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1
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Chen Y, Li H, Wang J, Yang S, Su Z, Wang W, Rao C, Hou L. The Ednrb-Aim2-AKT axis regulates neural crest-derived melanoblast proliferation during early development. Development 2024; 151:dev202444. [PMID: 39555938 DOI: 10.1242/dev.202444] [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: 10/26/2023] [Accepted: 10/17/2024] [Indexed: 11/19/2024]
Abstract
Ednrb is specifically required to develop neural crest (NC) stem cell-derived lineages. However, it is still unknown why Ednrb signaling is only needed for the early development of melanoblasts in the skin and eye. We show that Ednrb is required for the proliferation of melanoblasts during early mouse development. To understand the mechanism of melanoblast proliferation, we found that the gene absent in melanoma 2 (Aim2) is upregulated in Ednrb-deficient NC cells by RNA-sequencing analysis. Consequently, the knockdown or knockout of Aim2 partially rescued the proliferation of Ednrb-deficient melanoblasts. Conversely, the overexpression of Aim2 in melanoblasts suppressed their proliferation. We further show that Ednrb signaling could act through the microRNA miR-196b to block the suppression of melanoblast proliferation by Aim2 in primary NC cell cultures. These results reveal the Ednrb-Aim2-AKT axis in regulating melanocyte development and suggest that Ednrb signaling functions as a negative regulator of Aim2, which inhibits the proliferation of melanoblasts in early development. These findings uncover a previously unreported role for Aim2 outside the inflammasome, showing that it is a significant regulator controlling NC stem cell-derived lineage development.
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Affiliation(s)
- Yu Chen
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Huirong Li
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Jing Wang
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Shanshan Yang
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Zhongyuan Su
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Wanxiao Wang
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Chunbao Rao
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
| | - Ling Hou
- Laboratory of Developmental Cell Biology and Disease, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China
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Zhou B, Feng C, Sun S, Chen X, Zhuansun D, Wang D, Yu X, Meng X, Xiao J, Wu L, Wang J, Wang J, Chen K, Li Z, You J, Mao H, Yang S, Zhang J, Jiao C, Li Z, Yu D, Wu X, Zhu T, Yang J, Xiang L, Liu J, Chai T, Shen J, Mao CX, Hu J, Hao X, Xiong B, Zheng S, Liu Z, Feng J. Identification of signaling pathways that specify a subset of migrating enteric neural crest cells at the wavefront in mouse embryos. Dev Cell 2024; 59:1689-1706.e8. [PMID: 38636517 DOI: 10.1016/j.devcel.2024.03.034] [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: 07/25/2023] [Revised: 01/17/2024] [Accepted: 03/25/2024] [Indexed: 04/20/2024]
Abstract
During enteric nervous system (ENS) development, pioneering wavefront enteric neural crest cells (ENCCs) initiate gut colonization. However, the molecular mechanisms guiding their specification and niche interaction are not fully understood. We used single-cell RNA sequencing and spatial transcriptomics to map the spatiotemporal dynamics and molecular landscape of wavefront ENCCs in mouse embryos. Our analysis shows a progressive decline in wavefront ENCC potency during migration and identifies transcription factors governing their specification and differentiation. We further delineate key signaling pathways (ephrin-Eph, Wnt-Frizzled, and Sema3a-Nrp1) utilized by wavefront ENCCs to interact with their surrounding cells. Disruptions in these pathways are observed in human Hirschsprung's disease gut tissue, linking them to ENS malformations. Additionally, we observed region-specific and cell-type-specific transcriptional changes in surrounding gut tissues upon wavefront ENCC arrival, suggesting their role in shaping the gut microenvironment. This work offers a roadmap of ENS development, with implications for understanding ENS disorders.
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Affiliation(s)
- Bingyan Zhou
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Chenzhao Feng
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Song Sun
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Ministry of Health, Shanghai 201102, China
| | - Xuyong Chen
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Didi Zhuansun
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Di Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Xiaosi Yu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Xinyao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jun Xiao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Luyao Wu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jing Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jing Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Ke Chen
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Zejian Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jingyi You
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Handan Mao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Shimin Yang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jiaxin Zhang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Chunlei Jiao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Zhi Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Donghai Yu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Xiaojuan Wu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Tianqi Zhu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jixin Yang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Lei Xiang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China
| | - Jiazhe Liu
- BGI-Shenzhen, Shenzhen, Guangdong 518081, China
| | | | - Juan Shen
- BGI-Shenzhen, Shenzhen, Guangdong 518081, China
| | - Chuan-Xi Mao
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Juncheng Hu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, China
| | - Xingjie Hao
- Department of Epidemiology and Biostatistics, Key Laboratory for Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Bo Xiong
- Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Institute for Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Shan Zheng
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Children's Hospital of Fudan University, Ministry of Health, Shanghai 201102, China
| | - Zhihua Liu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei, China.
| | - Jiexiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, Hubei 430030, China.
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Dershowitz LB, Kaltschmidt JA. Enteric Nervous System Striped Patterning and Disease: Unexplored Pathophysiology. Cell Mol Gastroenterol Hepatol 2024; 18:101332. [PMID: 38479486 PMCID: PMC11176954 DOI: 10.1016/j.jcmgh.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/08/2024] [Accepted: 03/08/2024] [Indexed: 04/04/2024]
Abstract
The enteric nervous system (ENS) controls gastrointestinal (GI) motility, and defects in ENS development underlie pediatric GI motility disorders. In disorders such as Hirschsprung's disease (HSCR), pediatric intestinal pseudo-obstruction (PIPO), and intestinal neuronal dysplasia type B (INDB), ENS structure is altered with noted decreased neuronal density in HSCR and reports of increased neuronal density in PIPO and INDB. The developmental origin of these structural deficits is not fully understood. Here, we review the current understanding of ENS development and pediatric GI motility disorders incorporating new data on ENS structure. In particular, emerging evidence demonstrates that enteric neurons are patterned into circumferential stripes along the longitudinal axis of the intestine during mouse and human development. This novel understanding of ENS structure proposes new questions about the pathophysiology of pediatric GI motility disorders. If the ENS is organized into stripes, could the observed changes in enteric neuron density in HSCR, PIPO, and INDB represent differences in the distribution of enteric neuronal stripes? We review mechanisms of striped patterning from other biological systems and propose how defects in striped ENS patterning could explain structural deficits observed in pediatric GI motility disorders.
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Affiliation(s)
- Lori B Dershowitz
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California
| | - Julia A Kaltschmidt
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California.
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Shi CJ, Lian JJ, Zhang BW, Cha JX, Hua QH, Pi XP, Hou YJ, Xie X, Zhang R. TGFβR-1/ALK5 inhibitor RepSox induces enteric glia-to-neuron transition and influences gastrointestinal mobility in adult mice. Acta Pharmacol Sin 2023; 44:92-104. [PMID: 35794374 DOI: 10.1038/s41401-022-00932-4] [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: 01/05/2022] [Accepted: 05/30/2022] [Indexed: 01/18/2023] Open
Abstract
Promoting adult neurogenesis in the enteric nervous system (ENS) may be a potential therapeutic approach to cure enteric neuropathies. Enteric glial cells (EGCs) are the most abundant glial cells in the ENS. Accumulating evidence suggests that EGCs can be a complementary source to supply new neurons during adult neurogenesis in the ENS. In the brain, astrocytes have been intensively studied for their neuronal conversion properties, and small molecules have been successfully used to induce the astrocyte-to-neuron transition. However, research on glia-to-neuron conversion in the ENS is still lacking. In this study, we used GFAP-Cre:Rosa-tdTomato mice to trace glia-to-neuron transdifferentiation in the ENS in vivo and in vitro. We showed that GFAP promoter-driven tdTomato exclusively labelled EGCs and was a suitable marker to trace EGCs and their progeny cells in the ENS of adult mice. Interestingly, we discovered that RepSox or other ALK5 inhibitors alone induced efficient transdifferentiation of EGCs into neurons in vitro. Knockdown of ALK5 further confirmed that the TGFβR-1/ALK5 signalling pathway played an essential role in the transition of EGCs to neurons. RepSox-induced neurons were Calbindin- and nNOS-positive and displayed typical neuronal electrophysiological properties. Finally, we showed that administration of RepSox (3, 10 mg· kg-1 ·d-1, i.g.) for 2 weeks significantly promoted the conversion of EGCs to neurons in the ENS and influenced gastrointestinal motility in adult mice. This study provides a method for efficiently converting adult mouse EGCs into neurons by small-molecule compounds, which might be a promising therapeutic strategy for gastrointestinal neuropathy.
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Affiliation(s)
- Chang-Jie Shi
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jun-Jiang Lian
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Bo-Wen Zhang
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Jia-Xue Cha
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Qiu-Hong Hua
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xiao-Ping Pi
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yu-Jun Hou
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Xin Xie
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Ru Zhang
- Shanghai Key Laboratory of Signaling and Disease Research, Laboratory of Receptor-based Bio-medicine, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.
