to evaluate the effects of THSG on the pluripotent-like possibility and mechanism of DPSC. Materials and methods DPSCs were treated with THSG, and cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTS) assay. Real-time polymerase chain reaction was used to analyze the mRNA expression levels of pluripotency-associated genes and oncogenes and to detect telomerase activity in the cells. Embryoid body formation assay was conducted, and pluripotency-related proteins were identified using Western blotting. Data were analyzed using one-way analysis of variance. Results Cell viability, telomerase activity, and embryoid body formation were enhanced in THSG-treated DPSCs. The mRNA expression levels of pluripotent-like genes (including Nanog homeobox [NANOG], SRY-box 2 [SOX2], and POU class 5 homeobox 1 [POU5F1/OCT4]) significantly increased after THSG treatment. The expression levels of pluripotency-related genes (Janus kinase-signal transducer 2 [JAK2] and signal transducer and activator of transcription 3 [STAT3]) increased, whereas those of oncogenes (Ras, SRC, HER2, and C-sis) decreased. Furthermore, the expression levels of the phosphorylated JAK2 and STAT3 proteins significantly increased after THSG treatment. Conclusion THSG treatment may enhance the pluripotent-like possibility of DPSC through the JAK2/STAT3 axis. Hence, it may be used as an alternative cell-based therapeutic strategy in regenerative dentistry.
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Affiliation(s)
- Yen-Wen Huang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
| | - Chi-Yu Lin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Yu-Tang Chin
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Po-Jan Kuo
- Department of Periodontology, School of Dentistry, National Defense Medical Center and Tri-Service General Hospital, Taipei, Taiwan
| | - Yen Wu
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - I-Tsen Weng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Ting-Yi Chen
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
| | - Hsin-Hui Wang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
| | - Haw-Ming Huang
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
| | - Chao-Nan Hsiung
- College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Sheng-Yang Lee
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Dentistry, Wan-Fang Medical Center, Taipei Medical University, Taipei, Taiwan
- Center for Tooth Bank and Dental Stem Cell Technology, Taipei Medical University, Taipei, Taiwan
- Corresponding author. School of Dentistry, College of Oral Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan.
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Ihn HJ, Kim JA, Lim J, Nam SH, Hwang SH, Kim YK, Kim JY, Kim JE, Cho ES, Jiang R, Park EK. Bobby sox homolog regulates tooth root formation through modulation of dentin sialophosphoprotein. J Cell Physiol 2020; 236:480-488. [PMID: 32537777 DOI: 10.1002/jcp.29875] [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: 11/14/2019] [Revised: 06/01/2020] [Accepted: 06/01/2020] [Indexed: 11/09/2022]
Abstract
Tooth root development occurs through the interaction of multiple growth factors and transcription factors expressed in Hertwig's epithelial root sheath (HERS) and dental mesenchyme. Previously, we demonstrated that bobby sox homolog (Bbx) regulates odontoblast differentiation of human dental pulp stem cells. Here, we generated Bbx knockout (Bbx-/- ) mice to address the functional role of Bbx in tooth formation. During tooth development, Bbx was expressed in both dental epithelium and mesenchyme. However, molar and incisor morphology in Bbx-/- mice at postnatal Day 0 (P0) exhibited no prominent abnormalities compared with their wild-type (Bbx+/+ ) littermates. Until P28, the crown morphology in Bbx-/- mice was not distinctively different from Bbx+/+ littermates. Meanwhile, the length of the mandibular base in Bbx-/- mice was notably less at P28. Compared with Bbx+/+ mice, the mesial and distal root lengths of the first molar were reduced by 21.33% and 16.28% at P14 and 16.28% and 16.24% at P28, respectively, in Bbx-/- mice. The second molar of Bbx-/- mice also showed 10.16% and 6.4% reductions at P28 in the mesial and distal lengths, compared with Bbx+/+ mice, respectively. The gene expression analysis during early tooth root formation (P13) showed that the expression of dentin sialophosphoprotein (Dspp) was significantly decreased in Bbx-/- mice. Collectively, our data suggest that Bbx participates in tooth root formation and might be associated with the regulation of Dspp expression.
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Affiliation(s)
- Hye Jung Ihn
- Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
| | - Ju Ang Kim
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
| | - Jiwon Lim
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
| | - Sang-Hyeon Nam
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
| | - So Hyeon Hwang
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
| | - Young Kyung Kim
- Department of Conservative Dentistry, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Jae-Young Kim
- Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Jung-Eun Kim
- Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Eui-Sic Cho
- Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Chonbuk National University, Jeonju, Republic of Korea
| | - Rulang Jiang
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Eui Kyun Park
- Department of Oral Pathology and Regenerative Medicine, School of Dentistry, Institute for Hard Tissue and Biotooth Regeneration, Kyungpook National University, Daegu, Republic of Korea
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Sears CR, Boggs TE, Gross JB. Dark-rearing uncovers novel gene expression patterns in an obligate cave-dwelling fish. JOURNAL OF EXPERIMENTAL ZOOLOGY PART B-MOLECULAR AND DEVELOPMENTAL EVOLUTION 2020; 334:518-529. [PMID: 32372488 DOI: 10.1002/jez.b.22947] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 03/31/2020] [Accepted: 04/04/2020] [Indexed: 01/01/2023]
Abstract
Extreme environments often result in the evolution of dramatic adaptive features. The Mexican tetra, Astyanax mexicanus, includes 30 different populations of cave-dwelling forms that live in perpetual darkness. As a consequence, many populations have evolved eye loss, reduced pigmentation, and amplification of nonvisual sensory systems. Closely-related surface-dwelling morphs demonstrate typical vision, pigmentation, and sensation. Transcriptomic assessments in this system have revealed important developmental changes associated with the cave morph, however, they have not accounted for photic rearing conditions. Prior studies reared individuals under a 12:12 hr light/dark (LD) cycle. Here, we reared cavefish under constant darkness (DD) for 5+ years. From these experimental individuals, we performed mRNA sequencing and compared gene expression of surface fish reared under LD conditions to cavefish reared under DD conditions to identify photic-dependent gene expression differences. Gene Ontology enrichment analyses revealed a number of previously underappreciated cave-associated changes impacting blood physiology and olfaction. We further evaluated the position of differentially expressed genes relative to QTL positions from prior studies and found several candidate genes associated with these ecologically relevant lighting conditions. In sum, this work highlights photic conditions as a key environmental factor impacting gene expression patterns in blind cave-dwelling fish.
