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Bayindir-Bilgic M, Duman E, Turgut D, Kadikoylu AN, Ekimci-Gurcan N, Ozbey U, Kuskucu A, Bayrak OF. Investigation of the synergistic effect of metformin and FX11 on PANC-1 cell lines. Biol Res 2025; 58:15. [PMID: 40091035 PMCID: PMC11912783 DOI: 10.1186/s40659-025-00592-8] [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: 10/30/2024] [Accepted: 02/10/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Pancreatic cancer is among the most aggressive and malignant tumors and is a leading cause of cancer-related mortality. It is characterized by its metabolic Warburg effect and glucose dependence. Aerobic glycolysis is a key feature of metabolic reprogramming in cancer cells. This study investigates the combined effect of metformin and FX11, hypothesizing that disrupting cancer cell energetics through complementary mechanisms may result in a synergistic therapeutic effect. The combination of metformin and FX11 affects the axis that regulates vital functions in cancer cells; thus, the uncontrolled growth of tumor cells, especially those that use a lactose-dependent energy pathway, can be controlled. Several in vitro experiments were conducted to evaluate this hypothesis. PANC-1 cell proliferation was assessed using an MTS assay, lactate levels were measured via an LDH assay, and apoptosis was determined using a flow cytometry-based PE-annexin V assay. The downstream effects of metformin and FX11 treatment were evaluated via western blot analysis. RESULTS The findings of this study revealed that metformin and FX11 significantly decreased the viability of PANC-1 cells when used in combination, and this effect was achieved by significantly affecting the energy mechanism of the cells through the AMPKα axis. Furthermore, the lactate levels in PANC1 cells co-treated with metformin and FX11 were significantly decreased, while the increased cellular stress led the cells to apoptosis. CONCLUSIONS Compared with metformin treatment alone, the combination treatment of metformin and FX11 stimulates cellular stress in pancreatic cancer and targets various energy processes that encourage cancer cells to undergo apoptosis. This study provides a novel therapeutic strategy for the treatment of pancreatic cancer.
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Affiliation(s)
- Melike Bayindir-Bilgic
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
| | - Ezgi Duman
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Deniz Turgut
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Ayse Naz Kadikoylu
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Nur Ekimci-Gurcan
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
- Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Biruni University, Istanbul, Turkey
| | - Utku Ozbey
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey
| | - Aysegul Kuskucu
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey
| | - Omer F Bayrak
- Department of Medical Genetics, School of Medicine, Yeditepe University, Istanbul, Turkey.
- Department of Genetics and Bioengineering, Yeditepe University, Acıbadem Mah. Liseyolu sok. No:8 Kat: 3, Kadıköy/Istanbul, 34718, Turkey.
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Faraji N, Ebadpour N, Abavisani M, Gorji A. Unlocking Hope: Therapeutic Advances and Approaches in Modulating the Wnt Pathway for Neurodegenerative Diseases. Mol Neurobiol 2025; 62:3630-3652. [PMID: 39313658 PMCID: PMC11790780 DOI: 10.1007/s12035-024-04462-4] [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: 04/04/2024] [Accepted: 08/28/2024] [Indexed: 09/25/2024]
Abstract
Neurodegenerative diseases (NDs) are conditions characterized by sensory, motor, and cognitive impairments due to alterations in the structure and function of neurons in the central nervous system (CNS). Despite their widespread occurrence, the exact causes of NDs remain largely elusive, and existing treatments fall short in efficacy. The Wnt signaling pathway is an emerging molecular pathway that has been linked to the development and progression of various NDs. Wnt signaling governs numerous cellular processes, such as survival, polarity, proliferation, differentiation, migration, and fate specification, via a complex network of proteins. In the adult CNS, Wnt signaling regulates synaptic transmission, plasticity, memory formation, neurogenesis, neuroprotection, and neuroinflammation, all essential for maintaining neuronal function and integrity. Dysregulation of both canonical and non-canonical Wnt signaling pathways contributes to neurodegeneration through various mechanisms, such as amyloid-β accumulation, tau protein hyperphosphorylation, dopaminergic neuron degeneration, and synaptic dysfunction, prompting investigations into Wnt modulation as a therapeutic target to restore neuronal function and prevent or delay neurodegenerative processes. Modulating Wnt signaling has the potential to restore neuronal function and impede or postpone neurodegenerative processes, offering a therapeutic approach for targeting NDs. In this article, the current knowledge about how Wnt signaling works in Alzheimer's disease and Parkinson's disease is discussed. Our study aims to explore the molecular mechanisms, recent discoveries, and challenges involved in developing Wnt-based therapies.
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Affiliation(s)
- Navid Faraji
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Ebadpour
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abavisani
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Gorji
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Epilepsy Research Center, Münster University, Münster, Germany.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
- Neurosurgery Department, Münster University, Münster, Germany.
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Menon NA, Kumar CD, Ramachandran P, Blaize B, Gautam M, Cordani M, Lekha Dinesh Kumar. Small-molecule inhibitors of WNT signalling in cancer therapy and their links to autophagy and apoptosis. Eur J Pharmacol 2025; 986:177137. [PMID: 39551337 DOI: 10.1016/j.ejphar.2024.177137] [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: 08/01/2024] [Revised: 11/13/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Cancer represents an intricate and heterogeneous ailment that evolves from a multitude of epigenetic and genetic variations that disrupt normal cellular function. The WNT/β-catenin pathway is essential in maintaining the balance between cell renewal and differentiation in various tissues. Abnormal activation of this pathway can lead to uncontrolled cell growth and initiate cancer across a variety of tissues such as the colon, skin, liver, and ovary. It enhances characteristics that lead to cancer progression, including angiogenesis, invasion and metastasis. Processes like autophagy and apoptosis which regulate cell death and play a crucial role in maintaining cellular equilibrium are also intimately linked with WNT/ β-catenin pathway. Thus, targeting WNT pathway has become a key strategy in developing antitumor therapies. Employing small molecule inhibitors has emerged as a targeted therapy to improve the clinical outcome compared to conventional cancer treatments. Many strategies using small molecule inhibitors for modulating the WNT/β-catenin pathway, such as hindering WNT ligands' secretion or interaction, disrupting receptor complex, and blocking the nuclear translocation of β-catenin have been investigated. These interventions have shown promise in both preclinical and clinical settings. This review provides a comprehensive understanding of the role of WNT/β-catenin signalling pathway's role in cancer, emphasizing its regulation of autophagy and apoptosis. Our goal is to highlight the potential of specific small molecule inhibitors targeting this pathway, fostering the development of novel, tailored cancer treatments.
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Affiliation(s)
- Nayana A Menon
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Chethana D Kumar
- Department of Surgical ICU, Christian Medical College, IDA Scudder Road, Vellore, 632004, Tamil Nadu, India
| | - Pournami Ramachandran
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Britny Blaize
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Mridul Gautam
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Lekha Dinesh Kumar
- CSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad, 500007, Telangana, India.
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Suh HN, Choi GE. Wnt signaling in the tumor microenvironment: A driver of brain tumor dynamics. Life Sci 2024; 358:123174. [PMID: 39471897 DOI: 10.1016/j.lfs.2024.123174] [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: 07/29/2024] [Revised: 10/20/2024] [Accepted: 10/22/2024] [Indexed: 11/01/2024]
Abstract
The Wnt signaling pathway is important for cell growth and development in the central nervous system and its associated vasculature. Thus, it is an interesting factor for establishing anti-brain cancer therapy. However, simply inhibiting the Wnt signaling pathway in patients with brain tumors is not an effective anti-cancer therapy. Due to their complex microenvironment, which comprises various cell types and signaling molecules, brain tumors pose significant challenges. It is important to understand the interplay between tumor cells and the microenvironment for developing effective therapeutic strategies for both benign and malignant brain tumors. Thus, this research focused on the role of the tumor microenvironment (TME) in brain tumor progression, particularly the involvement of Wnt-dependent signaling pathways. The brain parenchyma comprises neurons, glia, endothelial cells, and other extracellular matrix elements that can contribute to the TME. The TME components can secrete Wnt ligands or associated molecules, resulting in the aberrant activation of the Wnt signaling pathway, followed by tumor progression and therapeutic resistance. Therefore, it is essential to understand the intricate crosstalk between the Wnt signaling pathway and the TME in developing targeted therapies. This review aimed to elucidate the complexities of the brain TME and its interactions with the Wnt signaling pathways to improve treatment outcomes and our understanding of brain tumor biology.
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Affiliation(s)
- Han Na Suh
- Center for Translational Toxicologic Research, Korea Institute of Toxicology, 30 Baekhak1-gil, Jeongeup, Jeonbukdo 56212, Republic of Korea.
| | - Gee Euhn Choi
- Laboratory of Veterinary Biochemistry, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju 63243, South Korea; Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, South Korea.
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Lee NY, Kyun ML, Yu JE, Kim SO, Lim KH, Lee KH. Transport of Golgi-localized β-catenin p-S47 by KIF11 or KIFC3 induces primary ciliogenesis. Mol Cells 2024; 47:100142. [PMID: 39476973 PMCID: PMC11609372 DOI: 10.1016/j.mocell.2024.100142] [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: 07/12/2024] [Revised: 10/23/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
Primary cilium is an important hub for cell signaling and dysregulation of primary cilia assembly and disassembly is associated with the development of cancer and chemotherapeutic drug resistance, as well as the genetic disorders collectively known as ciliopathy. β-catenin plays a major role in canonical Wnt signaling; however, its association with primary cilia has only recently been highlighted in reports of β-catenin-mediated primary ciliogenesis. In this study, we found that β-catenin p-S47 was localized to the Golgi apparatus and the nucleus, and the amount of β-catenin p-S47 at these locations was significantly higher during primary ciliogenesis compared with asynchronous cell growth conditions. In addition, the novel β-catenin-binding motor proteins KIF11 and KIFC3 were shown to have a lower binding affinity in β-catenin S47A than in β-catenin wild-type. Knockdown of KIF11 or KIFC3 resulted in primary cilia deficiency and increased β-catenin p-S47 levels in the Golgi apparatus and were accompanied by a decrease in β-catenin p-S47 at the centrosome. The accumulation of β-catenin p-S47 in the nucleus was increased during primary ciliogenesis along with β-catenin-dependent transcriptional activity. The collective findings indicate the existence of a novel mechanism of primary ciliogenesis involving KIF11-/KIFC3-associated β-catenin p-S47 in the Golgi apparatus and β-catenin p-S47 transcriptional activity in the nucleus. This study revealed a new mechanism for the study of ciliopathies, cancer, and chemotherapeutic drug resistance caused by primary ciliogenesis dysregulation and provides new targets for drug development to treat these diseases.