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Comparative role of SOX10 gene in the gliogenesis of central, peripheral, and enteric nervous systems. Differentiation 2022; 128:13-25. [DOI: 10.1016/j.diff.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 09/10/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022]
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6
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Boesmans W, Nash A, Tasnády KR, Yang W, Stamp LA, Hao MM. Development, Diversity, and Neurogenic Capacity of Enteric Glia. Front Cell Dev Biol 2022; 9:775102. [PMID: 35111752 PMCID: PMC8801887 DOI: 10.3389/fcell.2021.775102] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 12/09/2021] [Indexed: 12/15/2022] Open
Abstract
Enteric glia are a fascinating population of cells. Initially identified in the gut wall as the "support" cells of the enteric nervous system, studies over the past 20 years have unveiled a vast array of functions carried out by enteric glia. They mediate enteric nervous system signalling and play a vital role in the local regulation of gut functions. Enteric glial cells interact with other gastrointestinal cell types such as those of the epithelium and immune system to preserve homeostasis, and are perceptive to luminal content. Their functional versatility and phenotypic heterogeneity are mirrored by an extensive level of plasticity, illustrated by their reactivity in conditions associated with enteric nervous system dysfunction and disease. As one of the hallmarks of their plasticity and extending their operative relationship with enteric neurons, enteric glia also display neurogenic potential. In this review, we focus on the development of enteric glial cells, and the mechanisms behind their heterogeneity in the adult gut. In addition, we discuss what is currently known about the role of enteric glia as neural precursors in the enteric nervous system.
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Affiliation(s)
- Werend Boesmans
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Amelia Nash
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Kinga R. Tasnády
- Biomedical Research Institute (BIOMED), Hasselt University, Hasselt, Belgium
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, Netherlands
| | - Wendy Yang
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan, Taiwan
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Melbourne, VIC, Australia
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Diposarosa R, Bustam N, Sahiratmadja E, Susanto P, Sribudiani Y. Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease. Heliyon 2021; 7:e07308. [PMID: 34195419 PMCID: PMC8237298 DOI: 10.1016/j.heliyon.2021.e07308] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/16/2021] [Accepted: 06/10/2021] [Indexed: 01/13/2023] Open
Abstract
Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) derived from neural crest cells (NCCs), which affects their migration, proliferation, differentiation, or preservation in the digestive tract, resulting in aganglionosis in the distal intestine. The regulation of both NCCs and the surrounding environment involves various genes, signaling pathways, transcription factors, and morphogens. Therefore, changes in gene expression during the development of the ENS may contribute to the pathogenesis of HSCR. This review discusses several mechanisms involved in the development of ENS, confirming that deviant genetic and epigenetic patterns, such as DNA methylation, histone modification, and microRNA (miRNA) regulation, can contribute to the development of neurocristopathy. Specifically, the epigenetic regulation of miRNA expression and its relationship to cellular interactions and gene activation through various major pathways in Hirschsprung's disease will be discussed.
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Affiliation(s)
- R. Diposarosa
- Department of Surgery, Division of Pediatric Surgery, Dr. Hasan Sadikin General Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - N.A. Bustam
- Department of Surgery, Division of Pediatric Surgery, Dr. Hasan Sadikin General Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Edhyana Sahiratmadja
- Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - P.S. Susanto
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Y. Sribudiani
- Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
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Kang YN, Fung C, Vanden Berghe P. Gut innervation and enteric nervous system development: a spatial, temporal and molecular tour de force. Development 2021; 148:148/3/dev182543. [PMID: 33558316 DOI: 10.1242/dev.182543] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
During embryonic development, the gut is innervated by intrinsic (enteric) and extrinsic nerves. Focusing on mammalian ENS development, in this Review we highlight how important the different compartments of this innervation are to assure proper gut function. We specifically address the three-dimensional architecture of the innervation, paying special attention to the differences in development along the longitudinal and circumferential axes of the gut. We review recent information about the formation of both intrinsic innervation, which is fairly well-known, as well as the establishment of the extrinsic innervation, which, despite its importance in gut-brain signaling, has received much less attention. We further discuss how external microbial and nutritional cues or neuroimmune interactions may influence development of gut innervation. Finally, we provide summary tables, describing the location and function of several well-known molecules, along with some newer factors that have more recently been implicated in the development of gut innervation.
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Affiliation(s)
- Yi-Ning Kang
- Laboratory for Enteric NeuroScience (LENS), Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven 3000, Belgium
| | - Candice Fung
- Laboratory for Enteric NeuroScience (LENS), Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven 3000, Belgium
| | - Pieter Vanden Berghe
- Laboratory for Enteric NeuroScience (LENS), Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven 3000, Belgium
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Bourcier L, Crapoulet N, Ouellette RJ, Mallet M, Ben Amor M. Phenotypic spectrum associated with pathogenic mutation in the NRG1 gene in Acadian family. Am J Med Genet A 2021; 185:1211-1215. [PMID: 33421311 DOI: 10.1002/ajmg.a.62069] [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: 06/19/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 11/06/2022]
Abstract
NRG1 is a gene that encodes for a protein that binds to a receptor of the tyrosine kinase family which is essential for the survival of the central nervous system development during embryogenesis. Mutation of the NRG1 gene causes aganglionosis, which leads to Hirschsprung disease. Two brothers of Acadian descent presented with a history of Hirschsprung disease, in association with other anomalies including congenital heart disease, learning difficulties, developmental issues, and hypopigmented hair patch. Molecular analysis in both siblings revealed a heterozygous pathogenic mutation in the NGR1 gene (c.235C>T [p.Arg79*]), that was inherited from an unaffected father. This family expands our knowledge about the phenotypic spectrum associated with pathogenic mutation in the NRG1 gene with intrafamilial variability and the likely reduced penetrance for the phenotypic expression.
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Affiliation(s)
- Liane Bourcier
- Centre de Formation Médicale du Nouveau-Brunswick, Université de Sherbrooke, Moncton, Canada
| | - Nicolas Crapoulet
- Laboratoire de génétique moléculaire, Réseau de santé Vitalité, Moncton, Canada
| | - Rodney J Ouellette
- Laboratoire de génétique moléculaire, Réseau de santé Vitalité, Moncton, Canada
| | - Mathieu Mallet
- Bureau d'appui à la recherche régional, Réseau de santé Vitalité, Moncton, Canada
| | - Mouna Ben Amor
- Service de médecine génétique, Réseau de santé Vitalité, Moncton, Canada
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10
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Pawolski V, Schmidt MHH. Neuron-Glia Interaction in the Developing and Adult Enteric Nervous System. Cells 2020; 10:E47. [PMID: 33396231 PMCID: PMC7823798 DOI: 10.3390/cells10010047] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/17/2020] [Accepted: 12/29/2020] [Indexed: 12/31/2022] Open
Abstract
The enteric nervous system (ENS) constitutes the largest part of the peripheral nervous system. In recent years, ENS development and its neurogenetic capacity in homeostasis and allostasishave gained increasing attention. Developmentally, the neural precursors of the ENS are mainly derived from vagal and sacral neural crest cell portions. Furthermore, Schwann cell precursors, as well as endodermal pancreatic progenitors, participate in ENS formation. Neural precursorsenherite three subpopulations: a bipotent neuron-glia, a neuronal-fated and a glial-fated subpopulation. Typically, enteric neural precursors migrate along the entire bowel to the anal end, chemoattracted by glial cell-derived neurotrophic factor (GDNF) and endothelin 3 (EDN3) molecules. During migration, a fraction undergoes differentiation into neurons and glial cells. Differentiation is regulated by bone morphogenetic proteins (BMP), Hedgehog and Notch signalling. The fully formed adult ENS may react to injury and damage with neurogenesis and gliogenesis. Nevertheless, the origin of differentiating cells is currently under debate. Putative candidates are an embryonic-like enteric neural progenitor population, Schwann cell precursors and transdifferentiating glial cells. These cells can be isolated and propagated in culture as adult ENS progenitors and may be used for cell transplantation therapies for treating enteric aganglionosis in Chagas and Hirschsprung's diseases.
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Affiliation(s)
| | - Mirko H. H. Schmidt
- Institute of Anatomy, Medical Faculty Carl Gustav Carus, Technische Universität Dresden School of Medicine, 01307 Dresden, Germany;
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Cardinal T, Bergeron KF, Soret R, Souchkova O, Faure C, Guillon A, Pilon N. Male-biased aganglionic megacolon in the TashT mouse model of Hirschsprung disease involves upregulation of p53 protein activity and Ddx3y gene expression. PLoS Genet 2020; 16:e1009008. [PMID: 32898154 PMCID: PMC7500598 DOI: 10.1371/journal.pgen.1009008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 09/18/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
Hirschsprung disease (HSCR) is a complex genetic disorder of neural crest development resulting in incomplete formation of the enteric nervous system (ENS). This life-threatening neurocristopathy affects 1/5000 live births, with a currently unexplained male-biased ratio. To address this lack of knowledge, we took advantage of the TashT mutant mouse line, which is the only HSCR model to display a robust male bias. Our prior work revealed that the TashT insertional mutation perturbs a Chr.10 silencer-enriched non-coding region, leading to transcriptional dysregulation of hundreds of genes in neural crest-derived ENS progenitors of both sexes. Here, through sex-stratified transcriptome analyses and targeted overexpression in ENS progenitors, we show that male-biased ENS malformation in TashT embryos is not due to upregulation of Sry-the murine ortholog of a candidate gene for the HSCR male bias in humans-but instead involves upregulation of another Y-linked gene, Ddx3y. This discovery might be clinically relevant since we further found that the DDX3Y protein is also expressed in the ENS of a subset of male HSCR patients. Mechanistically, other data including chromosome conformation captured-based assays and CRISPR/Cas9-mediated deletions suggest that Ddx3y upregulation in male TashT ENS progenitors is due to increased transactivation by p53, which appears especially active in these cells yet without triggering apoptosis. Accordingly, in utero treatment of TashT embryos with the p53 inhibitor pifithrin-α decreased Ddx3y expression and abolished the otherwise more severe ENS defect in TashT males. Our data thus highlight novel pathogenic roles for p53 and DDX3Y during ENS formation in mice, a finding that might help to explain the intriguing male bias of HSCR in humans.