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Affiliation(s)
- Connor R Sears
- Department of Biological Sciences, University of Cincinnati, Cincinnati, Ohio
| | - Tyler E Boggs
- Department of Biological Sciences, University of Cincinnati, Cincinnati, Ohio
| | - Joshua B Gross
- Department of Biological Sciences, University of Cincinnati, Cincinnati, Ohio
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25
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Characterization of gonad differentially expressed SoxB2 genes in mud crab Scylla paramamosain. Gene 2020; 740:144507. [DOI: 10.1016/j.gene.2020.144507] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 01/26/2020] [Accepted: 02/21/2020] [Indexed: 12/25/2022]
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Tseng SJ, Huang ST, Wu CC, Cheng CH, Lin JC. Studies of proliferation and chondrogenic differentiation of rat adipose stem cells using an anti-oxidative polyurethane scaffold combined with cyclic compression culture. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 112:110964. [PMID: 32409092 DOI: 10.1016/j.msec.2020.110964] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 03/21/2020] [Accepted: 04/11/2020] [Indexed: 02/08/2023]
Abstract
The adipose stem cell is a potential candidate for the autologous chondrocytes repairing approach because of the abundance of fat in the animal body and its versatile differentiation capability. In this study, rat adipose stem cells (rASCs) were seeded into anti-oxidative N-acetylcysteine (NAC) grafted polyurethane (PU) scaffold and then combined with short dynamic compressive stimulation (24 h) to induce rASCs chondrogenesis differentiation in vitro. The inner pore surface of the PU scaffold was first modified via alginate and type I collagen to promote rASCs adherence. The modified layers crosslinked by genipin showed outstanding stability after ultrasonic treatment, indicating the modified layers were stable and can keep the cells adhesion well during dynamic compressive stimulation. After inner pore surface modification and 10 mM NAC grafting, the PU scaffold-A-C-G (graft 10 mM NAC) has shown the best proliferation efficiency with homogeneous cell distribution after 72hr static culture. After short term dynamic compressive stimulation, significant gene expression in chondrogenic markers, Sox-9, and Aggrecan, were noted in both PU scaffold-A-C-G and PU scaffold-A-C-G (graft 10 mM NAC). Considering the cell proliferation efficiency and gene expression, the anti-oxidative NAC grafted PU scaffold combined with short term dynamic compressive stimulation could be useful for cell culturing in stem cell therapy.
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Affiliation(s)
- Shen-Jui Tseng
- Department of Chemical Engineering, National Cheng Kung University, Tainan 70101, Taiwan
| | - Shih-Ting Huang
- Department of Chemical Engineering, National Cheng Kung University, Tainan 70101, Taiwan
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chi-Hui Cheng
- Department of Pediatrics, College of Medicine, Chang Gung University, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
| | - Jui-Che Lin
- Department of Chemical Engineering, National Cheng Kung University, Tainan 70101, Taiwan.
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Abstract
Wnt/Wingless (Wg) signaling controls many aspects of animal development and is deregulated in different human cancers. The transcription factor dTcf/Pangolin (Pan) is the final effector of the Wg pathway in Drosophila and has a dual role in regulating the expression of Wg target genes. In the presence of Wg, dTcf/Pan interacts with β-catenin/Armadillo (Arm) and induces the transcription of Wg targets. In absence of Wg, dTcf/Pan partners with the transcriptional corepressor TLE/Groucho (Gro) and inhibits gene expression. Here, we use the wing imaginal disk of Drosophila as a model to examine the functions that dTcf/Pan plays in a proliferating epithelium. We report a function of dTcf/Pan in growth control and tumorigenesis. Our results show that dTcf/Pan can limit tissue growth in normal development and suppresses tumorigenesis in the context of oncogene up-regulation. We identify the conserved transcription factors Sox box protein 15 (Sox15) and Ftz transcription factor 1 (Ftz-f1) as genes controlled by dTcf/Pan involved in tumor development. In conclusion, this study reports a role for dTcf/Pan as a repressor of normal and oncogenic growth and identifies the genes inducing tumorigenesis downstream of dTcf/Pan.
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Telias M. Molecular Mechanisms of Synaptic Dysregulation in Fragile X Syndrome and Autism Spectrum Disorders. Front Mol Neurosci 2019; 12:51. [PMID: 30899214 PMCID: PMC6417395 DOI: 10.3389/fnmol.2019.00051] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 02/12/2019] [Indexed: 12/21/2022] Open
Abstract
Fragile X syndrome (FXS) is the most common form of monogenic hereditary cognitive impairment. FXS patient exhibit a high comorbidity rate with autism spectrum disorders (ASDs). This makes FXS a model disease for understanding how synaptic dysregulation alters neuronal excitability, learning and memory, social behavior, and more. Since 1991, with the discovery of fragile X mental retardation 1 (FMR1) as the sole gene that is mutated in FXS, thousands of studies into the function of the gene and its encoded protein FMR1 protein (FMRP), have been conducted, yielding important information regarding the pathophysiology of the disease, as well as insight into basic synaptic mechanisms that control neuronal networking and circuitry. Among the most important, are molecular mechanisms directly involved in plasticity, including glutamate and γ-aminobutyric acid (GABA) receptors, which can control synaptic transmission and signal transduction, including short- and long-term plasticity. More recently, several novel mechanisms involving growth factors, enzymatic cascades and transcription factors (TFs), have been proposed to have the potential of explaining some of the synaptic dysregulation in FXS. In this review article, I summarize the main mechanisms proposed to underlie synaptic disruption in FXS and ASDs. I focus on studies conducted on the Fmr1 knock-out (KO) mouse model and on FXS-human pluripotent stem cells (hPSCs), emphasizing the differences and even contradictions between mouse and human, whenever possible. As FXS and ASDs are both neurodevelopmental disorders that follow a specific time-course of disease progression, I highlight those studies focusing on the differential developmental regulation of synaptic abnormalities in these diseases.