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Affiliation(s)
- Na Yeong Lee
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, Korea; College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Korea
| | - Mi-Lang Kyun
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, Daejeon 34114, Korea
| | - Ji Eun Yu
- College of Pharmacy, Mokpo National University, 1666, Yeongsan-ro, Muan-gun, Jeonnam 58554, Korea
| | - Sun-Ok Kim
- Department of Biochemistry and Pathology, Chungbuk National University College of Medicine and Medical Research Center, Cheongju, Chungbuk 28160, Korea
| | - Key-Hwan Lim
- College of Pharmacy, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Korea
| | - Kyung Ho Lee
- Chemical Biology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, Korea; Department of Bio-Molecular Science, KRIBB School of Bioscience, University of Science and Technology (UST), 217 Gajeong-ro, Yuseong-gu, Daejeon, Korea.
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Chen Z, Zhong W, Zhang R, Li G, Zhang Y, Zhang M. Down-regulation of PCBP2 suppresses the invasion and migration of trophoblasts via the WNT5A/ROR2 pathway in preeclampsia†. Biol Reprod 2024; 111:1142-1155. [PMID: 39115369 DOI: 10.1093/biolre/ioae122] [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: 01/26/2024] [Revised: 07/11/2024] [Accepted: 08/08/2024] [Indexed: 11/16/2024] Open
Abstract
Impaired extravillous trophoblast (EVT) invasion and resulted poor placentation play a vital role in the development of preeclampsia (PE). However, the underlying mechanisms of dysregulated EVTs remain unclear. This study aimed to explore the role of poly (C)-binding protein 2 (PCBP2), a multifunctional RNA-binding protein, in the pathogenesis of PE and to investigate the detailed signaling pathway. Using qRT-PCR, western blot, and immunohistochemistry, we confirmed that the expression of PCBP2 significantly decreased in placentas from 18 early-onset PE and 30 late-onset PE in comparison to those from 30 normotensive pregnancies. Besides, more significant suppression of PCBP2 was observed in the early-onset type. After transfection of HTR-8/SVneo with small-interfering RNA specific to PCBP2, the cellular biological behaviors including vitality, immigration, invasiveness, and apoptosis were evaluated by CCK-8 assay, wound-healing assay, transwell assay, and flow cytometry respectively. RNA-seq was applied to screen differentially expressed genes in HTR-8/SVneo upon PCBP2 silencing. GO and KEGG analysis indicated that WNT signaling pathway and the related processes such as extracellular matrix remodeling and cell adhesion were among the most enriched pathways or processes. Meanwhile, the alternative splicing of WNT5A regulated by PCBP2 was also identified by RIP-seq. Based on HTR-8/SVneo and villous explant, the regulatory roles of PCBP2 on trophoblast were confirmed to be mediated by WNT5A. Besides, it revealed that ROR2/JNK/MMP2/9 pathway was a vital pathway downstream WNT5A in trophoblast cells. In conclusion, this study suggests that down-regulated PCBP2 impaired the functions of EVTs via suppression of WNT5A-mediating ROR2/JNK/MMPs pathway, which may eventually contribute to the development of PE.
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Affiliation(s)
- Zhenlie Chen
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Shenshan Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 1, Henger Rd. Shanwei, 516621, P. R. China
| | - Wen Zhong
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
| | - Ruiqing Zhang
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
| | - Guigui Li
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
| | - Yuanzhen Zhang
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Hubei Clinical Research Center for Prenatal Diagnosis and Birth Health, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Wuhan Clinical Research Center for Reproductive Science and Birth Health, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
| | - Ming Zhang
- Reproductive Medicine Center, Zhongnan Hospital, Wuhan University, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Hubei Clinical Research Center for Prenatal Diagnosis and Birth Health, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Wuhan Clinical Research Center for Reproductive Science and Birth Health, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, No. 169, East Lake Rd., Wuhan 430071, Hubei Province, P. R. China
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Ahmad S, Attisano L. Wnt5a Promotes Axon Elongation in Coordination with the Wnt-Planar Cell Polarity Pathway. Cells 2024; 13:1268. [PMID: 39120298 PMCID: PMC11312420 DOI: 10.3390/cells13151268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/10/2024] Open
Abstract
The establishment of neuronal polarity, involving axon specification and outgrowth, is critical to achieve the proper morphology of neurons, which is important for neuronal connectivity and cognitive functions. Extracellular factors, such as Wnts, modulate diverse aspects of neuronal morphology. In particular, non-canonical Wnt5a exhibits differential effects on neurite outgrowth depending upon the context. Thus, the role of Wnt5a in axon outgrowth and neuronal polarization is not completely understood. In this study, we demonstrate that Wnt5a, but not Wnt3a, promotes axon outgrowth in dissociated mouse embryonic cortical neurons and does so in coordination with the core PCP components, Prickle and Vangl. Unexpectedly, exogenous Wnt5a-induced axon outgrowth was dependent on endogenous, neuronal Wnts, as the chemical inhibition of Porcupine using the IWP2- and siRNA-mediated knockdown of either Porcupine or Wntless inhibited Wnt5a-induced elongation. Importantly, delayed treatment with IWP2 did not block Wnt5a-induced elongation, suggesting that endogenous Wnts and Wnt5a act during specific timeframes of neuronal polarization. Wnt5a in fibroblast-conditioned media can associate with small extracellular vesicles (sEVs), and we also show that these Wnt5a-containing sEVs are primarily responsible for inducing axon elongation.
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Affiliation(s)
| | - Liliana Attisano
- Department of Biochemistry, Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada;
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Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol 2024; 17:46. [PMID: 38886806 PMCID: PMC11184729 DOI: 10.1186/s13045-024-01563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
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Affiliation(s)
- Pan Song
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Zirui Gao
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yige Bao
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China
| | - Li Chen
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuhe Huang
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yanyan Liu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Qiang Dong
- Department of Urology, Institute of Urology, West China Hospital of Sichuan University, Chengdu, Sichuan Province, 610041, China.
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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Cheng T, Agwu C, Shim K, Wang B, Jain S, Mahjoub MR. Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease. Development 2023; 150:dev201976. [PMID: 37982452 PMCID: PMC10753588 DOI: 10.1242/dev.201976] [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] [Accepted: 11/13/2023] [Indexed: 11/21/2023]
Abstract
Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in the pathways essential for development, fibrosis and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis and identifies new therapeutic targets for patients with renal centrosomopathies.
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Affiliation(s)
- Tao Cheng
- Department of Medicine, Division of Nephrology, Washington University in St Louis, St. Louis, MO 63110, USA
| | - Chidera Agwu
- Department of Medicine, Division of Nephrology, Washington University in St Louis, St. Louis, MO 63110, USA
| | - Kyuhwan Shim
- Department of Medicine, Division of Nephrology, Washington University in St Louis, St. Louis, MO 63110, USA
| | - Baolin Wang
- Department of Genetic Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA
| | - Sanjay Jain
- Department of Medicine, Division of Nephrology, Washington University in St Louis, St. Louis, MO 63110, USA
| | - Moe R. Mahjoub
- Department of Medicine, Division of Nephrology, Washington University in St Louis, St. Louis, MO 63110, USA
- Department of Cell Biology and Physiology, Washington University in St Louis, St. Louis, MO 63110, USA
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Díaz-Coránguez M, González-González L, Wang A, Liu X, Antonetti DA. Disheveled-1 Interacts with Claudin-5 and Contributes to Norrin-Induced Endothelial Barrier Restoration. Cells 2023; 12:2402. [PMID: 37830616 PMCID: PMC10571979 DOI: 10.3390/cells12192402] [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: 09/05/2023] [Revised: 09/27/2023] [Accepted: 09/29/2023] [Indexed: 10/14/2023] Open
Abstract
Previous studies have revealed that norrin can reverse vascular endothelial-growth-factor (VEGF)-induced permeability in a β-catenin-dependent pathway. Here, we have explored the contribution of disheveled-1 (DVL1) in norrin-induced blood-retinal barrier (BRB) restoration. We provide evidence that in addition to canonical signaling, DVL1 promotes tight junction (TJ) stabilization through a novel, non-canonical signaling pathway involving direct claudin-5 (CLDN5) binding. Immunofluorescence staining of rat retinal cross-sections showed enriched expression of DVL1 and 3 at endothelial capillaries and co-localization with CLDN5 and ZO-1 at the TJ complex in primary bovine retinal endothelial cells (BRECs). Barrier properties of BRECs were determined via measurements of trans-endothelial electrical resistance (TEER) or permeability to 70 kDa RITC-dextran. These studies demonstrated that norrin restoration of barrier properties after VEGF treatment required DVL1 as an siRNA knockdown of Dvl1 but not Dvl2 or Dvl3, reduced basal barrier properties and ablated norrin-induced barrier restoration. However, loss of Dvl1 did not decrease β-catenin signaling activity as measured by Axin2 mRNA expression, suggesting the contribution of a non-canonical pathway. DVL and TJ protein interactions were analyzed via co-immunoprecipitation of endogenous protein in BRECs, which demonstrated that DVL1 interacts with both CLDN5 and ZO-1, while DVL3 interacts only with ZO-1. These interactions were most abundant after inducing BRB restoration by treating BRECs with VEGF and norrin. DVL has previously been shown to form intramolecular bindings between the C-terminal PDZ-binding motif (PDZ-BM) with an internal PDZ domain. Co-transfection of HEK293 cells with DVL1 and CLDN5 or relevant mutants revealed that DVL1 interacts with CLDN5 through the DVL PDZ domain binding, CLDN5 PDZ-BM, in competition with DVL1 PDZ-BM, since DVL/CLDN5 interaction increases with deletion of the DVL1 PDZ-BM and decreases by co-expressing the C-terminal fragment of DVL1 containing the PDZ-BM or through deletion of CLDN5 PDZ-BM. In BREC cells, transfection of the C-terminal fragment of DVL1 downregulates the expression of CLDN5 but does not affect the expression of other proteins of the TJs, including ZO-1, occludin, CLDN1 or VE-cadherin. Blocking DVL1/CLDN5 interaction increased basal permeability and prevented norrin induction of barrier properties after VEGF. Combined with previous data, these results demonstrate that norrin signals through both a canonical β-catenin pathway and a non-canonical signaling pathway by which DVL1 directly binds to CLDN5 to promote barrier properties.
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Affiliation(s)
- Mónica Díaz-Coránguez
- Department of Pharmacobiology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Mexico City 07360, Mexico;
| | - Laura González-González
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA; (L.G.-G.); (A.W.); (X.L.)
| | - Amy Wang
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA; (L.G.-G.); (A.W.); (X.L.)
| | - Xuwen Liu
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA; (L.G.-G.); (A.W.); (X.L.)
| | - David A. Antonetti
- Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA; (L.G.-G.); (A.W.); (X.L.)