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Affiliation(s)
- Tatiana Cardinal
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
| | - Karl-Frédérik Bergeron
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
- Lipid Metabolism Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
| | - Rodolphe Soret
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
| | - Ouliana Souchkova
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
| | - Christophe Faure
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
- Département de pédiatrie, Université de Montréal, Montréal, Québec, Canada
- Division de gastroentérologie, hépatologie et nutrition pédiatrique, Centre hospitalier universitaire Sainte-Justine, Montréal, Québec, Canada
| | - Amélina Guillon
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
| | - Nicolas Pilon
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
- Centre d'excellence en recherche sur les maladies orphelines-Fondation Courtois (CERMO-FC), Université du Québec à Montréal, Montréal, Québec, Canada
- Département de pédiatrie, Université de Montréal, Montréal, Québec, Canada
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Kostouros A, Koliarakis I, Natsis K, Spandidos DA, Tsatsakis A, Tsiaoussis J. Large intestine embryogenesis: Molecular pathways and related disorders (Review). Int J Mol Med 2020; 46:27-57. [PMID: 32319546 PMCID: PMC7255481 DOI: 10.3892/ijmm.2020.4583] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 04/08/2020] [Indexed: 02/07/2023] Open
Abstract
The large intestine, part of the gastrointestinal tract (GI), is composed of all three germ layers, namely the endoderm, the mesoderm and the ectoderm, forming the epithelium, the smooth muscle layers and the enteric nervous system, respectively. Since gastrulation, these layers develop simultaneously during embryogenesis, signaling to each other continuously until adult age. Two invaginations, the anterior intestinal portal (AIP) and the caudal/posterior intestinal portal (CIP), elongate and fuse, creating the primitive gut tube, which is then patterned along the antero‑posterior (AP) axis and the radial (RAD) axis in the context of left‑right (LR) asymmetry. These events lead to the formation of three distinct regions, the foregut, midgut and hindgut. All the above‑mentioned phenomena are under strict control from various molecular pathways, which are critical for the normal intestinal development and function. Specifically, the intestinal epithelium constitutes a constantly developing tissue, deriving from the progenitor stem cells at the bottom of the intestinal crypt. Epithelial differentiation strongly depends on the crosstalk with the adjacent mesoderm. Major molecular pathways that are implicated in the embryogenesis of the large intestine include the canonical and non‑canonical wingless‑related integration site (Wnt), bone morphogenetic protein (BMP), Notch and hedgehog systems. The aberrant regulation of these pathways inevitably leads to several intestinal malformation syndromes, such as atresia, stenosis, or agangliosis. Novel theories, involving the regulation and homeostasis of intestinal stem cells, suggest an embryological basis for the pathogenesis of colorectal cancer (CRC). Thus, the present review article summarizes the diverse roles of these molecular factors in intestinal embryogenesis and related disorders.
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Affiliation(s)
- Antonios Kostouros
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Ioannis Koliarakis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
| | - Konstantinos Natsis
- Department of Anatomy and Surgical Anatomy, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki
| | | | - Aristidis Tsatsakis
- Laboratory of Toxicology, Medical School, University of Crete, 71409 Heraklion, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion
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Zhang Q, He HH, Janjua MU, Wang F, Yang YB, Mo ZH, Liu J, Jin P. Identification of two novel mutations in three Chinese families with Kallmann syndrome using whole exome sequencing. Andrologia 2020; 52:e13594. [PMID: 32400067 DOI: 10.1111/and.13594] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 03/03/2020] [Accepted: 03/23/2020] [Indexed: 11/28/2022] Open
Abstract
Kallmann syndrome (KS) is a rare developmental disorder that manifests as congenital hypogonadotropic hypogonadism with anosmia. More than 19 genes have been found to be associated with KS. However, approximately 70% of the causes of KS remain unclear. Here, we studied seven KS patients, from three families, who had delayed puberty and olfactory bulb dysplasia. However, the families of these patients showed a range of other unique clinical features, including hearing loss, anosmia (to varying degrees) and unilateral renal agenesis. We performed whole exome sequencing and copy number variation (CNV) sequencing on samples acquired from these patients. We identified two novel mutations (c.844delC in ANOS1, c.475C>T in SOX10) and a novel trigenic pattern, PROKR2/CHD7/FEZF1 (c.337T>C in PROKR2, c.748C>G in FEZF1, c.8773G>A in CHD7). The c.844delC mutation in the ANOS1 gene was predicted to generate a truncated form of the anosmin-1 protein. SIFT and PolyPhen-2 predicted that the c.475C>T mutation in SOX10 had a damaging effect. The PROKR2 mutation (c.337T>C) was previously reported as harmful. No pathogenic copy number alterations were detected. Our study expands the genotypic and phenotypic spectrum of KS, a disease that shows considerable clinical and genetic heterogeneity. The application of whole exome sequencing could facilitate our understanding of the pathogenesis of KS.
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Affiliation(s)
- Qin Zhang
- Department of Endocrinology, Central South University, Changsha, China
| | - Hong-Hui He
- Department of Endocrinology, Central South University, Changsha, China
| | | | - Fang Wang
- Department of Endocrinology, Central South University, Changsha, China
| | - You-Bo Yang
- Department of Endocrinology, Central South University, Changsha, China
| | - Zhao-Hui Mo
- Department of Endocrinology, Central South University, Changsha, China
| | - Jun Liu
- Department of Endocrinology, Central South University, Changsha, China
| | - Ping Jin
- Department of Endocrinology, Central South University, Changsha, China
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14
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Mehrotra P, Tseropoulos G, Bronner ME, Andreadis ST. Adult tissue-derived neural crest-like stem cells: Sources, regulatory networks, and translational potential. Stem Cells Transl Med 2019; 9:328-341. [PMID: 31738018 PMCID: PMC7031649 DOI: 10.1002/sctm.19-0173] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 10/22/2019] [Accepted: 10/25/2019] [Indexed: 12/15/2022] Open
Abstract
Neural crest (NC) cells are a multipotent stem cell population that give rise to a diverse array of cell types in the body, including peripheral neurons, Schwann cells (SC), craniofacial cartilage and bone, smooth muscle cells, and melanocytes. NC formation and differentiation into specific lineages takes place in response to a set of highly regulated signaling and transcriptional events within the neural plate border. Premigratory NC cells initially are contained within the dorsal neural tube from which they subsequently emigrate, migrating to often distant sites in the periphery. Following their migration and differentiation, some NC‐like cells persist in adult tissues in a nascent multipotent state, making them potential candidates for autologous cell therapy. This review discusses the gene regulatory network responsible for NC development and maintenance of multipotency. We summarize the genes and signaling pathways that have been implicated in the differentiation of a postmigratory NC into mature myelinating SC. We elaborate on the signals and transcription factors involved in the acquisition of immature SC fate, axonal sorting of unmyelinated neuronal axons, and finally the path toward mature myelinating SC, which envelope axons within myelin sheaths, facilitating electrical signal propagation. The gene regulatory events guiding development of SC in vivo provides insights into means for differentiating NC‐like cells from adult human tissues into functional SC, which have the potential to provide autologous cell sources for the treatment of demyelinating and neurodegenerative disorders.
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Affiliation(s)
- Pihu Mehrotra
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York
| | - Georgios Tseropoulos
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California
| | - Stelios T Andreadis
- Department of Chemical and Biological Engineering, University at Buffalo, Buffalo, New York.,Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York.,Department of Biomedical Engineering, University at Buffalo, Buffalo, New York
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15
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Chatterjee S, Chakravarti A. A gene regulatory network explains RET-EDNRB epistasis in Hirschsprung disease. Hum Mol Genet 2019; 28:3137-3147. [PMID: 31313802 PMCID: PMC7275776 DOI: 10.1093/hmg/ddz149] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 05/22/2019] [Accepted: 06/21/2019] [Indexed: 12/31/2022] Open
Abstract
Disruptions in gene regulatory networks (GRNs), driven by multiple deleterious variants, potentially underlie complex traits and diseases. Hirschsprung disease (HSCR), a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We previously demonstrated that RET transcription in the ENS is controlled by an extensive GRN involving the transcription factors (TFs) RARB, GATA2 and SOX10 and other HSCR genes. We now demonstrate, using human and mouse cellular and animal models, that EDNRB is transcriptionally regulated in the ENS by GATA2, SOX10 and NKX2.5 TFs. Significantly, RET and EDNRB expression is regulated by their shared use of GATA2 and SOX10, and in turn, these TFs are controlled by EDNRB and RET in a dose-dependent manner. This study expands the ENS development GRN to include both RET and EDNRB, uncovers the mechanistic basis for RET-EDNRB epistasis and emphasizes how functionally different genes associated with a complex disorder can be united through a common GRN.