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Affiliation(s)
- Michael Telias
- Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
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29
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Sox13 is a novel early marker for hair follicle development. Biochem Biophys Res Commun 2019; 509:862-868. [PMID: 30638933 DOI: 10.1016/j.bbrc.2018.12.163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 12/25/2018] [Indexed: 12/16/2022]
Abstract
Sox13, a group D member of the Sry-related high-mobility group box (Sox) transcription factor family, is expressed in various tissues including the hair follicle. However, its spatiotemporal expression patterns in the hair follicle and its role in hair development remain to be elucidated. To address these questions, we generated Sox13-LacZ-knock-in mice (Sox13LacZ/+), in which the LacZ reporter gene was inserted in-frame into exon 2, which contains the translation initiation codon. X-gal staining in Sox13LacZ/+ embryos revealed that Sox13 is initially expressed in the epithelial portion of the placode, and subsequently in the hair germ and the hair peg during early hair follicle development. In postnatal catagen and anagen, Sox13 was detected in the epithelial sheath, whereas in telogen, Sox13 was localized in the bulge region, where hair follicle stem cells reside. Immunohistochemistry with an anti-β-galactosidase antibody and anti-hair keratin antibodies that specifically mark the different layers of the hair follicle revealed that Sox13 was predominantly expressed in the outer root sheath in anagen. However, the integumentary structures of Sox13LacZ/LacZ mice were grossly and histologically indistinguishable from those of wild type mice. These results suggest that although Sox13 is dispensable for epidermal and adnexal development, Sox13 is a useful marker for early hair follicle development.
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The utility of anti-SOX2 antibodies for cancer prediction in patients with paraneoplastic neurological disorders. J Neuroimmunol 2018; 326:14-18. [PMID: 30445363 PMCID: PMC6375907 DOI: 10.1016/j.jneuroim.2018.11.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/05/2018] [Accepted: 11/05/2018] [Indexed: 01/23/2023]
Abstract
Antibodies to SOXB1 proteins in patients with paraneoplastic disorders are associated with small-cell lung cancer (SCLC), particularly in Lambert-Eaton myasthenic syndrome (LEMS). We aimed to establish if SOX2 antibodies could be used to identify SCLC and other tumours found in a range of paraneoplastic disorders and controls. SOX2 antibodies were detectable in 61% of patients with LEMS-SCLC, and in other paraneoplastic disorders, such as opsoclonus-myoclonus and paraneoplastic cerebellar degeneration, only when there was an underlying SCLC. SOX2 antibodies are specific (>90%) markers for SCLC, but are rarely found in patients with other tumours, whether neurological symptoms are present or not.
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31
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Wang X, Li X, Wang T, Wu SP, Jeong JW, Kim TH, Young SL, Lessey BA, Lanz RB, Lydon JP, DeMayo FJ. SOX17 regulates uterine epithelial-stromal cross-talk acting via a distal enhancer upstream of Ihh. Nat Commun 2018; 9:4421. [PMID: 30356064 PMCID: PMC6200785 DOI: 10.1038/s41467-018-06652-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 08/31/2018] [Indexed: 02/07/2023] Open
Abstract
Mammalian pregnancy depends on the ability of the uterus to support embryo implantation. Previous studies reveal the Sox17 gene as a downstream target of the Pgr-Gata2-dependent transcription network that directs genomic actions in the uterine endometrium receptive for embryo implantation. Here, we report that ablating Sox17 in the uterine epithelium impairs leukemia inhibitory factor (LIF) and Indian hedgehog homolog (IHH) signaling, leading to failure of embryo implantation. In vivo deletion of the SOX17-binding region 19 kb upstream of the Ihh locus by CRISPR-Cas technology reduces Ihh expression specifically in the uterus and alters proper endometrial epithelial-stromal interactions, thereby impairing pregnancy. This SOX17-binding interval is also bound by GATA2, FOXA2, and PGR. This cluster of transcription factor binding is common in 737 uterine genes and may represent a key regulatory element essential for uterine epithelial gene expression.
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Affiliation(s)
- Xiaoqiu Wang
- Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
- Department of Animal Science, North Carolina State University, Raleigh, NC, USA
| | - Xilong Li
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Tianyuan Wang
- Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - San-Pin Wu
- Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Jae-Wook Jeong
- Department of Obstetrics and Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Tae Hoon Kim
- Department of Obstetrics and Gynecology and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA
| | - Steven L Young
- Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC, USA
| | - Bruce A Lessey
- Deptartment of Obstetrics and Gynecology, University of South Carolina School of Medicine, Greenville, SC, USA
| | - Rainer B Lanz
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - John P Lydon
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Francesco J DeMayo
- Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
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Yamada S, Sakakibara SI. Expression profile of the STAND protein Nwd1 in the developing and mature mouse central nervous system. J Comp Neurol 2018; 526:2099-2114. [PMID: 30004576 DOI: 10.1002/cne.24495] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/02/2018] [Accepted: 06/13/2018] [Indexed: 12/12/2022]
Abstract
The orchestrated events required during brain development, as well as the maintenance of adult neuronal plasticity, highly depend on the accurate responses of neuronal cells to various cellular stress or environmental stimuli. Recent studies have defined a previously unrecognized, broad class of multidomain proteins, designated as signal transduction ATPases with numerous domains (STAND), which comprises a large number of proteins, including the apoptotic peptidase activating factor 1 (Apaf1) and nucleotide-binding oligomerization domain-like receptors (NLRs), central players in cell death and innate immune responses, respectively. Although the involvement of STANDs in the central nervous system (CNS) has been postulated in terms of neuronal development and function, it remains largely unclear. Here, we identified Nwd1 (NACHT and WD repeat domain-containing protein 1), as a novel STAND protein, expressed in neural stem/progenitor cells (NSPCs). Structurally, Nwd1 was most analogous to the apoptosis regulator Apaf1, also involved in mitosis and axonal outgrowth regulation in the CNS. Using a specific antibody, we show that, during the embryonic and postnatal period, Nwd1 is expressed in nestin-positive NSPCs in vivo and in vitro, while postnatally it is found in terminally differentiated neurons and blood vessels. At the subcellular level, we demonstrate that Nwd1 is preferentially located in the cytosolic compartment of cultured NSPCs, partially overlapping with cytochrome c. These observations imply that Nwd1 might be involved in the neuronal lineage as a new STAND gene, including having a pro-apoptotic or nonapoptotic role, similar to Apaf1.