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Westphal D, Meinhardt M, Grützmann K, Schöne L, Steininger J, Neuhaus LT, Wiegel M, Schrimpf D, Aust DE, Schröck E, Baretton GB, Beissert S, Juratli TA, Schackert GG, Gravemeyer J, Becker JC, von Deimling A, Koelsche C, Klink B, Meier F, Schulz A, Muders MH, Seifert M. Identification of Epigenetically Regulated Genes Distinguishing Intracranial from Extracranial Melanoma Metastases. J Invest Dermatol 2023; 143:1233-1245.e17. [PMID: 36716920 DOI: 10.1016/j.jid.2023.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 12/13/2022] [Accepted: 01/09/2023] [Indexed: 01/29/2023]
Abstract
Despite remarkable advances in treating patients with metastatic melanoma, the management of melanoma brain metastases remains challenging. Recent evidence suggests that epigenetic reprogramming is an important mechanism for the adaptation of melanoma cells to the brain environment. In this study, the methylomes and transcriptomes of a cohort of matched melanoma metastases were evaluated by integrated omics data analysis. The identified 38 candidate genes displayed distinct promoter methylation and corresponding gene expression changes in intracranial compared with extracranial metastases. The 11 most promising genes were validated on protein level in both tumor and surrounding normal tissue using immunohistochemistry. In accordance with the underlying promoter methylation and gene expression changes, a significantly different protein expression was confirmed for STK10, PDXK, WDR24, CSSP1, NMB, RASL11B, phosphorylated PRKCZ, PRKCZ, and phosphorylated GRB10 in the intracranial metastases. The observed changes imply a distinct intracranial phenotype with increased protein kinase B phosphorylation and a higher frequency of proliferating cells. Knockdown of PRKCZ or GRB10 altered the expression of phosphorylated protein kinase B and decreased the viability of a brain-specific melanoma cell line. In summary, epigenetically regulated cancer-relevant alterations were identified that provide insights into the molecular mechanisms that discriminate brain metastases from other organ metastases, which could be exploited by targeting the affected signaling pathways.
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Affiliation(s)
- Dana Westphal
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany.
| | - Matthias Meinhardt
- Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Konrad Grützmann
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany; Institute for Medical Informatics and Biometry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Lisa Schöne
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute for Medical Informatics and Biometry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Julian Steininger
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Lena T Neuhaus
- Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Miriam Wiegel
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Daniel Schrimpf
- Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniela E Aust
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; BioBank Dresden (BBD), Tumor and Normal Tissue Bank (TNTB), National Center for Tumor Diseases (NCT/UCC), University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Evelin Schröck
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Gustavo B Baretton
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany; BioBank Dresden (BBD), Tumor and Normal Tissue Bank (TNTB), National Center for Tumor Diseases (NCT/UCC), University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Stefan Beissert
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Tareq A Juratli
- Department of Neurosurgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Gabriele G Schackert
- Department of Neurosurgery, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Jan Gravemeyer
- Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jürgen C Becker
- Translational Skin Cancer Research, German Cancer Consortium (DKTK), Partner Site Essen, and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Andreas von Deimling
- Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christian Koelsche
- Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of General Pathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Barbara Klink
- Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany; Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Friedegund Meier
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Skin Cancer Center at the University Cancer Center and National Center for Tumor Diseases, Dresden, Germany
| | - Alexander Schulz
- Department of Dermatology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany
| | - Michael H Muders
- Institute of Pathology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Michael Seifert
- National Center for Tumor Diseases (NCT/UCC), Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany; Medizinische Fakultät and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; Institute for Medical Informatics and Biometry, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
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12
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Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Signal Transduct Target Ther 2023; 8:177. [PMID: 37137892 PMCID: PMC10154768 DOI: 10.1038/s41392-023-01427-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 02/17/2023] [Accepted: 03/30/2023] [Indexed: 05/05/2023] Open
Abstract
Neuropsychiatric disorders are multifactorial disorders with diverse aetiological factors. Identifying treatment targets is challenging because the diseases are resulting from heterogeneous biological, genetic, and environmental factors. Nevertheless, the increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge of molecular mechanisms and structural information of GPCRs will be advantageous for developing effective drugs. This review provides an overview of the role of GPCRs in various neurodegenerative and psychiatric diseases. Besides, we highlight the emerging opportunities of novel GPCR targets and address recent progress in GPCR drug development.
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Affiliation(s)
- Thian-Sze Wong
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
- School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Guangzhi Li
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, 518000, Shenzhen, Guangdong, China
| | - Shiliang Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
- Innovation Center for AI and Drug Discovery, East China Normal University, 200062, Shanghai, China
| | - Wei Gao
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
- Innovation Center for AI and Drug Discovery, East China Normal University, 200062, Shanghai, China
| | - Geng Chen
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
| | - Shiyi Gan
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China
| | - Manzhan Zhang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
- Innovation Center for AI and Drug Discovery, East China Normal University, 200062, Shanghai, China
| | - Honglin Li
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China.
- Innovation Center for AI and Drug Discovery, East China Normal University, 200062, Shanghai, China.
| | - Song Wu
- Institute of Urology, The Affiliated Luohu Hospital of Shenzhen University, Shenzhen University, 518000, Shenzhen, Guangdong, China.
- Department of Urology, South China Hospital, Health Science Center, Shenzhen University, 518116, Shenzhen, Guangdong, China.
| | - Yang Du
- Kobilka Institute of Innovative Drug Discovery, Shenzhen Key Laboratory of Steroid Drug Discovery and Development, School of Medicine, The Chinese University of Hong Kong, 518172, Shenzhen, Guangdong, China.
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13
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Gu X, Jia C, Wang J. Advances in Understanding the Molecular Mechanisms of Neuronal Polarity. Mol Neurobiol 2023; 60:2851-2870. [PMID: 36738353 DOI: 10.1007/s12035-023-03242-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 01/22/2023] [Indexed: 02/05/2023]
Abstract
The establishment and maintenance of neuronal polarity are important for neural development and function. Abnormal neuronal polarity establishment commonly leads to a variety of neurodevelopmental disorders. Over the past three decades, with the continuous development and improvement of biological research methods and techniques, we have made tremendous progress in the understanding of the molecular mechanisms of neuronal polarity establishment. The activity of positive and negative feedback signals and actin waves are both essential in this process. They drive the directional transport and aggregation of key molecules of neuronal polarity, promote the spatiotemporal regulation of ordered and coordinated interactions of actin filaments and microtubules, stimulate the specialization and growth of axons, and inhibit the formation of multiple axons. In this review, we focus on recent advances in these areas, in particular the important findings about neuronal polarity in two classical models, in vitro primary hippocampal/cortical neurons and in vivo cortical pyramidal neurons, and discuss our current understanding of neuronal polarity..
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Affiliation(s)
- Xi Gu
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.
| | - Chunhong Jia
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Junhao Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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14
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Cheng T, Agwu C, Shim K, Wang B, Jain S, Mahjoub MR. Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.04.535568. [PMID: 37066373 PMCID: PMC10104032 DOI: 10.1101/2023.04.04.535568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Mutations that disrupt centrosome structure or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, it remains unclear how mutations in proteins essential for centrosome biogenesis impact embryonic kidney development. Here, we examined the consequences of conditional deletion of a ciliopathy gene, Cep120 , in the two nephron progenitor niches of the embryonic kidney. Cep120 loss led to reduced abundance of both metanephric mesenchyme and ureteric bud progenitor populations. This was due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in filtration function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for branching morphogenesis, cystogenesis and fibrosis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney development, and identifies new therapeutic targets for renal centrosomopathies. Highlights Defective centrosome biogenesis in nephron progenitors causes:Reduced abundance of metanephric mesenchyme and premature differentiation into tubular structuresAbnormal branching morphogenesis leading to reduced nephron endowment and smaller kidneysChanges in cell-autonomous and paracrine signaling that drive cystogenesis and fibrosisUnique cellular and developmental defects when compared to Pkd1 knockout models.
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15
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Urrutia PJ, González-Billault C. A Role for Second Messengers in Axodendritic Neuronal Polarity. J Neurosci 2023; 43:2037-2052. [PMID: 36948585 PMCID: PMC10039749 DOI: 10.1523/jneurosci.1065-19.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 03/24/2023] Open
Abstract
Neuronal polarization is a complex molecular process regulated by intrinsic and extrinsic mechanisms. Nerve cells integrate multiple extracellular cues to generate intracellular messengers that ultimately control cell morphology, metabolism, and gene expression. Therefore, second messengers' local concentration and temporal regulation are crucial elements for acquiring a polarized morphology in neurons. This review article summarizes the main findings and current understanding of how Ca2+, IP3, cAMP, cGMP, and hydrogen peroxide control different aspects of neuronal polarization, and highlights questions that still need to be resolved to fully understand the fascinating cellular processes involved in axodendritic polarization.
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Affiliation(s)
- Pamela J Urrutia
- Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile 7800003
- School of Medical Technology, Faculty of Medicine and Science, Universidad San Sebastián, Santiago, Chile 7510157
| | - Christian González-Billault
- Department of Biology, Faculty of Sciences, Universidad de Chile, Santiago, Chile 7800003
- Department of Neurosciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile 8380453
- Geroscience Center for Brain Health and Metabolism, Santiago, Chile 7800003
- Buck Institute for Research on Aging, Novato, California 94945
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16
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Kot M, Neglur PK, Pietraszewska A, Buzanska L. Boosting Neurogenesis in the Adult Hippocampus Using Antidepressants and Mesenchymal Stem Cells. Cells 2022; 11:cells11203234. [PMID: 36291101 PMCID: PMC9600461 DOI: 10.3390/cells11203234] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/06/2022] [Accepted: 10/12/2022] [Indexed: 11/16/2022] Open
Abstract
The hippocampus is one of the few privileged regions (neural stem cell niche) of the brain, where neural stem cells differentiate into new neurons throughout adulthood. However, dysregulation of hippocampal neurogenesis with aging, injury, depression and neurodegenerative disease leads to debilitating cognitive impacts. These debilitating symptoms deteriorate the quality of life in the afflicted individuals. Impaired hippocampal neurogenesis is especially difficult to rescue with increasing age and neurodegeneration. However, the potential to boost endogenous Wnt signaling by influencing pathway modulators such as receptors, agonists, and antagonists through drug and cell therapy-based interventions offers hope. Restoration and augmentation of hampered Wnt signaling to facilitate increased hippocampal neurogenesis would serve as an endogenous repair mechanism and contribute to hippocampal structural and functional plasticity. This review focuses on the possible interaction between neurogenesis and Wnt signaling under the control of antidepressants and mesenchymal stem cells (MSCs) to overcome debilitating symptoms caused by age, diseases, or environmental factors such as stress. It will also address some current limitations hindering the direct extrapolation of research from animal models to human application, and the technical challenges associated with the MSCs and their cellular products as potential therapeutic solutions.