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Affiliation(s)
- Sumantra Chatterjee
- Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, USA
| | - Aravinda Chakravarti
- Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, USA
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Luzón‐Toro B, Villalba‐Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet 2019; 97:114-124. [DOI: 10.1111/cge.13615] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 01/01/2023]
Affiliation(s)
- Berta Luzón‐Toro
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Leticia Villalba‐Benito
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Ana Torroglosa
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Raquel M. Fernández
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Guillermo Antiñolo
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Salud Borrego
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
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Bondurand N, Dufour S, Pingault V. News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. Dev Biol 2018; 444 Suppl 1:S156-S169. [PMID: 30171849 DOI: 10.1016/j.ydbio.2018.08.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/27/2018] [Accepted: 08/27/2018] [Indexed: 01/08/2023]
Abstract
The endothelin system is a vertebrate-specific innovation with important roles in regulating the cardiovascular system and renal and pulmonary processes, as well as the development of the vertebrate-specific neural crest cell population and its derivatives. This system is comprised of three structurally similar 21-amino acid peptides that bind and activate two G-protein coupled receptors. In 1994, knockouts of the Edn3 and Ednrb genes revealed their crucial function during development of the enteric nervous system and melanocytes, two neural-crest derivatives. Since then, human and mouse genetics, combined with cellular and developmental studies, have helped to unravel the role of this signaling pathway during development and adulthood. In this review, we will summarize the known functions of the EDN3/EDNRB pathway during neural crest development, with a specific focus on recent scientific advances, and the enteric nervous system in normal and pathological conditions.
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Affiliation(s)
- Nadege Bondurand
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
| | - Sylvie Dufour
- INSERM, U955, Equipe 06, Créteil 94000, France; Université Paris Est, Faculté de Médecine, Créteil 94000, France
| | - Veronique Pingault
- Laboratory of Embryology and Genetics of Congenital Malformations, INSERM U1163, Institut Imagine, Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France; Service de Génétique Moléculaire, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France
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18
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Wang G, Guo F, Wang H, Liu W, Zhang L, Cui M, Wu X. Downregulation of microRNA-483-5p Promotes Cell Proliferation and Invasion by Targeting GFRA4 in Hirschsprung's Disease. DNA Cell Biol 2017; 36:930-937. [PMID: 29090971 DOI: 10.1089/dna.2017.3821] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Recent studies have suggested the critical roles of miRNAs for disease progression. miRNA-483-5p (miR-483-5p) was previously found to have a relationship with tumor cell behavior, but its biological function in Hirschsprung's disease (HSCR) remains undefined. Thus, we explored the role of miR-483-5p in the pathogenesis of HSCR. Histological changes of colonic tissues were evaluated by hematoxylin and eosin (HE) staining. Quantitative real-time PCR and western blotting were used to determine relative expression levels of miRNA, mRNA, and proteins in 20 HSCR patients and 20 normal colon tissues. In this study, we found that miR-483-5p expression in HSCR tissues was significantly increased and their downregulation promoted cell proliferation, cell cycle progression and invasion and inhibited cell apoptosis in human 293T and SH-SY5Y cell lines by the CCK-8, flow cytometry, and Transwell assay. GNDF family receptor alpha 4 (GFRA4) was confirmed as a downstream target of miR-483-5p by dual-luciferase reporter gene assay and inversely correlated with miR-483-5p expression in cell lines. Taken together, miR-483-5p may play a crucial role in the pathogenesis of HSCR by targeting GFRA4.
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Affiliation(s)
- Gang Wang
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Feng Guo
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Hefeng Wang
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Wei Liu
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Lijuan Zhang
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Mingyu Cui
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
| | - Xiangyu Wu
- Department of Pediatric Surgery, Shandong Province Hospital Affiliated to Shandong University , Jinan, China
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19
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Li H, Fan L, Zhu S, Shin MK, Lu F, Qu J, Hou L. Epilation induces hair and skin pigmentation through an EDN3/EDNRB-dependent regenerative response of melanocyte stem cells. Sci Rep 2017; 7:7272. [PMID: 28779103 PMCID: PMC5544680 DOI: 10.1038/s41598-017-07683-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 07/03/2017] [Indexed: 11/21/2022] Open
Abstract
In response to various types of injury, melanocyte stem cells (McSCs) located in the bulge of hair follicles can regenerate mature melanocytes for hair and skin pigmentation. How McSCs respond to injury, however, remains largely unknown. Here we show that after epilation of mice, McSCs regenerate follicular and epidermal melanocytes, resulting in skin and hair hyperpigmentation. We further show that epilation leads to endogenous EDN3 upregulation in the dermal papilla, the secondary hair germ cells, and the epidermis. Genetic and pharmacological disruption of the EDN3 receptor EDNRB in vivo significantly blocks the effect of epilation on follicular and epidermal melanocyte regeneration as well as skin and hair hyperpigmentation. Taken together, these results indicate that epilation induces McSCs activation through EDN3/EDNRB signaling and in turn leads to skin and hair hyperpigmentation. The findings suggest that EDN/EDNRB signaling may serve as a potential therapeutic target to promote repigmentation in hypopigmentation disorders.
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Affiliation(s)
- Huirong Li
- Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
- State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China
| | - Lilv Fan
- Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Shanpu Zhu
- Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Myung K Shin
- Genetically Engineered Models Department, Merck Research Laboratories, Rahway, NJ, 07065, USA
| | - Fan Lu
- State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China
| | - Jia Qu
- State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China
| | - Ling Hou
- Laboratory of Developmental Cell Biology and Disease, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, China.
- State Key Laboratory and Key Laboratory of Vision Science of Ministry of Health and Zhejiang Provincial Key Laboratory of Ophthalmology, Wenzhou, 325003, China.
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20
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Watanabe Y, Stanchina L, Lecerf L, Gacem N, Conidi A, Baral V, Pingault V, Huylebroeck D, Bondurand N. Differentiation of Mouse Enteric Nervous System Progenitor Cells Is Controlled by Endothelin 3 and Requires Regulation of Ednrb by SOX10 and ZEB2. Gastroenterology 2017; 152:1139-1150.e4. [PMID: 28063956 DOI: 10.1053/j.gastro.2016.12.034] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/09/2016] [Accepted: 12/28/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Maintenance and differentiation of progenitor cells in the developing enteric nervous system are controlled by molecules such as the signaling protein endothelin 3 (EDN3), its receptor (the endothelin receptor type B [EDNRB]), and the transcription factors SRY-box 10 (SOX10) and zinc finger E-box binding homeobox 2 (ZEB2). We used enteric progenitor cell (EPC) cultures and mice to study the roles of these proteins in enteric neurogenesis and their cross regulation. METHODS We performed studies in mice with a Zeb2 loss-of-function mutation (Zeb2Δ) and mice carrying a spontaneous recessive mutation that prevents conversion of EDN3 to its active form (Edn3ls). EPC cultures issued from embryos that expressed only wild-type Zeb2 (Zeb2+/+ EPCs) or were heterozygous for the mutation (Zeb2Δ/+ EPCs) were exposed to EDN3; we analyzed the effects on cell differentiation using immunocytochemistry. In parallel, Edn3ls mice were crossed with Zeb2Δ/+mice; intestinal tissues were collected from embryos for immunohistochemical analyses. We investigated regulation of the EDNRB gene in transactivation and chromatin immunoprecipitation assays; results were validated in functional rescue experiments using transgenes expression in EPCs from retroviral vectors. RESULTS Zeb2Δ/+ EPCs had increased neuronal differentiation compared to Zeb2+/+ cells. When exposed to EDN3, Zeb2+/+ EPCs continued expression of ZEB2 but did not undergo any neuronal differentiation. Incubation of Zeb2Δ/+ EPCs with EDN3, on the other hand, resulted in only partial inhibition of neuronal differentiation. This indicated that 2 copies of Zeb2 are required for EDN3 to prevent neuronal differentiation. Mice with combined mutations in Zeb2 and Edn3 (double mutants) had more severe enteric anomalies and increased neuronal differentiation compared to mice with mutations in either gene alone. The transcription factors SOX10 and ZEB2 directly activated the EDNRB promoter. Overexpression of EDNRB in Zeb2Δ/+ EPCs restored inhibition of neuronal differentiation, similar to incubation of Zeb2+/+ EPCs with EDN3. CONCLUSIONS In studies of cultured EPCs and mice, we found that control of differentiation of mouse enteric nervous system progenitor cells by EDN3 requires regulation of Ednrb expression by SOX10 and ZEB2.
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Affiliation(s)
- Yuli Watanabe
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Laure Stanchina
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Laure Lecerf
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Nadjet Gacem
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Andrea Conidi
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Viviane Baral
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Veronique Pingault
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France
| | - Danny Huylebroeck
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, Netherlands; Laboratory of Molecular Biology (Celgen), Department of Development and Regeneration, Katholieke Universiteit Leuven, Belgium
| | - Nadege Bondurand
- Institut National de la Santé et de la Recherche Médicale, Créteil, France; Université Paris-Est, Faculté de Médecine, Créteil, France.