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Affiliation(s)
- Seiya Yamada
- Laboratory for Molecular Neurobiology, Graduate School of Human Sciences, Waseda University, Saitama, Japan
| | - Shin-Ichi Sakakibara
- Laboratory for Molecular Neurobiology, Graduate School of Human Sciences, Waseda University, Saitama, Japan
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33
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Rowland MJ, Parkins CC, McAbee JH, Kolb AK, Hein R, Loh XJ, Watts C, Scherman OA. An adherent tissue-inspired hydrogel delivery vehicle utilised in primary human glioma models. Biomaterials 2018; 179:199-208. [PMID: 30037456 DOI: 10.1016/j.biomaterials.2018.05.054] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/29/2018] [Accepted: 05/29/2018] [Indexed: 11/17/2022]
Abstract
A physical hydrogel cross-linked via the host-guest interactions of cucurbit[8]uril and utilised as an implantable drug-delivery vehicle for the brain is described herein. Constructed from hyaluronic acid, this hydrogel is biocompatible and has a high water content of 98%. The mechanical properties have been characterised by rheology and compared with the modulus of human brain tissue demonstrating the production of a soft material that can be moulded into the cavity it is implanted into following surgical resection. Furthermore, effective delivery of therapeutic compounds and antibodies to primary human glioblastoma cell lines is showcased by a variety of in vitro and ex vivo viability and immunocytochemistry based assays.
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Affiliation(s)
- Matthew J Rowland
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
| | - Christopher C Parkins
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
| | - Joseph H McAbee
- Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, CB2 0PY, UK
| | - Anna K Kolb
- Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, CB2 0PY, UK
| | - Robert Hein
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK
| | - Xian Jun Loh
- Institute of Materials Research and Engineering, A*STAR, 2 Fusionopolis Way, Innovis, Singapore
| | - Colin Watts
- Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, CB2 0PY, UK; Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Oren A Scherman
- Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
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A role for SOX9 in post-transcriptional processes: insights from the amphibian oocyte. Sci Rep 2018; 8:7191. [PMID: 29740094 PMCID: PMC5940923 DOI: 10.1038/s41598-018-25356-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 03/22/2018] [Indexed: 11/13/2022] Open
Abstract
Sox9 is a member of the gene family of SOX transcription factors, which is highly conserved among vertebrates. It is involved in different developmental processes including gonadogenesis. In all amniote species examined thus far, Sox9 is expressed in the Sertoli cells of the male gonad, suggesting an evolutionarily conserved role in testis development. However, in the anamniotes, fishes and amphibians, it is also expressed in the oocyte but the significance of such an expression remains to be elucidated. Here, we have investigated the nuclear localization of the SOX9 protein in the oocyte of three amphibian species, the urodelan Pleurodeles waltl, and two anurans, Xenopus laevis and Xenopus tropicalis. We demonstrate that SOX9 is associated with ribonucleoprotein (RNP) transcripts of lampbrush chromosomes in an RNA-dependent manner. This association can be visualized by Super-resolution Structured Illumination Microscopy (SIM). Our results suggest that SOX9, known to bind DNA, also carries an additional function in the posttranscriptional processes. We also discuss the significance of the acquisition or loss of Sox9 expression in the oocyte during evolution at the transition between anamniotes and amniotes.
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35
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Memic F, Knoflach V, Morarach K, Sadler R, Laranjeira C, Hjerling-Leffler J, Sundström E, Pachnis V, Marklund U. Transcription and Signaling Regulators in Developing Neuronal Subtypes of Mouse and Human Enteric Nervous System. Gastroenterology 2018; 154:624-636. [PMID: 29031500 PMCID: PMC6381388 DOI: 10.1053/j.gastro.2017.10.005] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 10/03/2017] [Accepted: 10/04/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS The enteric nervous system (ENS) regulates gastrointestinal function via different subtypes of neurons, organized into fine-tuned neural circuits. It is not clear how cell diversity is created within the embryonic ENS; information required for development of cell-based therapies and models of enteric neuropathies. We aimed to identify proteins that regulate ENS differentiation and network formation. METHODS We generated and compared RNA expression profiles of the entire ENS, ENS progenitor cells, and non-ENS gut cells of mice, collected at embryonic days 11.5 and 15.5, when different subtypes of neurons are formed. Gastrointestinal tissues from R26ReYFP reporter mice crossed to Sox10-CreERT2 or Wnt1-Cre mice were dissected and the 6 populations of cells were isolated by flow cytometry. We used histochemistry to map differentially expressed proteins in mouse and human gut tissues at different stages of development, in different regions. We examined enteric neuronal diversity and gastric function in Wnt1-Cre x Sox6fl/fl mice, which do not express the Sox6 gene in the ENS. RESULTS We identified 147 transcription and signaling factors that varied in spatial and temporal expression during development of the mouse ENS. Of the factors also analyzed in human ENS, most were conserved. We uncovered 16 signaling pathways (such as fibroblast growth factor and Eph/ephrin pathways). Transcription factors were grouped according to their specific expression in enteric progenitor cells (such as MEF2C), enteric neurons (such as SOX4), or neuron subpopulations (such as SATB1 and SOX6). Lack of SOX6 in the ENS reduced the numbers of gastric dopamine neurons and delayed gastric emptying. CONCLUSIONS Using transcriptome and histochemical analyses of the developing mouse and human ENS, we mapped expression patterns of transcription and signaling factors. Further studies of these candidate determinants might elucidate the mechanisms by which enteric stem cells differentiate into neuronal subtypes and form distinct connectivity patterns during ENS development. We found expression of SOX6 to be required for development of gastric dopamine neurons.