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Affiliation(s)
- Marta Kot
- Correspondence: ; Tel.: +48-22-60-86-563
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17
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Khan TA, Guo A, Martin J, Te Chien C, Liu T, Szczurkowska J, Shelly M. Directed mechanisms for apical dendrite development during neuronal polarization. Dev Biol 2022; 490:110-116. [PMID: 35809631 DOI: 10.1016/j.ydbio.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 06/09/2022] [Accepted: 07/01/2022] [Indexed: 12/18/2022]
Abstract
The development of the dendrite and the axon during neuronal polarization underlies the directed flow of information in the brain. Seminal studies on axon development have dominated the mechanistic analysis of neuronal polarization. These studies, many originating from examinations in cultured hippocampal and cortical neurons in vitro, have established a prevalent view that axon formation precedes and is necessary for neuronal polarization. There is also in vivo evidence supporting this view. Nevertheless, the establishment of bipolar polarity and the leading edge, and apical dendrite development in pyramidal neurons in vivo occur when axon formation is prevented. Furthermore, recent mounting evidence suggest that directed mechanisms might mediate bipolar polarity/leading process and subsequent apical dendrite development. In the presence of spatially directed extracellular cues in the developing brain, these events may operate independently of axon forming events. In this perspective we summarize evidence in support of these evolving views in neuronal polarization and highlight recent findings on dedicated mechanisms acting in apical dendrite development.
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Affiliation(s)
- Tamor A Khan
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Alan Guo
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Jacqueline Martin
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Chia Te Chien
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Tianrui Liu
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Joanna Szczurkowska
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA
| | - Maya Shelly
- Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, 11794-5230, USA.
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The Roles of Par3, Par6, and aPKC Polarity Proteins in Normal Neurodevelopment and in Neurodegenerative and Neuropsychiatric Disorders. J Neurosci 2022; 42:4774-4793. [PMID: 35705493 DOI: 10.1523/jneurosci.0059-22.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 04/30/2022] [Accepted: 05/02/2022] [Indexed: 11/21/2022] Open
Abstract
Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as "Par complexes." In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differentiation, synaptic plasticity, and memory. These versatile functions rely on the fundamental roles of Par complexes in cell polarity in distinct cellular contexts. We also discuss how cell polarization may correlate with subcellular polarization in neurons. Finally, we review the involvement of Par complexes in neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease. While emerging evidence indicates that Par complexes are essential for proper neural development and maintenance, many questions on their in vivo functions have yet to be answered. Thus, Par3, Par6, and aPKC continue to be important research topics to advance neuroscience.
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Segi N, Ozaki T, Suzuki Y, Ouchida J, Imagama S, Kadomatsu K, Sakamoto K. Close association of polarization and LC3, a marker of autophagy, in axon determination in mouse hippocampal neurons. Exp Neurol 2022; 354:114112. [PMID: 35568188 DOI: 10.1016/j.expneurol.2022.114112] [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: 01/26/2022] [Revised: 04/28/2022] [Accepted: 05/06/2022] [Indexed: 11/04/2022]
Abstract
The autophagy-lysosome pathway is a cellular clearance system for intracellular organelles, macromolecules and microorganisms. It is indispensable for cells not only to maintain their homeostasis but also to achieve more active cellular processes such as differentiation. Therefore, impairment or disruption of the autophagy-lysosome pathway leads to a wide spectrum of human diseases, ranging from several types of neurodegenerative diseases to malignancies. In elongating axons, autophagy preferentially occurs at growth cones, and disruption of autophagy is closely associated with incapacity for axonal regeneration after injury in the central nervous system. However, the roles of autophagy in developing neurons remain elusive. In particular, whether autophagy is involved in axon-dendrite determination is largely unclear. Using primary cultured mouse embryonic hippocampal neurons, we here showed the polarized distribution of autophagosomes among minor processes of neurons at stage 2. Time-lapse observation of neurons from GFP-LC3 transgenic mice demonstrated that an "LC3 surge"-i.e., a rapid accumulation of autophagic marker LC3 that continues for several hours in one minor process-proceeded the differentiation of neurons into axons. In addition, pharmacological activation and inhibition of autophagy by trehalose and bafilomycin, respectively, accelerated and delayed axonal determination. Taken together, our findings revealed the close association between LC3, a marker of autophagy, and axon determination in developing neurons.
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Affiliation(s)
- Naoki Segi
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Departments of Orthopedics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Tomoya Ozaki
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Yuji Suzuki
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Jun Ouchida
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Departments of Orthopedics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Shiro Imagama
- Departments of Orthopedics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
| | - Kenji Kadomatsu
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
| | - Kazuma Sakamoto
- Departments of Biochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Institute for Glyco-core Research (iGCORE), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
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20
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Čada Š, Bryja V. Local Wnt signalling in the asymmetric migrating vertebrate cells. Semin Cell Dev Biol 2021; 125:26-36. [PMID: 34896020 DOI: 10.1016/j.semcdb.2021.11.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/27/2022]
Abstract
Wnt signalling is known to generate cellular asymmetry via Wnt/planar cell polarity pathway (Wnt/PCP). Wnt/PCP acts locally (i) to orient membrane polarity and asymmetric establishment of intercellular junctions via conserved set of PCP proteins most specifically represented by Vangl and Prickle, and (ii) to asymmetrically rearrange cytoskeletal structures via downstream effectors of Dishevelled (Dvl). This process is best described on stable phenotypes of epithelial cells. Here, however, we review the activity of Wnt signalling in migratory cells which experience the extensive rearrangements of cytoskeleton and consequently dynamic asymmetry, making the localised effects of Wnt signalling easier to distinguish. Firstly, we focused on migration of neuronal axons, which allows to study how the pre-existent cellular asymmetry can influence Wnt signalling outcome. Then, we reviewed the role of Wnt signalling in models of mesenchymal migration including neural crest, melanoma, and breast cancer cells. Last, we collected evidence for local Wnt signalling in amoeboid cells, especially lymphocytes. As the outcome of this review, we identify blank spots in our current understanding of this topic, propose models that synthesise the current observations and allow formulation of testable hypotheses for the future research.
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Affiliation(s)
- Štěpán Čada
- Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
| | - Vítězslav Bryja
- Department of Experimental Biology, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic; Department of Cytokinetics, Institute of Biophysics CAS, Královopolská 135, 61265 Brno, Czech Republic.
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21
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Liu YJ, Chen XF, Zhou LP, Rao F, Zhang DY, Wang YH. A nerve conduit filled with Wnt5a-loaded fibrin hydrogels promotes peripheral nerve regeneration. CNS Neurosci Ther 2021; 28:145-157. [PMID: 34729936 PMCID: PMC8673702 DOI: 10.1111/cns.13752] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 10/09/2021] [Accepted: 10/18/2021] [Indexed: 12/11/2022] Open
Abstract
Aims Peripheral nerve injury is a significant clinical problem with a substantial impact on quality of life, for which no optimal treatment has been found. This study aimed to analyze the effect and mechanism of Wnt5a‐loaded fibrin hydrogel on a 10‐mm rat sciatic nerve defect. Methods The Wnt5a‐loaded fibrin hydrogel was synthesized by mixing a Wnt5a solution with thrombin and fibrinogen solutions. The loading capacity and release profile of Wnt5a‐loaded fibrin hydrogel and the effect of Wnt5a on Schwann cells were evaluated in vitro. We also assessed the in vivo repair status via histological analysis of the regenerative nerve and gastrocnemius muscle, electrophysiological examination, gait analysis, and muscle wet weight. Results We developed a nerve conduit filled with Wnt5a‐loaded fibrin hydrogel (Fn) as a sustained‐release system to repair a 10‐mm rat sciatic nerve defect. In vitro, Wnt5a could promote SC proliferation and the gene expression of vascular endothelial growth factor (VEGF), nerve growth factor (NGF), and cholinergic neurotrophic factor (CNTF), as well as the protein secretion of VEGF and NGF. In vivo, the Wnt5a/Fn group was superior to the hollow, fibrin hydrogel, and Wnt5a groups in terms of axonal growth, myelination, electrophysiological recovery, target organ innervation, and motor function recovery 12 weeks after the operation. Conclusion The Wnt5a/Fn nerve conduit can promote peripheral nerve defect regeneration, with potential clinical applications. The mechanism for this may be the facilitation of multiple neurotrophin secretion, combining vascularization and neurotrophic growth cues.
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Affiliation(s)
- Yi-Jun Liu
- Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China.,Department of Foot and Ankle Surgery, Center for Orthopaedic Surgery, the Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Xiao-Feng Chen
- Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China.,Department of Orthopedics and Trauma, Key Laboratory of Trauma and Neural Regeneration (Ministry of Education/ Peking University), Beijing, China
| | - Li-Ping Zhou
- Beijing Key Laboratory for Bioengineering and Sensing Technology, Daxing Research Institute, School of Chemistry & Biological Engineering, University of Science & Technology Beijing, Beijing, China
| | - Feng Rao
- Trauma Medicine Center, Peking University People's Hospital, Beijing, China
| | - Dian-Ying Zhang
- Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China.,Department of Orthopedics and Trauma, Key Laboratory of Trauma and Neural Regeneration (Ministry of Education/ Peking University), Beijing, China
| | - Yan-Hua Wang
- Department of Orthopedics and Trauma, Peking University People's Hospital, Beijing, China.,Department of Orthopedics and Trauma, Key Laboratory of Trauma and Neural Regeneration (Ministry of Education/ Peking University), Beijing, China
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22
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Rogers S, Scholpp S. Vertebrate Wnt5a - At the crossroads of cellular signalling. Semin Cell Dev Biol 2021; 125:3-10. [PMID: 34686423 DOI: 10.1016/j.semcdb.2021.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/08/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023]
Abstract
Wnt signalling is an essential pathway in embryogenesis, differentiation, cell motility, development, and adult tissue homeostasis in vertebrates. The Wnt signalling network can activate several downstream pathways such as the β-catenin-dependent TCF/LEF transcription, the Wnt/planar cell polarity (PCP) pathway, and the Wnt/Calcium pathway. Wnt5a is a vertebrate Wnt ligand that is most often associated with the Wnt/PCP signalling pathway. Wnt5a/PCP signalling has a well-described role in embryogenesis via binding to a receptor complex of Frizzled and its co-receptors to initiate downstream activation of the c-Jun N-terminal kinase (JNK) signalling cascade and the Rho and Rac GTPases, Rho-Kinase (ROCK). This activation results in the cytoskeletal remodelling required for cell polarity, migration, and subsequently, tissue re-arrangement and organ formation. This review will focus on more recent work that has revealed new roles for Wnt5a ligands and consequently, an emerging broader function. This is partly due to our growing understanding of the crosstalk between the Wnt/PCP pathway with both the Wnt/β-catenin pathway and other signalling pathways, and in part due to the identification of novel atypical receptors for Wnt5a that demonstrate a far broader role for this ligand.
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Affiliation(s)
- Sally Rogers
- Living Systems Institute, School of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK
| | - Steffen Scholpp
- Living Systems Institute, School of Biosciences, College of Life and Environmental Sciences, University of Exeter, Exeter, UK.