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21
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Yoshihara M, Sato T, Saito D, Ohara O, Kuramoto T, Suyama M. A deletion in the intergenic region upstream of Ednrb causes head spot in the rat strain KFRS4/Kyo. BMC Genet 2017; 18:29. [PMID: 28356074 PMCID: PMC5372274 DOI: 10.1186/s12863-017-0497-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 03/25/2017] [Indexed: 11/17/2022] Open
Abstract
Background Head spot is one of the phenotypes identified in the KFRS4/Kyo rat strain. Although previous linkage analysis suggested that Ednrb, which is frequently involved in coat color variations in various animals, could be the gene responsible for this phenotype, no mutations have been identified in its coding region. Results To identify mutations causative of this phenotype in KFRS4/Kyo, we analyzed target capture sequencing data that we recently generated. Our target capture method has a unique feature, i.e., it covers not only exonic regions but also conserved non-coding sequences (CNSs) among vertebrates; therefore, it has the potential to detect regulatory mutations. We identified a deletion of approximately 50 kb in length approximately 50 kb upstream of Ednrb. A comparative analysis with the epigenomic data in the corresponding region in humans and mice showed that one of the CNSs might be an enhancer. Further comparison with Hi-C data, which provide information about chromosome conformation, indicated that the putative enhancer is spatially close to the promoter of Ednrb, suggesting that it acts as an enhancer of Ednrb. Conclusions These in silico data analyses strongly suggest that the identified deletion in the intergenic region upstream of Ednrb, which might contain a melanocyte-specific enhancer, is the mutation causative of the head spot phenotype in the KFRS4/Kyo rat strain. Electronic supplementary material The online version of this article (doi:10.1186/s12863-017-0497-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Minako Yoshihara
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, Fukuoka, 812-8582, Japan
| | - Tetsuya Sato
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, Fukuoka, 812-8582, Japan
| | - Daisuke Saito
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, Fukuoka, 812-8582, Japan
| | - Osamu Ohara
- Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Chiba, 292-0818, Japan
| | - Takashi Kuramoto
- Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Mikita Suyama
- Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan. .,AMED-CREST, Japan Agency for Medical Research and Development, Fukuoka, 812-8582, Japan.
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22
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Venkatesh H, Monje M. Neuronal Activity in Ontogeny and Oncology. Trends Cancer 2017; 3:89-112. [PMID: 28718448 DOI: 10.1016/j.trecan.2016.12.008] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 12/29/2016] [Accepted: 12/30/2016] [Indexed: 01/06/2023]
Abstract
The nervous system plays a central role in regulating the stem cell niche in many organs, and thereby pivotally modulates development, homeostasis, and plasticity. A similarly powerful role for neural regulation of the cancer microenvironment is emerging. Neurons promote the growth of cancers of the brain, skin, prostate, pancreas, and stomach. Parallel mechanisms shared in development and cancer suggest that neural modulation of the tumor microenvironment may prove a universal theme, although the mechanistic details of such modulation remain to be discovered for many malignancies. We review here what is known about the influences of active neurons on stem cell and cancer microenvironments across a broad range of tissues, and we discuss emerging principles of neural regulation of development and cancer.
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Affiliation(s)
- Humsa Venkatesh
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Cancer Biology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Michelle Monje
- Department of Neurology, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
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23
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Nagy N, Goldstein AM. Enteric nervous system development: A crest cell's journey from neural tube to colon. Semin Cell Dev Biol 2017; 66:94-106. [PMID: 28087321 DOI: 10.1016/j.semcdb.2017.01.006] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/03/2017] [Accepted: 01/09/2017] [Indexed: 12/31/2022]
Abstract
The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation.
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Affiliation(s)
- Nandor Nagy
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Center for Neurointestinal Health, Massachusetts General Hospital, Boston, MA, United States; Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States; Center for Neurointestinal Health, Massachusetts General Hospital, Boston, MA, United States.
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24
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Bondurand N, Southard-Smith EM. Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players. Dev Biol 2016; 417:139-57. [PMID: 27370713 DOI: 10.1016/j.ydbio.2016.06.042] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 06/27/2016] [Accepted: 06/27/2016] [Indexed: 12/18/2022]
Abstract
Hirschsprung disease (HSCR, intestinal aganglionosis) is a multigenic disorder with variable penetrance and severity that has a general population incidence of 1/5000 live births. Studies using animal models have contributed to our understanding of the developmental origins of HSCR and the genetic complexity of this disease. This review summarizes recent progress in understanding control of enteric nervous system (ENS) development through analyses in mouse models. An overview of signaling pathways that have long been known to control the migration, proliferation and differentiation of enteric neural progenitors into and along the developing gut is provided as a framework for the latest information on factors that influence enteric ganglia formation and maintenance. Newly identified genes and additional factors beyond discrete genes that contribute to ENS pathology including regulatory sequences, miRNAs and environmental factors are also introduced. Finally, because HSCR has become a paradigm for complex oligogenic diseases with non-Mendelian inheritance, the importance of gene interactions, modifier genes, and initial studies on genetic background effects are outlined.
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Affiliation(s)
- Nadege Bondurand
- INSERM, U955, Equipe 6, F-94000 Creteil, France; Universite Paris-Est, UPEC, F-94000 Creteil, France.
| | - E Michelle Southard-Smith
- Vanderbilt University Medical Center, Department of Medicine, 2215 Garland Ave, Nashville, TN 37232, USA.
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25
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Coe A, Avansino JR, Kapur RP. Distal Rectal Skip-Segment Hirschsprung Disease and the Potential for False-Negative Diagnosis. Pediatr Dev Pathol 2016; 19:123-31. [PMID: 26372258 DOI: 10.2350/15-08-1686-oa.1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
In skip-segment Hirschsprung disease (SS-HSCR), an aganglionic segment of bowel, which extends proximally from the distal rectum, is interrupted by a ganglionated "skip segment." Skip segments are usually located far proximal to the rectum where they do not interfere with initial diagnosis, although the possibility of distal SS-HSCR should be considered during interpretation of intraoperative biopsies or patients with atypical postoperative courses. We report 2 cases of SS-HSCR with skip areas in the distal rectum, 1 of which led to a false-negative diagnosis by suction rectal biopsy. These 2 cases of SS-HSCR, along with others in the literature, highlight the point that ganglionic skip segments can confuse clinicians and lead to inadequate bowel resection, diagnostic delay, or a false-negative diagnosis. The pathogenesis of SS-HSCR is discussed in light of recent discoveries regarding transmesenteric migration of vagal neural crest cells and the role of sacral neural crest cells in hindgut neurodevelopment.
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Affiliation(s)
- Alexander Coe
- 1 University of Nevada School of Medicine, Reno, NV, USA
| | - Jeffrey R Avansino
- 2 Department of Surgery, University of Washington and Seattle Children's Hospital, Seattle, WA, USA
| | - Raj P Kapur
- 3 Department of Pathology, University of Washington and Seattle Children's Hospital, Seattle, WA, USA
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26
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Enguix-Riego MV, Torroglosa A, Fernández RM, Moya-Jiménez MJ, de Agustín JC, Antiñolo G, Borrego S. Identification of different mechanisms leading to PAX6 down-regulation as potential events contributing to the onset of Hirschsprung disease. Sci Rep 2016; 6:21160. [PMID: 26879676 PMCID: PMC4754768 DOI: 10.1038/srep21160] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 01/08/2016] [Indexed: 12/11/2022] Open
Abstract
Hirschsprung disease (HSCR) is attributed to a failure of neural crest derived cells to migrate, proliferate, differentiate or survive in the bowel wall during embryonic Enteric Nervous System (ENS) development. This process requires a wide and complex variety of molecules and signaling pathways which are activated by transcription factors. In an effort to better understand the etiology of HSCR, we have designed a study to identify new transcription factors participating in different stages of the colonization process. A differential expression study has been performed on a set of transcription factors using Neurosphere-like bodies from both HSCR and control patients. Differential expression levels were found for CDYL, MEIS1, STAT3 and PAX6. A significantly lower expression level for PAX6 in HSCR patients, would suit with the finding of an over-representation of the larger tandem (AC)m(AG)n repeats within the PAX6 promoter in HSCR patients, with the subsequent loss of protein P300 binding. Alternatively, PAX6 is a target for DNMT3B-dependant methylation, a process already proposed as a mechanism with a role in HSCR. Such decrease in PAX6 expression may influence in the proper function of signaling pathways involved in ENS with the confluence of additional genetic factors to the manifestation of HSCR phenotype.
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Affiliation(s)
- María Valle Enguix-Riego
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Ana Torroglosa
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Raquel María Fernández
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - María José Moya-Jiménez
- Department of Pediatric Surgery, University Hospital Virgen del Rocío, Seville, 41013, Spain
| | - Juan Carlos de Agustín
- Department of Pediatric Surgery, General University Hospital Gregorio Marañon, Madrid, 28009, Spain
| | - Guillermo Antiñolo
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
| | - Salud Borrego
- Department of Genetics, Reproduction and Fetal Medicine. Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, 41013, Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, 41013, Spain
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Gasc JM, Clemessy M, Corvol P, Kempf H. A chicken model of pharmacologically-induced Hirschsprung disease reveals an unexpected role of glucocorticoids in enteric aganglionosis. Biol Open 2015; 4:666-71. [PMID: 25836673 PMCID: PMC4434818 DOI: 10.1242/bio.201410454] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The enteric nervous system originates from neural crest cells that migrate in chains as they colonize the embryonic gut, eventually forming the myenteric and submucosal plexus. Failure of the neural crest cells to colonize the gut leads to aganglionosis in the terminal gut, a pathological condition called Hirschsprung disease (HSCR) in humans, also known as congenital megacolon or intestinal aganglionosis. One of the characteristics of the human HSCR is its variable penetrance, which may be attributable to the interaction between genetic factors, such as the endothelin-3/endothelin receptor B pathway, and non-genetic modulators, although the role of the latter has not well been established. We have created a novel HSCR model in the chick embryo allowing to test the ability of non-genetic modifiers to alter the HSCR phenotype. Chick embryos treated by phosphoramidon, which blocks the generation of endothelin-3, failed to develop enteric ganglia in the very distal bowel, characteristic of an HSCR-like phenotype. Administration of dexamethasone influenced the phenotype, suggesting that glucocorticoids may be environmental modulators of the penetrance of the aganglionosis in HSCR disease.