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Affiliation(s)
- Fatima Memic
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Viktoria Knoflach
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Khomgrit Morarach
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Rebecca Sadler
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Catia Laranjeira
- Division of Molecular Neurobiology, National Institute for Medical Research, Medical Research Council, London, United Kingdom
| | - Jens Hjerling-Leffler
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
| | - Erik Sundström
- Division of Neurodegeneration, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden,Stockholms Sjukhem, Stockholm, Sweden
| | | | - Ulrika Marklund
- Division of Molecular Neurobiology, Department for Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
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Taboada X, Viñas A, Adrio F. Comparative expression patterns ofSox2andSox19genes in the forebrain of developing and adult turbot (Scophthalmus maximus). J Comp Neurol 2017; 526:899-919. [DOI: 10.1002/cne.24374] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 12/04/2017] [Accepted: 12/04/2017] [Indexed: 12/13/2022]
Affiliation(s)
- Xoana Taboada
- Department of Zoology; Genetics and Physical Anthropology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela; Santiago de Compostela Spain
| | - Ana Viñas
- Department of Zoology; Genetics and Physical Anthropology, CIBUS, Faculty of Biology, Universidade de Santiago de Compostela; Santiago de Compostela Spain
| | - Fátima Adrio
- Department of Functional Biology, CIBUS, Faculty of Biology; Universidade de Santiago de Compostela; Santiago de Compostela Spain
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Xia P, Wang X, Qu Y, Lin Q, Cheng K, Gao M, Ren S, Zhang T, Li X. TGF-β1-induced chondrogenesis of bone marrow mesenchymal stem cells is promoted by low-intensity pulsed ultrasound through the integrin-mTOR signaling pathway. Stem Cell Res Ther 2017; 8:281. [PMID: 29237506 PMCID: PMC5729425 DOI: 10.1186/s13287-017-0733-9] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 11/19/2017] [Accepted: 11/23/2017] [Indexed: 02/06/2023] Open
Abstract
Background Low-intensity pulsed ultrasound (LIPUS) is a mechanical stimulus that plays a key role in regulating the differentiation of bone marrow mesenchymal stem cells (BMSCs). However, the way in which it affects the chondrogenic differentiation of BMSCs remains unknown. In this study, we aimed to investigate whether LIPUS is able to influence TGF-β1-induced chondrogenesis of BMSCs through the integrin-mechanistic target of the Rapamycin (mTOR) signaling pathway. Methods BMSCs were isolated from rat bone marrow and cultured in either standard or TGF-β1-treated culture medium. BMSCs were then subjected to LIPUS at a frequency of 3 MHz and a duty cycle of 20%, and integrin and mTOR inhibitors added in order to analyze their influence on cell differentiation. BMSCs were phenotypically analyzed by flow cytometry and the degree of chondrogenesis evaluated through toluidine blue staining, immunofluorescence, and immunocytochemistry. Furthermore, expression of COL2, aggrecan, SOX9, and COL1 was assessed by qRT-PCR and western blot analysis. Results We found that LIPUS promoted TGF-β1-induced chondrogenesis of BMSCs, represented by increased expression of COL2, aggrecan and SOX9 genes, and decreased expression of COL1. Notably, these effects were prevented following addition of integrin and mTOR inhibitors. Conclusions Taken together, these results indicate that mechanical stimulation combined with LIPUS promotes TGF-β1-induced chondrogenesis of BMSCs through the integrin-mTOR signaling pathway.
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Affiliation(s)
- Peng Xia
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Xiaoju Wang
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Yanping Qu
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Qiang Lin
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Kai Cheng
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Mingxia Gao
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Shasha Ren
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Tingting Zhang
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China
| | - Xueping Li
- Department of Rehabilitation Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, China.
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SOX6 Downregulation Induces γ-Globin in Human β-Thalassemia Major Erythroid Cells. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9496058. [PMID: 29333458 PMCID: PMC5733236 DOI: 10.1155/2017/9496058] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 10/30/2017] [Accepted: 11/02/2017] [Indexed: 11/27/2022]
Abstract
Background Fetal hemoglobin (HbF; α2γ2) is a potent genetic modifier of the severity of β-thalassemia and sickle cell anemia. Differences in the levels of HbF that persist into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Sry type HMG box (SOX6) is a potent silencer of HbF. Here, we reactivated γ-globin expression by downregulating SOX6 to alleviate anemia in the β-thalassemia patients. Methods SOX6 was downregulated by lentiviral RNAi (RNA interference) in K562 cell line and an in vitro culture model of human erythropoiesis in which erythroblasts are derived from the normal donor mononuclear cells (MNC) or β-thalassemia major MNC. The expression of γ-globin was analyzed by qPCR (quantitative real-time PCR) and WB (western blot). Results Our data showed that downregulation of SOX6 induces γ-globin production in K562 cell line and human erythrocytes from normal donors and β-thalassemia major donors, without altering erythroid maturation. Conclusions This is the first report on γ-globin induction by downregulation of SOX6 in human erythroblasts derived from β-thalassemia major.
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Kautzman AG, Keeley PW, Nahmou MM, Luna G, Fisher SK, Reese BE. Sox2 regulates astrocytic and vascular development in the retina. Glia 2017; 66:623-636. [PMID: 29178409 DOI: 10.1002/glia.23269] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Revised: 11/06/2017] [Accepted: 11/07/2017] [Indexed: 12/13/2022]
Abstract
Sox2 is a transcriptional regulator that is highly expressed in retinal astrocytes, yet its function in these cells has not previously been examined. To understand its role, we conditionally deleted Sox2 from the population of astrocytes and examined the consequences on retinal development. We found that Sox2 deletion does not alter the migration of astrocytes, but it impairs their maturation, evidenced by the delayed upregulation of glial fibrillary acidic protein (GFAP) across the retina. The centro-peripheral gradient of angiogenesis is also delayed in Sox2-CKO retinas. In the mature retina, we observed lasting abnormalities in the astrocytic population evidenced by the sporadic loss of GFAP immunoreactivity in the peripheral retina as well as by the aberrant extension of processes into the inner retina. Blood vessels in the adult retina are also under-developed and show a decrease in the frequency of branch points and in total vessel length. The developmental relationship between maturing astrocytes and angiogenesis suggests a causal relationship between the astrocytic loss of Sox2 and the vascular architecture in maturity. We suggest that the delay in astrocytic maturation and vascular invasion may render the retina hypoxic, thereby causing the abnormalities we observe in adulthood. These studies uncover a novel role for Sox2 in the development of retinal astrocytes and indicate that its removal can lead to lasting changes to retinal homeostasis.