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23
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Li A, Zhu HM, Chen Y, Yan F, Liu ZY, Li ZL, Dong WR, Zhang L, Wang HH. Cdc42 Facilitates Axonogenesis by Enhancing Microtubule Stabilization in Primary Hippocampal Neurons. Cell Mol Neurobiol 2021; 41:1599-1610. [PMID: 33575839 PMCID: PMC11448644 DOI: 10.1007/s10571-021-01051-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 01/28/2021] [Indexed: 01/07/2023]
Abstract
The establishment of polarity is an essential process in early neuronal development. Cdc42, a GTPase of the Rho family, is a key regulator of cytoskeletal dynamics and neuronal polarity. However, the mechanisms underlying the action of cdc42 in regulating axonogenesis have not been elucidated. Here, we expressed wild-type cdc42, a constitutively active cdc42 mutant (cdc42F28L) and a dominant negative cdc42 mutant (cdc42N17), respectively, in the primary hippocampal neurons to alter the activity of cdc42. We found that cdc42 activities were paralleled with the capacities to promote axonogenesis in the cultured neurons. Cdc42 also enhanced microtubule stability in the cultured neurons. Pharmacologically stabilizing microtubules significantly abrogated the defective axonogenesis induced by cdc42 inhibition. Moreover, cdc42 promoted the dephosphorylation of collapsing response mediator protein-2 (CRMP-2) at Thr514 by increasing GSK-3β phosphorylation at Ser9 in the cultured neurons. These findings suggest that cdc42 may facilitate axonogenesis by promoting microtubule stabilization in rat primary hippocampal neurons.
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Affiliation(s)
- Ang Li
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Hui-Ming Zhu
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Yu Chen
- Experimental Education & Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Fang Yan
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhong-Ying Liu
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Zhen-Lin Li
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Wei-Ren Dong
- Experimental Education & Administration Center, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Lin Zhang
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
| | - Hai-Hong Wang
- Department of Histology and Embryology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.
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24
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Ni Y, Liu B, Wu X, Liu J, Ba R, Zhao C. FOXG1 Directly Suppresses Wnt5a During the Development of the Hippocampus. Neurosci Bull 2021; 37:298-310. [PMID: 33389683 PMCID: PMC7954983 DOI: 10.1007/s12264-020-00618-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022] Open
Abstract
The Wnt signaling pathway plays key roles in various developmental processes. Wnt5a, which activates the non-canonical pathway, has been shown to be particularly important for axon guidance and outgrowth as well as dendrite morphogenesis. However, the mechanism underlying the regulation of Wnt5a remains unclear. Here, through conditional disruption of Foxg1 in hippocampal progenitors and postmitotic neurons achieved by crossing Foxg1fl/fl with Emx1-Cre and Nex-Cre, respectively, we found that Wnt5a rather than Wnt3a/Wnt2b was markedly upregulated. Overexpression of Foxg1 had the opposite effects along with decreased dendritic complexity and reduced mossy fibers in the hippocampus. We further demonstrated that FOXG1 directly repressed Wnt5a by binding to its promoter and one enhancer site. These results expand our knowledge of the interaction between Foxg1 and Wnt signaling and help elucidate the mechanisms underlying hippocampal development.
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Affiliation(s)
- Yang Ni
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Bin Liu
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Xiaojing Wu
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Junhua Liu
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Ru Ba
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Chunjie Zhao
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, 210009, China.
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25
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Hussen DF, Kamel AK, Mekkawy MK, Ashaat EA, El Ruby MO. Phenotypic and Molecular Cytogenetic Analysis of a Case of Monosomy 1p36 Syndrome due to Unbalanced Translocation. Mol Syndromol 2021; 11:284-295. [PMID: 33510599 DOI: 10.1159/000510428] [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: 03/19/2020] [Accepted: 07/23/2020] [Indexed: 11/19/2022] Open
Abstract
Monosomy 1p36 syndrome is one of the most common submicroscopic deletion syndromes, which is characterized by the presence of delayed developmental milestones, intellectual disability, and clinically recognizable dysmorphic craniofacial features. The syndrome comprises 4 cytogenetic groups including pure terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes 1 due to unbalanced translocations, where unbalanced translocations represent the least percentage of all cases of monosomy 1p36 (7%). Most patients with monosomy 1p36 due to an unbalanced translocation can be cytogenetically diagnosed using conventional techniques. However, chromosomal microarray analysis is mandatory in these cases to detect copy number variance and size of the deletion and allows for setting a phenotype-genotype correlation. Here, we studied a 1.5-year-old female patient who showed intellectual disability, delayed milestones, hypotonia, seizures, and characteristic dysmorphic features including brachycephaly, straight eyebrows, deep-set eyes, downslanting palpebral fissures, midface hypoplasia, depressed nasal bridge, long philtrum, and pointed chin. Conventional cytogenetic analysis (CCA), microarray study, and fluorescence in situ hybridization (FISH) analysis were performed. CCA showed a translocation involving chromosomes 1 and 21, 45,XX,der(1)t(1;21)(p36.32;q21.1)dn. Microarray analysis revealed copy number losses at both 1p36 and proximal 21q. FISH confirmed the presence of the 1p36 deletion, but was not performed for 21q. We have concluded that phenotype-genotype correlation for monosomy 1p36 syndrome can be performed for the fundamental clinical manifestations; however, the final aspect of the syndrome depends on composite factors. Monosomy 1p36 due to unbalanced translocation may present either classically or with additional altered features of various severity based on the copy number variations involving different chromosomes.
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Affiliation(s)
- Dalia F Hussen
- Human Cytogenetics Department, National Research Centre, Cairo, Egypt
| | - Alaa K Kamel
- Human Cytogenetics Department, National Research Centre, Cairo, Egypt
| | - Mona K Mekkawy
- Human Cytogenetics Department, National Research Centre, Cairo, Egypt
| | - Engy A Ashaat
- Clinical Genetics Department, National Research Centre, Cairo, Egypt
| | - Mona O El Ruby
- Clinical Genetics Department, National Research Centre, Cairo, Egypt
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26
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Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol 2020; 13:165. [PMID: 33276800 PMCID: PMC7716495 DOI: 10.1186/s13045-020-00990-3] [Citation(s) in RCA: 818] [Impact Index Per Article: 163.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/02/2020] [Indexed: 12/16/2022] Open
Abstract
The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.
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Affiliation(s)
- Ya Zhang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.,Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China.,School of medicine, Shandong University, Jinan, 250021, Shandong, China.,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China.,Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China.,National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 250021, China
| | - Xin Wang
- Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China. .,Department of Hematology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250021, Shandong, China. .,School of medicine, Shandong University, Jinan, 250021, Shandong, China. .,Shandong Provincial Engineering Research Center of Lymphoma, Jinan, 250021, Shandong, China. .,Branch of National Clinical Research Center for Hematologic Diseases, Jinan, 250021, Shandong, China. .,National Clinical Research Center for Hematologic Diseases, the First Affiliated Hospital of Soochow University, Suzhou, 250021, China.
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27
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Aghaizu ND, Jin H, Whiting PJ. Dysregulated Wnt Signalling in the Alzheimer's Brain. Brain Sci 2020; 10:E902. [PMID: 33255414 PMCID: PMC7761504 DOI: 10.3390/brainsci10120902] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/16/2020] [Accepted: 11/21/2020] [Indexed: 02/07/2023] Open
Abstract
The Wnt signalling system is essential for both the developing and adult central nervous system. It regulates numerous cellular functions ranging from neurogenesis to blood brain barrier biology. Dysregulated Wnt signalling can thus have significant consequences for normal brain function, which is becoming increasingly clear in Alzheimer's disease (AD), an age-related neurodegenerative disorder that is the most prevalent form of dementia. AD exhibits a range of pathophysiological manifestations including aberrant amyloid precursor protein processing, tau pathology, synapse loss, neuroinflammation and blood brain barrier breakdown, which have been associated to a greater or lesser degree with abnormal Wnt signalling. Here we provide a comprehensive overview of the role of Wnt signalling in the CNS, and the research that implicates dysregulated Wnt signalling in the ageing brain and in AD pathogenesis. We also discuss the opportunities for therapeutic intervention in AD via modulation of the Wnt signalling pathway, and highlight some of the challenges and the gaps in our current understanding that need to be met to enable that goal.
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Affiliation(s)
- Nozie D. Aghaizu
- UK Dementia Research Institute at University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK;
| | - Hanqing Jin
- UK Dementia Research Institute at University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK;
| | - Paul J. Whiting
- UK Dementia Research Institute at University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK;
- ARUK Drug Discovery Institute (DDI), University College London, Cruciform Building, Gower Street, London WC1E 6BT, UK
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28
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Lee KH. Involvement of Wnt signaling in primary cilia assembly and disassembly. FEBS J 2020; 287:5027-5038. [PMID: 33015954 DOI: 10.1111/febs.15579] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/21/2020] [Accepted: 09/29/2020] [Indexed: 11/28/2022]
Abstract
The primary cilium is a nonmotile microtubule-based structure, which functions as an antenna-like cellular sensing organelle. The primary cilium is assembled from the basal body, a mother centriole-based structure, during interphase or a quiescent cell stage, and rapidly disassembles before entering mitosis in a dynamic cycle. Defects in this ciliogenesis dynamics are associated with human diseases such as ciliopathy and cancer, but the molecular mechanisms of the ciliogenesis dynamics are still largely unknown. To date, various cellular signaling pathways associated with primary cilia have been proposed, but the main signaling pathways regulating primary cilia assembly/disassembly remain enigmatic. This review describes recent findings in Wnt-induced primary cilia assembly/disassembly and potential future directions for the study of the cellular signaling related to the primary ciliogenesis dynamics.
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Affiliation(s)
- Kyung Ho Lee
- Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang, Korea
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29
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Giannocco G, Kizys MML, Maciel RM, de Souza JS. Thyroid hormone, gene expression, and Central Nervous System: Where we are. Semin Cell Dev Biol 2020; 114:47-56. [PMID: 32980238 DOI: 10.1016/j.semcdb.2020.09.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 09/09/2020] [Accepted: 09/14/2020] [Indexed: 12/27/2022]
Abstract
Thyroid hormones (TH; T3 and T4) play a fundamental role in the fetal stage to the adult phase, controlling gene and protein expression in virtually all tissues. The endocrine and CNS systems have relevant interaction, and the TH are pivotal for the proper functioning of the CNS. A slight failure to regulate TH availability during pregnancy and/or childhood can lead to neurological disorders, for example, autism and cognitive impairment, or depression. In this review, we highlight how TH acts in controlling gene expression, its role in the CNS, and what substances widely found in the environment can cause in this tissue. We highlight the role of Endocrine Disruptors used on an everyday basis in the processing of mRNAs responsible for neurodevelopment. We conclude that TH, more precisely T3, acts mainly throughout its nuclear receptors, that the deficiency of this hormone, either due to the lack of its main substrate iodine, or by to incorrect organification of T4 and T3 in the gland, or by a mutation in transporters, receptors and deiodinases may cause mild (dysregulated mood in adulthood) to severe neurological impairment (Allan-Herndon-Dudley syndrome, presented as early as childhood); T3 is responsible for the expression of numerous CNS genes related to oxygen transport, growth factors, myelination, cell maturation. Substances present in the environment and widely used can interfere with the functioning of the thyroid gland, the action of TH, and the functioning of the CNS.