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Affiliation(s)
- Jean-Marie Gasc
- Centre Interdisciplinaire de Recherche Biomédicale (CIRB), Collège de France, 75005 Paris, France Chaire de Médecine Expérimentale, Collège de France, 75005 Paris, France
| | - Maud Clemessy
- Centre Interdisciplinaire de Recherche Biomédicale (CIRB), Collège de France, 75005 Paris, France Chaire de Médecine Expérimentale, Collège de France, 75005 Paris, France Centre de Recherche St-Antoine UMRS-938, INSERM-Université Pierre et Marie Curie, Paris 6, 75012 Paris, France
| | - Pierre Corvol
- Centre Interdisciplinaire de Recherche Biomédicale (CIRB), Collège de France, 75005 Paris, France Chaire de Médecine Expérimentale, Collège de France, 75005 Paris, France
| | - Hervé Kempf
- Centre Interdisciplinaire de Recherche Biomédicale (CIRB), Collège de France, 75005 Paris, France Chaire de Médecine Expérimentale, Collège de France, 75005 Paris, France UMR 7365 CNRS-Université de Lorraine, IMoPA, Faculté de Médecine, 54500 Vandoeuvre-lès-Nancy, France
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28
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Sharan A, Zhu H, Xie H, Li H, Tang J, Tang W, Zhang H, Xia Y. Down-regulation of miR-206 is associated with Hirschsprung disease and suppresses cell migration and proliferation in cell models. Sci Rep 2015; 5:9302. [PMID: 25792468 PMCID: PMC4366810 DOI: 10.1038/srep09302] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 02/25/2015] [Indexed: 01/07/2023] Open
Abstract
Hirschsprung disease (HSCR) is a well-known congenital digestive disease that originates due to the developmental disorder of neural crest cells. MiR-206 is kown to have a relationship with digestive malfunctions. Therefore, we investigated whether or not miR-206 was involved in the pathogenesis of HSCR. qRT-PCR and Western blot assays were used to detect the expression levels of miRNA and mRNAs, and proteins in case and control tissue samples and two cell lines (293T and SH-SY5Y). The functions of miR-206 in vitro were measured by transwell assay, CCK8 assay and flow cytometry. Finally, we conducted dual-luciferase reporter assay to verify the connections between miR-206 and the target mRNA SDPR. Down-regulation of miR-206 was found in HSCR case tissue samples compared with controls, which was validated to be connected with the increased level of mRNA and protein of SDPR by qRT-PCR and dual-luciferase reporter assay. Moreover, miR-206 suppressed the cell migration and proliferation and silencing of SDPR could rescue the extent of the suppressing effects by miR-206 inhibitor. The findings suggest that miR-206 may play a significant role in the pathogenesis of HSCR, as well as inhibiting the cell migration and proliferation by targeting SDPR in disease models.
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Affiliation(s)
- Ankur Sharan
- Key Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Hairong Zhu
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Hua Xie
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Hongxing Li
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Junwei Tang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Weibing Tang
- State Key Laboratory of Reproductive Medicine, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
| | - Hongwei Zhang
- Department of Pediatric Surgery, Xuzhou Children's Hospital Affiliated to Xuzhou Medical University, Xuzhou 221002, China
| | - Yankai Xia
- Key Laboratory of Modern Toxicology (Nanjing Medical University), Ministry of Education, China
- Department of Pediatric Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing 210008, China
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29
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Huang J, Dang R, Torigoe D, Lei C, Lan X, Chen H, Sasaki N, Wang J, Agui T. Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis. PLoS One 2015; 10:e0122068. [PMID: 25790447 PMCID: PMC4366197 DOI: 10.1371/journal.pone.0122068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Accepted: 02/12/2015] [Indexed: 01/17/2023] Open
Abstract
Hirschsprung’s disease (HSCR) is a congenital disease in neonates characterized by the absence of the enteric ganglia in a variable length of the distal colon. This disease results from multiple genetic interactions that modulate the ability of enteric neural crest cells to populate developing gut. We previously reported that three rat strains with different backgrounds (susceptible AGH-Ednrbsl/sl, resistant F344-Ednrbsl/sl, and LEH-Ednrbsl/sl) but the same null mutation of Ednrb show varying severity degrees of aganglionosis. This finding suggests that strain-specific genetic factors affect the severity of HSCR. Consistent with this finding, a quantitative trait locus (QTL) for the severity of HSCR on chromosome (Chr) 2 was identified using an F2 intercross between AGH and F344 strains. In the present study, we performed QTL analysis using an F2 intercross between the susceptible AGH and resistant LEH strains to identify the modifier/resistant loci for HSCR in Ednrb-deficient rats. A significant locus affecting the severity of HSCR was also detected within the Chr 2 region. These findings strongly suggest that a modifier gene of aganglionosis exists on Chr 2. In addition, two potentially causative SNPs (or mutations) were detected upstream of a known HSCR susceptibility gene, Gdnf. These SNPs were possibly responsible for the varied length of gut affected by aganglionosis.
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Affiliation(s)
- Jieping Huang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Ruihua Dang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- * E-mail: (RD); (CL)
| | - Daisuke Torigoe
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
- * E-mail: (RD); (CL)
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hong Chen
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Nobuya Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Jinxi Wang
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
| | - Takashi Agui
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
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30
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Sinagoga KL, Wells JM. Generating human intestinal tissues from pluripotent stem cells to study development and disease. EMBO J 2015; 34:1149-63. [PMID: 25792515 DOI: 10.15252/embj.201490686] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Accepted: 03/09/2015] [Indexed: 01/05/2023] Open
Abstract
As one of the largest and most functionally complex organs of the human body, the intestines are primarily responsible for the breakdown and uptake of macromolecules from the lumen and the subsequent excretion of waste from the body. However, the intestine is also an endocrine organ, regulating digestion, metabolism, and feeding behavior. Intricate neuronal, lymphatic, immune, and vascular systems are integrated into the intestine and are required for its digestive and endocrine functions. In addition, the gut houses an extensive population of microbes that play roles in digestion, global metabolism, barrier function, and host-parasite interactions. With such an extensive array of cell types working and performing in one essential organ, derivation of functional intestinal tissues from human pluripotent stem cells (PSCs) represents a significant challenge. Here we will discuss the intricate developmental processes and cell types that are required for assembly of this highly complex organ and how embryonic processes, particularly morphogenesis, have been harnessed to direct differentiation of PSCs into 3-dimensional human intestinal organoids (HIOs) in vitro. We will further describe current uses of HIOs in development and disease research and how additional tissue complexity might be engineered into HIOs for better functionality and disease modeling.
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Affiliation(s)
- Katie L Sinagoga
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - James M Wells
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
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31
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Ross AP, Zarbalis KS. The emerging roles of ribosome biogenesis in craniofacial development. Front Physiol 2014; 5:26. [PMID: 24550838 PMCID: PMC3912750 DOI: 10.3389/fphys.2014.00026] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 01/13/2014] [Indexed: 12/29/2022] Open
Abstract
Neural crest cells (NCCs) are a transient, migratory cell population, which originates during neurulation at the neural folds and contributes to the majority of tissues, including the mesenchymal structures of the craniofacial skeleton. The deregulation of the complex developmental processes that guide migration, proliferation, and differentiation of NCCs may result in a wide range of pathological conditions grouped together as neurocristopathies. Recently, due to their multipotent properties neural crest stem cells have received considerable attention as a possible source for stem cell based regenerative therapies. This exciting prospect underlines the need to further explore the developmental programs that guide NCC differentiation. This review explores the particular importance of ribosome biogenesis defects in this context since a specific interface between ribosomopathies and neurocristopathies exists as evidenced by disorders such as Treacher-Collins-Franceschetti syndrome (TCS) and Diamond-Blackfan anemia (DBA).
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Affiliation(s)
- Adam P Ross
- Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, University of California at Davis Sacramento, CA, USA
| | - Konstantinos S Zarbalis
- Department of Pathology and Laboratory Medicine, Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, University of California at Davis Sacramento, CA, USA
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Burkardt DD, Graham JM, Short SS, Frykman PK. Advances in Hirschsprung disease genetics and treatment strategies: an update for the primary care pediatrician. Clin Pediatr (Phila) 2014; 53:71-81. [PMID: 24002048 DOI: 10.1177/0009922813500846] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hirschsprung disease (HSCR) is a multigenic condition with variable presentation. Most commonly, it presents in the neonatal period as a functional intestinal obstruction secondary to failure of caudal migration of the enteric nervous system. Classically, this manifests as dilated proximal bowel and constricted distal bowel with absent ganglia and hypertrophic nerve trunks. When recognized early, medical and surgical therapies can be instituted to minimize associated morbidity and mortality. This article reviews current understanding of the etiology of HSCR, its multigenic associations, the historical evolution of HSCR diagnosis and treatment, and current HSCR therapies.