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Affiliation(s)
- Amanda G Kautzman
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060.,Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
| | - Patrick W Keeley
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
| | - Michael M Nahmou
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060.,Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
| | - Gabriel Luna
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
| | - Steven K Fisher
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
| | - Benjamin E Reese
- Neuroscience Research Institute, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060.,Department of Psychological and Brain Sciences, University of California at Santa Barbara, Santa Barbara, CA, 93106-5060
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Stanisavljevic D, Petrovic I, Vukovic V, Schwirtlich M, Gredic M, Stevanovic M, Popovic J. SOX14 activates the p53 signaling pathway and induces apoptosis in a cervical carcinoma cell line. PLoS One 2017; 12:e0184686. [PMID: 28926586 PMCID: PMC5604970 DOI: 10.1371/journal.pone.0184686] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 08/29/2017] [Indexed: 12/28/2022] Open
Abstract
SOX14 is a member of the SOX family of transcription factors mainly involved in the regulation of neural development. Recently, it became evident that SOX14 is one of four hypermethylated genes in cervical carcinoma, considered as a tumor suppressor candidate in this type of malignancy. In this paper we elucidated the role of SOX14 in the regulation of malignant properties of cervical carcinoma cells in vitro. Functional analysis performed in HeLa cells revealed that SOX14 overexpression decreased viability and promoted apoptosis through altering the expression of apoptosis related genes. Our results demonstrated that overexpression of SOX14 initiated accumulation of p53, demonstrating potential cross-talk between SOX14 and the p53 signaling pathway. Further analysis unambiguously showed that SOX14 triggered posttranslational modification of p53 protein, as detected by the significantly increased level of phospho-p53 (Ser-15) in SOX14-overexpressing HeLa cells. Moreover, the obtained results revealed that SOX14 activated p53 protein, which was confirmed by elevated p21Waf1/Cip1, a well known target gene of p53. This study advances our understanding about the role of SOX14 and might explain the molecular mechanism by which this transcription factor could exert tumor suppressor properties in cervical carcinoma.
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Affiliation(s)
- Danijela Stanisavljevic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Isidora Petrovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Vladanka Vukovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Schwirtlich
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Marija Gredic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
| | - Milena Stevanovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
- University of Belgrade, Faculty of Biology, Belgrade, Serbia
- Serbian Academy of Sciences and Arts, Belgrade, Serbia
| | - Jelena Popovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia
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Chiba R, Akiya M, Hashimura M, Oguri Y, Inukai M, Hara A, Saegusa M. ALK signaling cascade confers multiple advantages to glioblastoma cells through neovascularization and cell proliferation. PLoS One 2017; 12:e0183516. [PMID: 28837676 PMCID: PMC5570309 DOI: 10.1371/journal.pone.0183516] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 08/04/2017] [Indexed: 02/04/2023] Open
Abstract
Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Here we examined the functional role of the ALK gene in glioblastomas (GBMs). In clinical samples of GBMs, high ALK expression without gene rearrangements or mutations was frequently observed in perivascular lesions, in contrast to the relatively low expression in the perinecrotic areas, which was positively correlated with N-myc and phosphorylated (p) Stat3 scores and Ki-67 labeling indices. ALK immunoreactivity was also found to be associated with neovascular features including vascular co-option and vascular mimicry. In astrocytoma cell lines, cells stably overexpressing full-length ALK showed an increase in expression of pStat3 and pAkt proteins, as well as hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor-A (VEGF-A) mRNAs, in contrast to cells with knockdown of endogenous ALK which showed decreased expression of these molecules. Transfection of the constitutively active form of Stat3 induced an increase in HIF-1α promoter activity, and the overexpression of HIF-1α in turn resulted in enhancement of VEGF-A promoter activity. In addition, cells with overexpression or knockdown of ALK also showed a tendency toward increased and decreased proliferation, respectively, through changes in expression of pAkt and pStat3. Finally, ALK promoter was significantly activated by transfection of Sox4 and N-myc, which are known to contribute to neuronal properties. These findings therefore suggest that N-myc/Sox4-mediated ALK signaling cascades containing Stat3, Akt, HIF-1α, and VEGF-A confer multiple advantages to tumor growth through alterations in neovascularization and cell proliferation in GBMs.
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Affiliation(s)
- Risako Chiba
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Masashi Akiya
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Miki Hashimura
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Yasuko Oguri
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Madoka Inukai
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Atsuko Hara
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
| | - Makoto Saegusa
- Department of Pathology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan
- * E-mail:
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Sox11 Balances Dendritic Morphogenesis with Neuronal Migration in the Developing Cerebral Cortex. J Neurosci 2017; 36:5775-84. [PMID: 27225767 DOI: 10.1523/jneurosci.3250-15.2016] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Accepted: 04/12/2016] [Indexed: 11/21/2022] Open
Abstract
UNLABELLED The coordinated mechanisms balancing promotion and suppression of dendritic morphogenesis are crucial for the development of the cerebral cortex. Although previous studies have revealed important transcription factors that promote dendritic morphogenesis during development, those that suppress dendritic morphogenesis are still largely unknown. Here we found that the expression levels of the transcription factor Sox11 decreased dramatically during dendritic morphogenesis. Our loss- and gain-of-function studies using postnatal electroporation and in utero electroporation indicate that Sox11 is necessary and sufficient for inhibiting dendritic morphogenesis of excitatory neurons in the mouse cerebral cortex during development. Interestingly, we found that precocious suppression of Sox11 expression caused precocious branching of neurites and a neuronal migration defect. We also found that the end of radial migration induced the reduction of Sox11 expression. These findings indicate that suppression of dendritic morphogenesis by Sox11 during radial migration is crucial for the formation of the cerebral cortex. SIGNIFICANCE STATEMENT Because dendritic morphology has profound impacts on neuronal information processing, the mechanisms underlying dendritic morphogenesis during development are of great interest. Our loss- and gain-of-function studies indicate that Sox11 is necessary and sufficient for inhibiting dendritic morphogenesis of excitatory neurons in the mouse cerebral cortex during development. Interestingly, we found that precocious suppression of Sox11 expression caused a neuronal migration defect. These findings indicate that suppression of dendritic morphogenesis by Sox11 during radial migration is crucial for the formation of the cerebral cortex.