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Affiliation(s)
- Gisele Giannocco
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Departamento de Ciências Biológicas, Universidade Federal de São Paulo, UNIFESP, Diadema, SP 09920-000, Brazil
| | - Marina Malta Letro Kizys
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Rui Monteiro Maciel
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil
| | - Janaina Sena de Souza
- Departamento de Medicina, Laboratório de Endocrinologia e Medicina Translacional, Universidade Federal de São Paulo, UNIFESP/EPM, Rua Pedro de Toledo, 669 - 11 andar, São Paulo, SP 04039-032, Brazil; Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
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30
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Vural A, Lanier SM. Intersection of two key signal integrators in the cell: activator of G-protein signaling 3 and dishevelled-2. J Cell Sci 2020; 133:jcs247908. [PMID: 32737219 PMCID: PMC7490517 DOI: 10.1242/jcs.247908] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 07/23/2020] [Indexed: 10/23/2022] Open
Abstract
Activator of G-protein signaling 3 (AGS3, encoded by GPSM1) was discovered as a one of several receptor-independent activators of G-protein signaling, which are postulated to provide a platform for divergence between canonical and noncanonical G-protein signaling pathways. Similarly, Dishevelled (DVL) proteins serve as a point of divergence for β-catenin-dependent and -independent signaling pathways involving the family of Frizzled (FZD) ligands and cell-surface WNT receptors. We recently discovered the apparent regulated localization of dishevelled-2 (DVL2) and AGS3 to distinct cellular puncta, suggesting that the two proteins interact as part of various cell signaling systems. To address this hypothesis, we asked the following questions: (1) do AGS3 signaling pathways influence the activation of β-catenin (CTNNB1)-regulated transcription through the WNT-Frizzled-Dishevelled axis, and (2) is the AGS3 and DVL2 interaction regulated? The interaction of AGS3 and DVL2 was regulated by protein phosphorylation, subcellular distribution, and a cell-surface G-protein-coupled receptor. These data, and the commonality of functional system impacts observed for AGS3 and DVL2, suggest that the AGS3-DVL2 complex presents an unexpected path for functional integration within the cell.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Ali Vural
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Stephen M Lanier
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Viale B, Song L, Petrenko V, Wenger Combremont AL, Contestabile A, Bocchi R, Salmon P, Carleton A, An L, Vutskits L, Kiss JZ. Transient Deregulation of Canonical Wnt Signaling in Developing Pyramidal Neurons Leads to Dendritic Defects and Impaired Behavior. Cell Rep 2020; 27:1487-1502.e6. [PMID: 31042475 DOI: 10.1016/j.celrep.2019.04.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 02/28/2019] [Accepted: 04/03/2019] [Indexed: 12/30/2022] Open
Abstract
During development, the precise implementation of molecular programs is a key determinant of proper dendritic development. Here, we demonstrate that canonical Wnt signaling is active in dendritic bundle-forming layer II pyramidal neurons of the rat retrosplenial cortex during dendritic branching and spine formation. Transient downregulation of canonical Wnt transcriptional activity during the early postnatal period irreversibly reduces dendritic arbor architecture, leading to long-lasting deficits in spatial exploration and/or navigation and spatial memory in the adult. During the late phase of dendritogenesis, canonical Wnt-dependent transcription regulates spine formation and maturation. We identify neurotrophin-3 as canonical Wnt target gene in regulating dendritogenesis. Our findings demonstrate how temporary imbalance in canonical Wnt signaling during specific time windows can result in irreversible dendritic defects, leading to abnormal behavior in the adult.
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Affiliation(s)
- Beatrice Viale
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | - Lin Song
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland; School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Volodymyr Petrenko
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | | | - Alessandro Contestabile
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | - Riccardo Bocchi
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | - Patrick Salmon
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | - Alan Carleton
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland
| | - Lijia An
- School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China
| | - Laszlo Vutskits
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland; Department of Anesthesiology, Pharmacology and Intensive Care, University Hospitals of Geneva, 1211 Geneva 4, Switzerland
| | - Jozsef Zoltan Kiss
- Department of Basic Neurosciences, University of Geneva Medical School, 1211 Geneva 4, Switzerland.
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Advances in defining signaling networks for the establishment of neuronal polarity. Curr Opin Cell Biol 2020; 63:76-87. [DOI: 10.1016/j.ceb.2019.12.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/22/2019] [Accepted: 12/24/2019] [Indexed: 12/18/2022]
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Hunter GL, Giniger E. Phosphorylation and Proteolytic Cleavage of Notch in Canonical and Noncanonical Notch Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1227:51-68. [DOI: 10.1007/978-3-030-36422-9_4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Arredondo SB, Guerrero FG, Herrera-Soto A, Jensen-Flores J, Bustamante DB, Oñate-Ponce A, Henny P, Varas-Godoy M, Inestrosa NC, Varela-Nallar L. Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling. Stem Cells 2019; 38:422-436. [PMID: 31721364 DOI: 10.1002/stem.3121] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 10/08/2019] [Accepted: 10/22/2019] [Indexed: 12/20/2022]
Abstract
In the adult hippocampus, new neurons are generated in the dentate gyrus. The Wnt signaling pathway regulates this process, but little is known about the endogenous Wnt ligands involved. We investigated the role of Wnt5a on adult hippocampal neurogenesis. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus. Here, we determined that Wnt5a knockdown in the mouse dentate gyrus by lentivirus-mediated shRNA impaired neuronal differentiation of progenitor cells, and reduced dendritic development of adult-born neurons. In cultured adult hippocampal progenitors (AHPs), Wnt5a knockdown reduced neuronal differentiation and morphological development of AHP-derived neurons, whereas treatment with Wnt5a had the opposite effect. Interestingly, no changes in astrocytic differentiation were observed in vivo or in vitro, suggesting that Wnt5a does not affect fate-commitment. By using specific inhibitors, we determined that Wnt5a signals through CaMKII to induce neurogenesis, and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling. Our results indicate Wnt5a as a niche factor in the adult hippocampus that promotes neuronal differentiation and development through activation of noncanonical Wnt signaling pathways.
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Affiliation(s)
- Sebastian B Arredondo
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Fernanda G Guerrero
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Andrea Herrera-Soto
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Joaquin Jensen-Flores
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Daniel B Bustamante
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Alejandro Oñate-Ponce
- Laboratorio de Neuroanatomía, Departamento de Anatomía, Facultad de Medicina and Centro Interdisciplinario de Neurociencias, NeuroUC, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Pablo Henny
- Laboratorio de Neuroanatomía, Departamento de Anatomía, Facultad de Medicina and Centro Interdisciplinario de Neurociencias, NeuroUC, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Manuel Varas-Godoy
- Cancer Cell Biology Lab, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago, Chile.,Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile
| | - Lorena Varela-Nallar
- Institute of Biomedical Sciences, Faculty of Medicine and Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
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aPKC in neuronal differentiation, maturation and function. Neuronal Signal 2019; 3:NS20190019. [PMID: 32269838 PMCID: PMC7104321 DOI: 10.1042/ns20190019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 09/10/2019] [Accepted: 09/11/2019] [Indexed: 12/17/2022] Open
Abstract
The atypical Protein Kinase Cs (aPKCs)—PRKCI, PRKCZ and PKMζ—form a subfamily within the Protein Kinase C (PKC) family. These kinases are expressed in the nervous system, including during its development and in adulthood. One of the aPKCs, PKMζ, appears to be restricted to the nervous system. aPKCs are known to play a role in a variety of cellular responses such as proliferation, differentiation, polarity, migration, survival and key metabolic functions such as glucose uptake, that are critical for nervous system development and function. Therefore, these kinases have garnered a lot of interest in terms of their functional role in the nervous system. Here we review the expression and function of aPKCs in neural development and in neuronal maturation and function. Despite seemingly paradoxical findings with genetic deletion versus gene silencing approaches, we posit that aPKCs are likely candidates for regulating many important neurodevelopmental and neuronal functions, and may be associated with a number of human neuropsychiatric diseases.
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Hakanen J, Ruiz-Reig N, Tissir F. Linking Cell Polarity to Cortical Development and Malformations. Front Cell Neurosci 2019; 13:244. [PMID: 31213986 PMCID: PMC6558068 DOI: 10.3389/fncel.2019.00244] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 05/16/2019] [Indexed: 01/23/2023] Open
Abstract
Cell polarity refers to the asymmetric distribution of signaling molecules, cellular organelles, and cytoskeleton in a cell. Neural progenitors and neurons are highly polarized cells in which the cell membrane and cytoplasmic components are compartmentalized into distinct functional domains in response to internal and external cues that coordinate polarity and behavior during development and disease. In neural progenitor cells, polarity has a prominent impact on cell shape and coordinate several processes such as adhesion, division, and fate determination. Polarity also accompanies a neuron from the beginning until the end of its life. It is essential for development and later functionality of neuronal circuitries. During development, polarity governs transitions between multipolar and bipolar during migration of postmitotic neurons, and directs the specification and directional growth of axons. Once reaching final positions in cortical layers, neurons form dendrites which become compartmentalized to ensure proper establishment of neuronal connections and signaling. Changes in neuronal polarity induce signaling cascades that regulate cytoskeletal changes, as well as mRNA, protein, and vesicle trafficking, required for synapses to form and function. Hence, defects in establishing and maintaining cell polarity are associated with several neural disorders such as microcephaly, lissencephaly, schizophrenia, autism, and epilepsy. In this review we summarize the role of polarity genes in cortical development and emphasize the relationship between polarity dysfunctions and cortical malformations.
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Affiliation(s)
- Janne Hakanen
- Université catholique de Louvain, Institute of Neuroscience, Developmental Neurobiology, Brussels, Belgium
| | - Nuria Ruiz-Reig
- Université catholique de Louvain, Institute of Neuroscience, Developmental Neurobiology, Brussels, Belgium
| | - Fadel Tissir
- Université catholique de Louvain, Institute of Neuroscience, Developmental Neurobiology, Brussels, Belgium
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Takano T, Funahashi Y, Kaibuchi K. Neuronal Polarity: Positive and Negative Feedback Signals. Front Cell Dev Biol 2019; 7:69. [PMID: 31069225 PMCID: PMC6491837 DOI: 10.3389/fcell.2019.00069] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/09/2019] [Indexed: 12/21/2022] Open
Abstract
Establishment and maintenance of neuronal polarity are critical for neuronal development and function. One of the fundamental questions in neurodevelopment is how neurons generate only one axon and several dendrites from multiple minor neurites. Over the past few decades, molecular and cell biological approaches have unveiled a large number of signaling networks regulating neuronal polarity in cultured hippocampal neurons and the developing cortex. Emerging evidence reveals that positive and negative feedback signals play a crucial role in axon and dendrite specification. Positive feedback signals are continuously activated in one of minor neurites and result in axon specification and elongation, whereas negative feedback signals are propagated from a nascent axon terminal to all minor neurites and inhibit the formation of multiple axon, thereby leading to dendrite specification, and maintaining neuronal polarity. This current insight provides a holistic picture of the signaling mechanisms underlying neuronal polarization during neuronal development. Here, our review highlights recent advancements in this fascinating field, with a focus on the positive, and negative feedback signals as key regulatory mechanisms underlying neuronal polarization.