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Bondurand N, Sham MH. The role of SOX10 during enteric nervous system development. Dev Biol 2013; 382:330-43. [DOI: 10.1016/j.ydbio.2013.04.024] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Accepted: 04/24/2013] [Indexed: 12/30/2022]
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Gisser JM, Cohen AR, Yin H, Gariepy CE. A novel bidirectional interaction between endothelin-3 and retinoic acid in rat enteric nervous system precursors. PLoS One 2013; 8:e74311. [PMID: 24040226 PMCID: PMC3767828 DOI: 10.1371/journal.pone.0074311] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 08/02/2013] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Signaling through the endothelin receptor B (EDNRB) is critical for the development of the enteric nervous system (ENS) and mutations in endothelin system genes cause Hirschsprung's aganglionosis in humans. Penetrance of the disease is modulated by other genetic factors. Mutations affecting retinoic acid (RA) signaling also produce aganglionosis in mice. Thus, we hypothesized that RA and endothelin signaling pathways may interact in controlling development of the ENS. METHODS Rat immunoselected ENS precursor cells were cultured with the EDNRB ligand endothelin-3, an EDNRB-selective antagonist (BQ-788), and/or RA for 3 or 14 days. mRNA levels of genes related to ENS development, RA- and EDNRB-signaling were measured at 3 days. Proliferating cells and cells expressing neuronal, glial, and myofibroblast markers were quantified. RESULTS Culture of isolated ENS precursors for 3 days with RA decreases expression of the endothelin-3 gene and that of its activation enzyme. These changes are associated with glial proliferation, a higher percentage of glia, and a lower percentage of neurons compared to cultures without RA. These changes are independent of EDNRB signaling. Conversely, EDNRB activation in these cultures decreases expression of RA receptors β and γ mRNA and affects the expression of the RA synthetic and degradative enzymes. These gene expression changes are associated with reduced glial proliferation and a lower percentage of glia in the culture. Over 14 days in the absence of EDNRB signaling, RA induces the formation of a heterocellular plexus replete with ganglia, glia and myofibroblasts. CONCLUSIONS A complex endothelin-RA interaction exists that coordinately regulates the development of rat ENS precursors in vitro. These results suggest that environmental RA may modulate the expression of aganglionosis in individuals with endothelin mutations.
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Affiliation(s)
- Jonathan M. Gisser
- The Center for Molecular and Human Genetics, the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, the Ohio State University, Columbus, Ohio, United States of America
| | - Ariella R. Cohen
- The Center for Molecular and Human Genetics, the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Han Yin
- The Biostatistics Shared Resources, Nationwide Children’s Hospital, Columbus, Ohio, United States of America
| | - Cheryl E. Gariepy
- The Center for Molecular and Human Genetics, the Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, United States of America
- Department of Pediatrics, the Ohio State University, Columbus, Ohio, United States of America
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Lake JI, Heuckeroth RO. Enteric nervous system development: migration, differentiation, and disease. Am J Physiol Gastrointest Liver Physiol 2013; 305:G1-24. [PMID: 23639815 PMCID: PMC3725693 DOI: 10.1152/ajpgi.00452.2012] [Citation(s) in RCA: 239] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.
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Affiliation(s)
- Jonathan I. Lake
- 1Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; and
| | - Robert O. Heuckeroth
- 1Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri; and ,2Department of Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, Missouri
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Harrison C, Shepherd IT. Choices choices: regulation of precursor differentiation during enteric nervous system development. Neurogastroenterol Motil 2013; 25:554-62. [PMID: 23634805 PMCID: PMC4062358 DOI: 10.1111/nmo.12142] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2012] [Accepted: 03/30/2013] [Indexed: 02/08/2023]
Abstract
Background The enteric nervous system (ENS) is the largest subdivision of the peripheral nervous system and forms a complex circuit of neurons and glia that controls the function of the gastrointestinal (GI) tract. Within this circuit, there are multiple subtypes of neurons and glia. Appropriate differentiation of these various cell subtypes is vital for normal ENS and GI function. Studies of the pediatric disorder Hirschprung's Disease (HSCR) have provided a number of important insights into the mechanisms and molecules involved in ENS development; however, there are numerous other GI disorders that potentially may result from defects in development/differentiation of only a subset of ENS neurons or glia. Purpose Our understanding of the mechanisms and molecules involved in enteric nervous system differentiation is far from complete. Critically, it remains unclear at what point the fates of enteric neural crest cells (ENCCs) become committed to a specific subtype cell fate and how these cell fate choices are made. We will review our current understanding of ENS differentiation and highlight key questions that need to be addressed to gain a more complete understanding of this biological process.
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Affiliation(s)
- Colin Harrison
- Department of Biology, Emory University, 1510 Clifton Road, Atlanta GA 30322, USA
| | - Iain T. Shepherd
- Department of Biology, Emory University, 1510 Clifton Road, Atlanta GA 30322, USA
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Butler Tjaden NE, Trainor PA. The developmental etiology and pathogenesis of Hirschsprung disease. Transl Res 2013; 162:1-15. [PMID: 23528997 PMCID: PMC3691347 DOI: 10.1016/j.trsl.2013.03.001] [Citation(s) in RCA: 149] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 02/25/2013] [Accepted: 03/01/2013] [Indexed: 02/08/2023]
Abstract
The enteric nervous system is the part of the autonomic nervous system that directly controls the gastrointestinal tract. Derived from a multipotent, migratory cell population called the neural crest, a complete enteric nervous system is necessary for proper gut function. Disorders that arise as a consequence of defective neural crest cell development are termed neurocristopathies. One such disorder is Hirschsprung disease (HSCR), also known as congenital megacolon or intestinal aganglionosis. HSCR occurs in 1/5000 live births and typically presents with the inability to pass meconium, along with abdominal distension and discomfort that usually requires surgical resection of the aganglionic bowel. This disorder is characterized by a congenital absence of neurons in a portion of the intestinal tract, usually the distal colon, because of a disruption of normal neural crest cell migration, proliferation, differentiation, survival, and/or apoptosis. The inheritance of HSCR disease is complex, often non-Mendelian, and characterized by variable penetrance. Extensive research has identified a number of key genes that regulate neural crest cell development in the pathogenesis of HSCR including RET, GDNF, GFRα1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHH. However, mutations in these genes account for only ∼50% of the known cases of HSCR. Thus, other genetic mutations and combinations of genetic mutations and modifiers likely contribute to the etiology and pathogenesis of HSCR. The aims of this review are to summarize the HSCR phenotype, diagnosis, and treatment options; to discuss the major genetic causes and the mechanisms by which they disrupt normal enteric neural crest cell development; and to explore new pathways that may contribute to HSCR pathogenesis.
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Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, Fouveaut C, Leroy C, Vérier-Mine O, Francannet C, Dupin-Deguine D, Archambeaud F, Kurtz FJ, Young J, Bertherat J, Marlin S, Goossens M, Hardelin JP, Dodé C, Bondurand N. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness. Am J Hum Genet 2013; 92:707-24. [PMID: 23643381 DOI: 10.1016/j.ajhg.2013.03.024] [Citation(s) in RCA: 140] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 02/25/2013] [Accepted: 03/29/2013] [Indexed: 12/11/2022] Open
Abstract
Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs.
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Affiliation(s)
- Veronique Pingault
- Equipe 11, Institut National de la Santé et de la Recherche Médicale Unité 955, 94000 Créteil, France.
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Watanabe Y, Broders-Bondon F, Baral V, Paul-Gilloteaux P, Pingault V, Dufour S, Bondurand N. Sox10 and Itgb1 interaction in enteric neural crest cell migration. Dev Biol 2013; 379:92-106. [PMID: 23608456 DOI: 10.1016/j.ydbio.2013.04.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2013] [Revised: 04/10/2013] [Accepted: 04/12/2013] [Indexed: 01/11/2023]
Abstract
SOX10 involvement in syndromic form of Hirschsprung disease (intestinal aganglionosis, HSCR) in humans as well as developmental defects in animal models highlight the importance of this transcription factor in control of the pool of enteric progenitors and their differentiation. Here, we characterized the role of SOX10 in cell migration and its interactions with β1-integrins. To this end, we crossed the Sox10(lacZ/+) mice with the conditional Ht-PA::Cre; beta1(neo/+) and beta1(fl/fl) mice and compared the phenotype of embryos of different genotypes during enteric nervous system (ENS) development. The Sox10(lacZ/+); Ht-PA::Cre; beta1(neo/fl) double mutant embryos presented with increased intestinal aganglionosis length and more severe neuronal network disorganization compared to single mutants. These defects, detected by E11.5, are not compensated after birth, showing that a coordinated and balanced interaction between these two genes is required for normal ENS development. Use of video-microscopy revealed that defects observed result from reduced migration speed and altered directionality of enteric neural crest cells. Expression of β1-integrins upon SOX10 overexpression or in Sox10(lacZ/+) mice was also analyzed. The modulation of SOX10 expression altered β1-integrins, suggesting that SOX10 levels are critical for proper expression and function of this adhesion molecule. Together with previous studies, our results strongly indicate that SOX10 mediates ENCC adhesion and migration, and contribute to the understanding of the molecular and cellular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 mutations.
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Affiliation(s)
- Yuli Watanabe
- INSERM U955, Equipe 11, F-94000 Créteil, France; Université Paris-Est, UMR_S955, UPEC, F-94000 Créteil, France
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Obermayr F, Hotta R, Enomoto H, Young HM. Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol 2013; 10:43-57. [PMID: 23229326 DOI: 10.1038/nrgastro.2012.234] [Citation(s) in RCA: 148] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The enteric nervous system (ENS) arises from neural crest-derived cells that migrate into and along the gut, leading to the formation of a complex network of neurons and glial cells that regulates motility, secretion and blood flow. This Review summarizes the progress made in the past 5 years in our understanding of ENS development, including the migratory pathways of neural crest-derived cells as they colonize the gut. The importance of interactions between neural crest-derived cells, between signalling pathways and between developmental processes (such as proliferation and migration) in ensuring the correct development of the ENS is also presented. The signalling pathways involved in ENS development that were determined using animal models are also described, as is the evidence for the involvement of the genes encoding these molecules in Hirschsprung disease-the best characterized paediatric enteric neuropathy. Finally, the aetiology and treatment of Hirschsprung disease in the clinic and the potential involvement of defects in ENS development in other paediatric motility disorders are outlined.