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An Integrative Developmental Genomics and Systems Biology Approach to Identify an In Vivo Sox Trio-Mediated Gene Regulatory Network in Murine Embryos. BIOMED RESEARCH INTERNATIONAL 2017. [PMID: 28630873 PMCID: PMC5467288 DOI: 10.1155/2017/8932583] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Embryogenesis is an intricate process involving multiple genes and pathways. Some of the key transcription factors controlling specific cell types are the Sox trio, namely, Sox5, Sox6, and Sox9, which play crucial roles in organogenesis working in a concerted manner. Much however still needs to be learned about their combinatorial roles during this process. A developmental genomics and systems biology approach offers to complement the reductionist methodology of current developmental biology and provide a more comprehensive and integrated view of the interrelationships of complex regulatory networks that occur during organogenesis. By combining cell type-specific transcriptome analysis and in vivo ChIP-Seq of the Sox trio using mouse embryos, we provide evidence for the direct control of Sox5 and Sox6 by the transcriptional trio in the murine model and by Morpholino knockdown in zebrafish and demonstrate the novel role of Tgfb2, Fbxl18, and Tle3 in formation of Sox5, Sox6, and Sox9 dependent tissues. Concurrently, a complete embryonic gene regulatory network has been generated, identifying a wide repertoire of genes involved and controlled by the Sox trio in the intricate process of normal embryogenesis.
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Molecular basis for the genome engagement by Sox proteins. Semin Cell Dev Biol 2017; 63:2-12. [DOI: 10.1016/j.semcdb.2016.08.005] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 08/09/2016] [Accepted: 08/09/2016] [Indexed: 01/11/2023]
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Inoue H, Hashimura M, Akiya M, Chiba R, Saegusa M. Functional role of ALK-related signal cascades on modulation of epithelial-mesenchymal transition and apoptosis in uterine carcinosarcoma. Mol Cancer 2017; 16:37. [PMID: 28193280 PMCID: PMC5307825 DOI: 10.1186/s12943-017-0609-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Accepted: 01/30/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Anaplastic lymphoma kinase (ALK), which is a receptor tyrosine kinase, is essentially and transiently expressed in the developing nervous system. Recently, the deregulated expression of full-length ALK has been observed in some primary solid tumors, but little is known about its involvement in the tumorigenesis of uterine carcinosarcomas (UCSs). Here we examined the functional role of the ALK gene in UCSs. METHODS Regulation and function of the ALK gene were assessed using two endometrial carcinoma cell lines. Expression of ALK and its related molecules were also investigated using clinical samples of UCSs. RESULTS In cell lines, ALK promoter activity was significantly increased by transfection of Sox11 and N-myc, which are known to contribute to neuronal properties. Cells stably overexpressing full-length ALK showed an enhancement of EMT properties mediated by TGF-β1 and HGF, along with an increase in phosphorylated (p) Akt and nuclear p65. Overexpression of p65 also led to transactivation of Twist1 gene, known as an EMT inducer. Finally, treatment of the stable ALK-overexpressing cells with doxorubicin resulted in inhibition of apoptosis with progressive increase in the expression ratio of both pAkt and bcl2 relative to total Akt and bax, respectively. In clinical samples, strong cytoplasmic ALK immunoreactivity and mRNA signals without rearrangement or amplification of the ALK locus were frequently observed in UCSs, particularly in the sarcomatous components. Further, ALK IHC score was found to be positively correlated with Sox11, N-myc, Twist1, and bcl2 scores. CONCLUSION ALK-related signal cascades containing Akt, NF-κB, Twist1, and bcl2 may participate in initial signaling for divergent sarcomatous differentiation driven from carcinomatous components in UCSs through induction of the EMT process and inhibition of apoptotic features.
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Affiliation(s)
- H Inoue
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374 Kanagawa Japan
| | - M Hashimura
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374 Kanagawa Japan
| | - M Akiya
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374 Kanagawa Japan
| | - R Chiba
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374 Kanagawa Japan
| | - M Saegusa
- Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, 252-0374 Kanagawa Japan
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Waldmann T, Grinberg M, König A, Rempel E, Schildknecht S, Henry M, Holzer AK, Dreser N, Shinde V, Sachinidis A, Rahnenführer J, Hengstler JG, Leist M. Stem Cell Transcriptome Responses and Corresponding Biomarkers That Indicate the Transition from Adaptive Responses to Cytotoxicity. Chem Res Toxicol 2016; 30:905-922. [PMID: 28001369 DOI: 10.1021/acs.chemrestox.6b00259] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Analysis of transcriptome changes has become an established method to characterize the reaction of cells to toxicants. Such experiments are mostly performed at compound concentrations close to the cytotoxicity threshold. At present, little information is available on concentration-dependent features of transcriptome changes, in particular, at the transition from noncytotoxic concentrations to conditions that are associated with cell death. Thus, it is unclear in how far cell death confounds the results of transcriptome studies. To explore this gap of knowledge, we treated pluripotent stem cells differentiating to human neuroepithelial cells (UKN1 assay) for short periods (48 h) with increasing concentrations of valproic acid (VPA) and methyl mercury (MeHg), two compounds with vastly different modes of action. We developed various visualization tools to describe cellular responses, and the overall response was classified as "tolerance" (minor transcriptome changes), "functional adaptation" (moderate/strong transcriptome responses, but no cytotoxicity), and "degeneration". The latter two conditions were compared, using various statistical approaches. We identified (i) genes regulated at cytotoxic, but not at noncytotoxic, concentrations and (ii) KEGG pathways, gene ontology term groups, and superordinate biological processes that were only regulated at cytotoxic concentrations. The consensus markers and processes found after 48 h treatment were then overlaid with those found after prolonged (6 days) treatment. The study highlights the importance of careful concentration selection and of controlling viability for transcriptome studies. Moreover, it allowed identification of 39 candidate "biomarkers of cytotoxicity". These could serve to provide alerts that data sets of interest may have been affected by cell death in the model system studied.