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Affiliation(s)
- Tetsuya Takano
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,Department of Cell Biology, Duke University Medical School, Durham, NC, United States
| | - Yasuhiro Funahashi
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kozo Kaibuchi
- Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Courchesne E, Pramparo T, Gazestani VH, Lombardo MV, Pierce K, Lewis NE. The ASD Living Biology: from cell proliferation to clinical phenotype. Mol Psychiatry 2019; 24:88-107. [PMID: 29934544 PMCID: PMC6309606 DOI: 10.1038/s41380-018-0056-y] [Citation(s) in RCA: 152] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 02/08/2018] [Accepted: 02/19/2018] [Indexed: 12/17/2022]
Abstract
Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child's development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD.
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Affiliation(s)
- Eric Courchesne
- Autism Center of Excellence, Department of Neuroscience, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA, 92037, USA.
| | - Tiziano Pramparo
- Autism Center of Excellence, Department of Neuroscience, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA, 92037, USA
| | - Vahid H Gazestani
- Autism Center of Excellence, Department of Neuroscience, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA, 92037, USA
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
| | - Michael V Lombardo
- Department of Psychology, Center for Applied Neuroscience, University of Cyprus, Nicosia, Cyprus
- Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, UK
| | - Karen Pierce
- Autism Center of Excellence, Department of Neuroscience, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA, 92037, USA
| | - Nathan E Lewis
- Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
- Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
- Novo Nordisk Foundation Center for Biosustainability at University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA
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He CW, Liao CP, Pan CL. Wnt signalling in the development of axon, dendrites and synapses. Open Biol 2018; 8:rsob.180116. [PMID: 30282660 PMCID: PMC6223216 DOI: 10.1098/rsob.180116] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 09/07/2018] [Indexed: 12/12/2022] Open
Abstract
Wnts are a highly conserved family of secreted glycoproteins that play essential roles in the morphogenesis and body patterning during the development of metazoan species. In recent years, mounting evidence has revealed important functions of Wnt signalling in diverse aspects of neural development, including neuronal polarization, guidance and branching of the axon and dendrites, as well as synapse formation and its structural remodelling. In contrast to Wnt signalling in cell proliferation and differentiation, which mostly acts through β-catenin-dependent pathways, Wnts engage a diverse array of non-transcriptional cascades in neuronal development, such as the planar cell polarity, cytoskeletal or calcium signalling pathways. In this review, we summarize recent advances in the mechanisms of Wnt signalling in the development of axon, dendrite and synapse formation.
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Affiliation(s)
- Chun-Wei He
- Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan, Republic of China
| | - Chien-Po Liao
- Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan, Republic of China
| | - Chun-Liang Pan
- Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei 10002, Taiwan, Republic of China
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40
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NMDA receptors inhibit axonal outgrowth by inactivating Akt and activating GSK-3β via calcineurin in cultured immature hippocampal neurons. Exp Cell Res 2018; 371:389-398. [PMID: 30176218 DOI: 10.1016/j.yexcr.2018.08.033] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 07/10/2018] [Accepted: 08/30/2018] [Indexed: 12/16/2022]
Abstract
Neurons are highly polarized cells with an axon and dendritic arbors. It is still not well studied that how formation and elaboration of axon and dendrites is controlled by diffusible signaling factors such as glutamate via specific receptors. We found that N-methyl-D-aspartate (NMDA) receptors were enriched (stage 2-3) but decreased expression (stage 4-5) at tip of axon of cultured hippocampal neurons during distinct development stages. Inhibition of NMDA receptor activity by competitive antagonist DL-2-amino-5-phosphonovalerate (APV) or channel blocker MK801 promoted axonal outgrowth at the early stages, whereas inhibited dendritic development in later stages. Meanwhile, knockdown of NMDA receptors also promoted axonal outgrowth and branch in immature neurons. Furthermore, GluN2B but not GluN2A subunit inhibited axonal outgrowth in immature hippocampal neurons. Finally, we found that NMDA receptors inhibited axonal outgrowth by inactivating Akt and activating GSK-3β signaling in a calcineurin-dependent manner. Taken together, our results demonstrate that stabilization GSK-3β activation in the axon growth cone by Ca2+ influx through NMDA receptors may be involved in regulation of axon formation in immature neurons at early stages.
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Shen C, Li L, Zhao K, Bai L, Wang A, Shu X, Xiao Y, Zhang J, Zhang K, Hui T, Chen W, Zhang B, Hsu W, Xiong WC, Mei L. Motoneuron Wnts regulate neuromuscular junction development. eLife 2018; 7:e34625. [PMID: 30113308 PMCID: PMC6128691 DOI: 10.7554/elife.34625] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 08/09/2018] [Indexed: 12/14/2022] Open
Abstract
The neuromuscular junction (NMJ) is a synapse between motoneurons and skeletal muscles to control motor behavior. Unlike extensively investigated postsynaptic differentiation, less is known about mechanisms of presynaptic assembly. Genetic evidence of Wnt in mammalian NMJ development was missing due to the existence of multiple Wnts and their receptors. We show when Wnt secretion is abolished from motoneurons by mutating the Wnt ligand secretion mediator (Wls) gene, mutant mice showed muscle weakness and neurotransmission impairment. NMJs were unstable with reduced synaptic junctional folds and fragmented AChR clusters. Nerve terminals were swollen; synaptic vesicles were fewer and mislocated. The presynaptic deficits occurred earlier than postsynaptic deficits. Intriguingly, these phenotypes were not observed when deleting Wls in muscles or Schwann cells. We identified Wnt7A and Wnt7B as major Wnts for nerve terminal development in rescue experiments. These observations demonstrate a necessary role of motoneuron Wnts in NMJ development, in particular presynaptic differentiation.
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Affiliation(s)
- Chengyong Shen
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Lei Li
- Department of NeurosciencesSchool of Medicine, Case Western Reserve UniversityCleveland, OhioUnited States
| | - Kai Zhao
- Department of Neuroscience and Regenerative Medicine, Medical College of GeorgiaAugusta UniversityAugusta, GeorgiaUnited States
| | - Lei Bai
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Ailian Wang
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Xiaoqiu Shu
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Yatao Xiao
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Jianmin Zhang
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Kejing Zhang
- Department of Neurology, the First Affiliated Hospital, Institute of Translational Medicine, School of MedicineZhejiang UniversityZhejiangChina
| | - Tiankun Hui
- Institute of Life ScienceNanchang UniversityNanchang, JiangxiChina
| | - Wenbing Chen
- Department of NeurosciencesSchool of Medicine, Case Western Reserve UniversityCleveland, OhioUnited States
- Institute of Life ScienceNanchang UniversityNanchang, JiangxiChina
| | - Bin Zhang
- Department of Physiology, School of Basic MedicineInstitute of Brain Research, Huazhong University of Science and TechnologyWuhan, HubeiChina
| | - Wei Hsu
- Department of Biomedical Genetics, Center for Oral Biology, James Wilmot Cancer CenterUniversity of Rochester Medical CenterRochester, New YorkUnited States
| | - Wen-Cheng Xiong
- Department of NeurosciencesSchool of Medicine, Case Western Reserve UniversityCleveland, OhioUnited States
- Louis Stokes Cleveland Veterans Affairs Medical CenterCleveland, OhioUnited States
| | - Lin Mei
- Department of NeurosciencesSchool of Medicine, Case Western Reserve UniversityCleveland, OhioUnited States
- Louis Stokes Cleveland Veterans Affairs Medical CenterCleveland, OhioUnited States
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Hapak SM, Rothlin CV, Ghosh S. PAR3-PAR6-atypical PKC polarity complex proteins in neuronal polarization. Cell Mol Life Sci 2018; 75:2735-2761. [PMID: 29696344 PMCID: PMC11105418 DOI: 10.1007/s00018-018-2828-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 04/03/2018] [Accepted: 04/23/2018] [Indexed: 01/01/2023]
Abstract
Polarity is a fundamental feature of cells. Protein complexes, including the PAR3-PAR6-aPKC complex, have conserved roles in establishing polarity across a number of eukaryotic cell types. In neurons, polarity is evident as distinct axonal versus dendritic domains. The PAR3, PAR6, and aPKC proteins also play important roles in neuronal polarization. During this process, either aPKC kinase activity, the assembly of the PAR3-PAR6-aPKC complex or the localization of these proteins is regulated downstream of a number of signaling pathways. In turn, the PAR3, PAR6, and aPKC proteins control various effector molecules to establish neuronal polarity. Herein, we discuss the many signaling mechanisms and effector functions that have been linked to PAR3, PAR6, and aPKC during the establishment of neuronal polarity.
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Affiliation(s)
- Sophie M Hapak
- Department of Medicine, School of Medicine, University of Minnesota, 401 East River Parkway, Minneapolis, MN, 55455, USA.
| | - Carla V Rothlin
- Department of Immunobiology, School of Medicine, Yale University, 300 Cedar Street, New Haven, CT, 06520, USA
- Department of Pharmacology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
| | - Sourav Ghosh
- Department of Neurology, School of Medicine, Yale University, 300 George Street, New Haven, CT, 06511, USA
- Department of Pharmacology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT, 06520, USA
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Park SY, Kang MJ, Han JS. Interleukin-1 beta promotes neuronal differentiation through the Wnt5a/RhoA/JNK pathway in cortical neural precursor cells. Mol Brain 2018; 11:39. [PMID: 29973222 PMCID: PMC6033214 DOI: 10.1186/s13041-018-0383-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023] Open
Abstract
Pro-inflammatory cytokine interleukin-1 beta (IL-1β) is a key mediator of inflammation and stress in the central nervous system (CNS), and is highly expressed in the developing brain. In this study, we investigated the possible role of IL-1β in neuronal differentiation of cortical neural precursor cells (NPCs). We showed that stimulation with IL-1β increased expression levels of neurotrophin-3 (NT3) and neurogenin 1 (Ngn1) and promoted neurite outgrowth. We also found that IL-1β increased mRNA and protein levels of Wnt5a. Knockdown of Wnt5a by transfection with Wnt5a siRNA inhibited IL-1β-induced neuronal differentiation. Moreover, IL-1β-induced Wnt5a expression was regulated by nuclear factor kappa B (NF-κB) activation, which is involved in IL-1β-mediated neuronal differentiation. To examine the role of Wnt5a in neuronal differentiation of NPCs, we exogenously added Wnt5a. We found that exogenous Wnt5a promotes neuronal differentiation, and activates the RhoA/Rho-associated kinase (ROCK)/c-jun N-terminal kinase (JNK) pathway. In addition, Wnt5a-induced neuronal differentiation was blocked by RhoA siRNA, as well as by a specific Rho-kinase inhibitor (Y27632) or a SAPK/JNK inhibitor (SP600125). Furthermore, treatment with RhoA siRNA, Y27632, or SP600125 suppressed the IL-1β-induced neuronal differentiation. Therefore, these results suggest that the sequential Wnt5a/RhoA/ROCK/JNK pathway is involved in IL-1β-induced neuronal differentiation of NPCs.
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Affiliation(s)
- Shin-Young Park
- Biomedical Research Institute and Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
| | - Min-Jeong Kang
- Biomedical Research Institute and Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea
| | - Joong-Soo Han
- Biomedical Research Institute and Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
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Planar cell polarity signalling coordinates heart tube remodelling through tissue-scale polarisation of actomyosin activity. Nat Commun 2018; 9:2161. [PMID: 29867082 PMCID: PMC5986786 DOI: 10.1038/s41467-018-04566-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 04/27/2018] [Indexed: 11/13/2022] Open
Abstract
Development of a multiple-chambered heart from the linear heart tube is inherently linked to cardiac looping. Although many molecular factors regulating the process of cardiac chamber ballooning have been identified, the cellular mechanisms underlying the chamber formation remain unclear. Here, we demonstrate that cardiac chambers remodel by cell neighbour exchange of cardiomyocytes guided by the planar cell polarity (PCP) pathway triggered by two non-canonical Wnt ligands, Wnt5b and Wnt11. We find that PCP signalling coordinates the localisation of actomyosin activity, and thus the efficiency of cell neighbour exchange. On a tissue-scale, PCP signalling planar-polarises tissue tension by restricting the actomyosin contractility to the apical membranes of outflow tract cells. The tissue-scale polarisation of actomyosin contractility is required for cardiac looping that occurs concurrently with chamber ballooning. Taken together, our data reveal that instructive PCP signals couple cardiac chamber expansion with cardiac looping through the organ-scale polarisation of actomyosin-based tissue tension. The molecular mechanisms underlying cardiac chamber formation are not well understood. Here, the authors show that planar cell polarity signalling through Wnt5b and Wnt11 coordinates localised and tissue-scale polarised actomyosin contractility in the zebrafish heart, regulating cardiac chamber formation and looping.
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Sharma M, Castro-Piedras I, Simmons GE, Pruitt K. Dishevelled: A masterful conductor of complex Wnt signals. Cell Signal 2018; 47:52-64. [PMID: 29559363 DOI: 10.1016/j.cellsig.2018.03.004] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 03/14/2018] [Accepted: 03/14/2018] [Indexed: 12/21/2022]
Abstract
The Dishevelled gene was first identified in Drosophila mutants with disoriented hair and bristle polarity [1-3]. The Dsh gene (Dsh/Dvl, in Drosophila and vertebrates respectively) gained popularity when it was discovered that it plays a key role in segment polarity during early embryonic development in Drosophila [4]. Subsequently, the vertebrate homolog of Dishevelled genes were identified in Xenopus (Xdsh), mice (Dvl1, Dvl2, Dvl3), and in humans (DVL1, DVL2, DVL3) [5-10]. Dishevelled functions as a principal component of Wnt signaling pathway and governs several cellular processes including cell proliferation, survival, migration, differentiation, polarity and stem cell renewal. This review will revisit seminal discoveries and also summarize recent advances in characterizing the role of Dishevelled in both normal and pathophysiological settings.
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Affiliation(s)
- Monica Sharma
- Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Isabel Castro-Piedras
- Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Glenn E Simmons
- Department of Biomedical Sciences, University of Minnesota, School of Medicine, Duluth, MN, USA
| | - Kevin Pruitt
- Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, TX, USA.
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Abstract
Background The placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life. Study design Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated. Results Spontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age. Conclusion A hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).
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Vangl2 regulates spermatid planar cell polarity through microtubule (MT)-based cytoskeleton in the rat testis. Cell Death Dis 2018; 9:340. [PMID: 29497043 PMCID: PMC5832773 DOI: 10.1038/s41419-018-0339-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 01/15/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
During spermatogenesis, developing elongating/elongated spermatids are highly polarized cells, displaying unique apico-basal polarity. For instance, the heads of spermatids align perpendicular to the basement membrane with their tails pointing to the tubule lumen. Thus, the maximal number of spermatids are packed within the limited space of the seminiferous epithelium to support spermatogenesis. Herein, we reported findings that elongating/elongated spermatids displayed planar cell polarity (PCP) in adult rat testes in which the proximal end of polarized spermatid heads were aligned uniformly across the plane of the seminiferous epithelium based on studies using confocal microscopy and 3-dimensional (D) reconstruction of the seminiferous tubules. We also discovered that spermatid PCP was regulated by PCP protein Vangl2 (Van Gogh-like protein 2) since Vangl2 knockdown by RNAi was found to perturb spermatid PCP. More important, Vangl2 exerted its regulatory effects through changes in the organization of the microtubule (MT)-based cytoskeleton in the seminiferous epithelium. These changes were mediated via the downstream signaling proteins atypical protein kinase C ξ (PKCζ) and MT-associated protein (MAP)/microtubule affinity-regulating kinase 2 (MARK2). These findings thus provide new insights regarding the biology of spermatid PCP during spermiogenesis.
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Chen H, Mruk DD, Lui WY, Wong CKC, Lee WM, Cheng CY. Cell polarity and planar cell polarity (PCP) in spermatogenesis. Semin Cell Dev Biol 2017; 81:71-77. [PMID: 28923514 DOI: 10.1016/j.semcdb.2017.09.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 09/04/2017] [Accepted: 09/06/2017] [Indexed: 12/22/2022]
Abstract
In adult mammalian testes, spermatids, most notably step 17-19 spermatids in stage IV-VIII tubules, are aligned with their heads pointing toward the basement membrane and their tails toward the tubule lumen. On the other hand, these polarized spermatids also align across the plane of seminiferous epithelium, mimicking planar cell polarity (PCP) found in other hair cells in cochlea (inner ear). This orderly alignment of developing spermatids during spermiogenesis is important to support spermatogenesis, such that the maximal number of developing spermatids can be packed and supported by a fixed population of differentiated Sertoli cells in the limited space of the seminiferous epithelium in adult testes. In this review, we provide emerging evidence to demonstrate spermatid PCP in the seminiferous epithelium to support spermatogenesis. We also review findings in the field regarding the biology of spermatid cellular polarity (e.g., head-tail polarity and apico-basal polarity) and its inter-relationship to spermatid PCP. Furthermore, we also provide a hypothetical concept on the importance of PCP proteins in endocytic vesicle-mediated protein trafficking events to support spermatogenesis through protein endocytosis and recycling.
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Affiliation(s)
- Haiqi Chen
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, United States
| | - Dolores D Mruk
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, United States
| | - Wing-Yee Lui
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chris K C Wong
- Department of Biology, Hong Kong Baptist University, Kowloon, Hong Kong, China
| | - Will M Lee
- School of Biological Sciences, University of Hong Kong, Pokfulam, Hong Kong, China
| | - C Yan Cheng
- The Mary M. Wohlford Laboratory for Male Contraceptive Research, Center for Biomedical Research, Population Council, 1230 York Ave, New York, NY 10065, United States.
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Ahrari S, Mogharrab N, Navapour L. Interconversion of inactive to active conformation of MARK2: Insights from molecular modeling and molecular dynamics simulation. Arch Biochem Biophys 2017; 630:66-80. [PMID: 28711359 DOI: 10.1016/j.abb.2017.07.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 07/09/2017] [Accepted: 07/10/2017] [Indexed: 12/18/2022]
Abstract
The Ser/Thr protein kinase MARK2, also known as Par1b, belongs to the highly-conserved family of PAR proteins which regulate cell polarity and partitioning through the animal kingdom. In the current study, inactive and active structures of human MARK2 were constructed by modeling and molecular dynamics simulation, based on available incomplete crystal structures in Protein Data Bank, to investigate local structural changes through which MARK2 switches from inactive to active state. None of the MARK2 wild type inactive crystal structures represent the position of activation segment. So, the contribution of this loop to the formation of inactive state is not clear. In the modeled structure of inactive MARK2, activation segment occludes the enzyme active site and assumes a relatively stable position. We also presented a detailed description of the major structural changes occur through the activation process and proposed a framework on how these deviations might be affected by the phosphorylation of Thr208 or existence of the UBA domain. Inspection of protein active state in the presence of Mg-ATP, demonstrated the precise arrangement of the various parts of enzyme around Mg-ATP and the importance of their stability in localization of the resulting complex. The results also confirmed the alleged mild auto-inhibitory role of the UBA domain and suggested a reason for the necessity of this role, based on structural similarities to other related kinases.
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Affiliation(s)
- Sajjad Ahrari
- Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
| | - Navid Mogharrab
- Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran.
| | - Leila Navapour
- Biophysics and Computational Biology Laboratory (BCBL), Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran
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Banerjee JJ, Aerne BL, Holder MV, Hauri S, Gstaiger M, Tapon N. Meru couples planar cell polarity with apical-basal polarity during asymmetric cell division. eLife 2017; 6:e25014. [PMID: 28665270 PMCID: PMC5493435 DOI: 10.7554/elife.25014] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 06/14/2017] [Indexed: 12/15/2022] Open
Abstract
Polarity is a shared feature of most cells. In epithelia, apical-basal polarity often coexists, and sometimes intersects with planar cell polarity (PCP), which orients cells in the epithelial plane. From a limited set of core building blocks (e.g. the Par complexes for apical-basal polarity and the Frizzled/Dishevelled complex for PCP), a diverse array of polarized cells and tissues are generated. This suggests the existence of little-studied tissue-specific factors that rewire the core polarity modules to the appropriate conformation. In Drosophila sensory organ precursors (SOPs), the core PCP components initiate the planar polarization of apical-basal determinants, ensuring asymmetric division into daughter cells of different fates. We show that Meru, a RASSF9/RASSF10 homologue, is expressed specifically in SOPs, recruited to the posterior cortex by Frizzled/Dishevelled, and in turn polarizes the apical-basal polarity factor Bazooka (Par3). Thus, Meru belongs to a class of proteins that act cell/tissue-specifically to remodel the core polarity machinery.
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Affiliation(s)
- Jennifer J Banerjee
- Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Birgit L Aerne
- Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Maxine V Holder
- Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Simon Hauri
- Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland
- Competence Center Personalized Medicine UZH/ETH, Zürich, Switzerland
| | - Matthias Gstaiger
- Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland
- Competence Center Personalized Medicine UZH/ETH, Zürich, Switzerland
| | - Nicolas Tapon
- Apoptosis and Proliferation Control Laboratory, The Francis Crick Institute, London, United Kingdom
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