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Affiliation(s)
- Tanja Waldmann
- In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Chair Foundation, University of Konstanz , 78457 Konstanz, Germany
| | - Marianna Grinberg
- Department of Statistics, Technical University of Dortmund , D-44221 Dortmund, Germany
| | - André König
- Department of Statistics, Technical University of Dortmund , D-44221 Dortmund, Germany
| | - Eugen Rempel
- Department of Statistics, Technical University of Dortmund , D-44221 Dortmund, Germany
| | - Stefan Schildknecht
- In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Chair Foundation, University of Konstanz , 78457 Konstanz, Germany
| | - Margit Henry
- Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne (UKK) , D-50931 Cologne, Germany
| | - Anna-Katharina Holzer
- In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Chair Foundation, University of Konstanz , 78457 Konstanz, Germany
| | - Nadine Dreser
- In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Chair Foundation, University of Konstanz , 78457 Konstanz, Germany
| | - Vaibhav Shinde
- Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne (UKK) , D-50931 Cologne, Germany
| | - Agapios Sachinidis
- Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne (UKK) , D-50931 Cologne, Germany
| | - Jörg Rahnenführer
- Department of Statistics, Technical University of Dortmund , D-44221 Dortmund, Germany
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo), Technical University of Dortmund , D-44139 Dortmund, Germany
| | - Marcel Leist
- In Vitro Toxicology and Biomedicine, Department inaugurated by the Doerenkamp-Zbinden Chair Foundation, University of Konstanz , 78457 Konstanz, Germany
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Rad A, Esmaeili Dizghandi S, Abbaszadegan MR, Taghechian N, Najafi M, Forghanifard MM. SOX1 is correlated to stemness state regulator SALL4 through progression and invasiveness of esophageal squamous cell carcinoma. Gene 2016; 594:171-175. [DOI: 10.1016/j.gene.2016.08.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/22/2016] [Accepted: 08/26/2016] [Indexed: 02/07/2023]
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Arnold N, Girke T, Sureshchandra S, Messaoudi I. Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia. J Virol 2016; 90:10823-10843. [PMID: 27681124 PMCID: PMC5110160 DOI: 10.1128/jvi.01272-16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 09/19/2016] [Indexed: 12/13/2022] Open
Abstract
Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCE Many aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection.
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Affiliation(s)
- Nicole Arnold
- Graduate Program in Microbiology, University of California-Riverside, Riverside, California, USA
| | - Thomas Girke
- Department of Botany and Plant Sciences, University of California-Riverside, Riverside, California, USA
| | - Suhas Sureshchandra
- Graduate Program in Genetics, Genomics and Bioinformatics, University of California-Riverside, Riverside, California, USA
| | - Ilhem Messaoudi
- Graduate Program in Microbiology, University of California-Riverside, Riverside, California, USA
- Graduate Program in Genetics, Genomics and Bioinformatics, University of California-Riverside, Riverside, California, USA
- Division of Biomedical Sciences, School of Medicine, University of California-Riverside, Riverside, California, USA
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Gonzalez G, Mehra S, Wang Y, Akiyama H, Behringer RR. Sox9 overexpression in uterine epithelia induces endometrial gland hyperplasia. Differentiation 2016; 92:204-215. [PMID: 27262401 PMCID: PMC5133190 DOI: 10.1016/j.diff.2016.05.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 04/22/2016] [Accepted: 05/23/2016] [Indexed: 01/03/2023]
Abstract
SOX9 is a high mobility group transcription factor that is required in many biological processes, including cartilage differentiation, endoderm progenitor maintenance, hair differentiation, and testis determination. SOX9 has also been linked to colorectal, prostate, and lung cancer. We found that SOX9 is expressed in the epithelium of the adult mouse and human uterus, predominantly marking the uterine glands. To determine if SOX9 plays a role in the development of endometrial cancer we overexpressed Sox9 in the uterine epithelium using a progesterone receptor-Cre mouse model. Sox9 overexpression in the uterine epithelium led to the formation of simple and complex cystic glandular structures in the endometrium of aged-females. Histological analysis revealed that these structures appeared morphologically similar to structures present in patients with endometrial hyperplastic lesions and endometrial polyps that are thought to be precursors of endometrial cancer. The molecular mechanisms that cause the glandular epithelium to become hyperplastic, leading to endometrial cancer are still poorly understood. These findings indicate that chronic overexpression of Sox9 in the uterine epithelium can induce the development of endometrial hyperplastic lesions. Thus, SOX9 expression may be a factor in the formation of endometrial cancer.
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Affiliation(s)
- Gabriel Gonzalez
- Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Shyamin Mehra
- Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Ying Wang
- Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Haruhiko Akiyama
- Department of Orthopedic Surgery, Gifu University, Gifu City 501-1194, Japan
| | - Richard R Behringer
- Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
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Mor-Shaked H, Eiges R. Modeling Fragile X Syndrome Using Human Pluripotent Stem Cells. Genes (Basel) 2016; 7:genes7100077. [PMID: 27690107 PMCID: PMC5083916 DOI: 10.3390/genes7100077] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/02/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from a loss-of-function mutation by a CGG repeat expansion at the 5′ untranslated region of the X-linked fragile X mental retardation 1 (FMR1) gene. Expansion of the CGG repeats beyond 200 copies results in protein deficiency by leading to aberrant methylation of the FMR1 promoter and the switch from active to repressive histone modifications. Additionally, the CGGs become increasingly unstable, resulting in high degree of variation in expansion size between and within tissues of affected individuals. It is still unclear how the FMR1 protein (FMRP) deficiency leads to disease pathology in neurons. Nor do we know the mechanisms by which the CGG expansion results in aberrant DNA methylation, or becomes unstable in somatic cells of patients, at least in part due to the lack of appropriate animal or cellular models. This review summarizes the current contribution of pluripotent stem cells, mutant human embryonic stem cells, and patient-derived induced pluripotent stem cells to disease modeling of FXS for basic and applied research, including the development of new therapeutic approaches.
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Affiliation(s)
- Hagar Mor-Shaked
- Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
| | - Rachel Eiges
- Stem Cell Research Laboratory, Medical Genetics Institute, Shaare Zedek Medical Center Affiliated with the Hebrew University School of Medicine, Jerusalem 91031, Israel.
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