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Affiliation(s)
- Florian Obermayr
- Department of Pediatric Surgery, University Children's Hospital, University of Tübingen, Hoppe-Seyler Straße 3, Tübingen 72076, Germany
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Goldstein AM, Hofstra RMW, Burns AJ. Building a brain in the gut: development of the enteric nervous system. Clin Genet 2012; 83:307-16. [PMID: 23167617 DOI: 10.1111/cge.12054] [Citation(s) in RCA: 114] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 11/01/2012] [Accepted: 11/01/2012] [Indexed: 12/29/2022]
Abstract
The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is an essential component of the gut neuromusculature and controls many aspects of gut function, including coordinated muscular peristalsis. The ENS is entirely derived from neural crest cells (NCC) which undergo a number of key processes, including extensive migration into and along the gut, proliferation, and differentiation into enteric neurons and glia, during embryogenesis and fetal life. These mechanisms are under the molecular control of numerous signaling pathways, transcription factors, neurotrophic factors and extracellular matrix components. Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies, arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR), or aganglionic megacolon. This review focuses on the molecular and genetic factors regulating ENS development from NCC, the clinical genetics of HSCR and its associated syndromes, and recent advances aimed at improving our understanding and treatment of enteric neuropathies.
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Affiliation(s)
- A M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Moore SW. Chromosomal and related Mendelian syndromes associated with Hirschsprung's disease. Pediatr Surg Int 2012; 28:1045-58. [PMID: 23001136 DOI: 10.1007/s00383-012-3175-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/28/2012] [Indexed: 12/12/2022]
Abstract
Hirschsprung's disease (HSCR) is a fairly frequent cause of intestinal obstruction in children. It is characterized as a sex-linked heterogonous disorder with variable severity and incomplete penetrance giving rise to a variable pattern of inheritance. Although Hirschsprung's disease occurs as an isolated phenotype in at least 70% of cases, it is not infrequently associated with a number of congenital abnormalities and associated syndromes, demonstrating a spectrum of congenital anomalies. Certain of these syndromic phenotypes have been linked to distinct genetic sites, indicating underlying genetic associations of the disease and probable gene-gene interaction, in its pathogenesis. These associations with HSCR include Down's syndrome and other chromosomal anomalies, Waardenburg syndrome and other Dominant sensorineural deafness, the Congenital Central Hypoventilation and Mowat-Wilson and other brain-related syndromes, as well as the MEN2 and other tumour associations. A number of other autosomal recessive syndromes include the Shah-Waardenburg, the Bardet-Biedl and Cartilage-hair hypoplasia, Goldberg-Shprintzen syndromes and other syndromes related to cholesterol and fat metabolism among others. The genetics of Hirschsprung's disease are highly complex with the majority of known genetic sites relating to the main susceptibility pathways (RET an EDNRB). Non-syndromic non-familial, short-segment HSCR appears to represent a non-Mendelian condition with variable expression and sex-dependent penetrance. Syndromic and familial forms, on the other hand, have complex patterns of inheritance and being reported as autosomal dominant, recessive and polygenic patterns of inheritance. The phenotypic variability and incomplete penetrance observed in Hirschsprung's disease could also be explained by the involvement of modifier genes, especially in its syndromic forms. In this review, we look at the chromosomal and Mendelian associations and their underlying signalling pathways, to obtain a better understanding of the pathogenetic mechanisms involved in developing aganglionosis of the distal bowel.
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Affiliation(s)
- S W Moore
- Division of Pediatric Surgery, Department of Surgical Sciences, Faculty of Health Sciences, University of Stellenbosch, P.O. Box 19063, Tygerberg, South Africa.
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Trans-mesenteric neural crest cells are the principal source of the colonic enteric nervous system. Nat Neurosci 2012; 15:1211-8. [PMID: 22902718 DOI: 10.1038/nn.3184] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Accepted: 07/12/2012] [Indexed: 12/23/2022]
Abstract
Cell migration is fundamental to organogenesis. During development, the enteric neural crest cells (ENCCs) that give rise to the enteric nervous system (ENS) migrate and colonize the entire length of the gut, which undergoes substantial growth and morphological rearrangement. How ENCCs adapt to such changes during migration, however, is not fully understood. Using time-lapse imaging analyses of mouse ENCCs, we show that a population of ENCCs crosses from the midgut to the hindgut via the mesentery during a developmental time period in which these gut regions are transiently juxtaposed, and that such 'trans-mesenteric' ENCCs constitute a large part of the hindgut ENS. This migratory process requires GDNF signaling, and evidence suggests that impaired trans-mesenteric migration of ENCCs may underlie the pathogenesis of Hirschsprung disease (intestinal aganglionosis). The discovery of this trans-mesenteric ENCC population provides a basis for improving our understanding of ENS development and pathogenesis.
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McKeown SJ, Stamp L, Hao MM, Young HM. Hirschsprung disease: a developmental disorder of the enteric nervous system. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2012; 2:113-29. [PMID: 23799632 DOI: 10.1002/wdev.57] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hirschsprung disease (HSCR), which is also called congenital megacolon or intestinal aganglionosis, is characterized by an absence of enteric (intrinsic) neurons from variable lengths of the most distal bowel. Because enteric neurons are essential for propulsive intestinal motility, infants with HSCR suffer from severe constipation and have a distended abdomen. Currently the only treatment is surgical removal of the affected bowel. HSCR has an incidence of around 1:5,000 live births, with a 4:1 male:female gender bias. Most enteric neurons arise from neural crest cells that emigrate from the caudal hindbrain and then migrate caudally along the entire gut. The absence of enteric neurons from variable lengths of the bowel in HSCR results from a failure of neural crest-derived cells to colonize the affected gut regions. HSCR is therefore regarded as a neurocristopathy. HSCR is a multigenic disorder and has become a paradigm for understanding complex factorial disorders. The major HSCR susceptibility gene is RET. The penetrance of several mutations in HSCR susceptibility genes is sex-dependent. HSCR can occur as an isolated disorder or as part of syndromes; for example, Type IV Waardenburg syndrome is characterized by deafness and pigmentation defects as well as intestinal aganglionosis. Studies using animal models have shown that HSCR genes regulate multiple processes including survival, proliferation, differentiation, and migration. Research into HSCR and the development of enteric neurons is an excellent example of the cross fertilization of ideas that can occur between human molecular geneticists and researchers using animal models. WIREs Dev Biol 2013, 2:113-129. doi: 10.1002/wdev.57 For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- Sonja J McKeown
- Department of Anatomy & Cell Biology, University of Melbourne, Melbourne 3010, VIC, Australia
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Abstract
The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, consists of numerous types of neurons, and glial cells, that are distributed in two intramuscular plexuses that extend along the entire length of the gut and control co-ordinated smooth muscle contractile activity and other gut functions. All enteric neurons and glia are derived from neural crest cells (NCC). Vagal (hindbrain) level NCC provide the majority of enteric precursors along the entire length of the gut, while a lesser contribution, that is restricted to the hindgut, arises from the sacral region of the neuraxis. After leaving the dorsal neural tube NCC undergo extensive migration, proliferation, survival and differentiation in order to form a functional ENS. This article reviews the molecular mechanisms underlying these key developmental processes and highlights the major groups of molecules that affect enteric NCC proliferation and survival (Ret/Gdnf and EdnrB/Et-3 pathways, Sox10 and Phox2b transcription factors), cell migration (Ret and EdnrB signalling, semaphorin 3A, cell adhesion molecules, Rho GTPases), and the development of enteric neuronal subtypes and morphologies (Mash1, Gdnf/neurturin, BMPs, Hand2, retinoic acid). Finally, looking to the future, we discuss the need to translate the wealth of data gleaned from animal studies to the clinical area and thus better understand, and develop treatments for, congenital human diseases affecting the ENS.
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Mundell NA, Plank JL, LeGrone AW, Frist AY, Zhu L, Shin MK, Southard-Smith EM, Labosky PA. Enteric nervous system specific deletion of Foxd3 disrupts glial cell differentiation and activates compensatory enteric progenitors. Dev Biol 2012; 363:373-87. [PMID: 22266424 DOI: 10.1016/j.ydbio.2012.01.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2011] [Revised: 01/02/2012] [Accepted: 01/03/2012] [Indexed: 11/16/2022]
Abstract
The enteric nervous system (ENS) arises from the coordinated migration, expansion and differentiation of vagal and sacral neural crest progenitor cells. During development, vagal neural crest cells enter the foregut and migrate in a rostro-to-caudal direction, colonizing the entire gastrointestinal tract and generating the majority of the ENS. Sacral neural crest contributes to a subset of enteric ganglia in the hindgut, colonizing the colon in a caudal-to-rostral wave. During this process, enteric neural crest-derived progenitors (ENPs) self-renew and begin expressing markers of neural and glial lineages as they populate the intestine. Our earlier work demonstrated that the transcription factor Foxd3 is required early in neural crest-derived progenitors for self-renewal, multipotency and establishment of multiple neural crest-derived cells and structures including the ENS. Here, we describe Foxd3 expression within the fetal and postnatal intestine: Foxd3 was strongly expressed in ENPs as they colonize the gastrointestinal tract and was progressively restricted to enteric glial cells. Using a novel Ednrb-iCre transgene to delete Foxd3 after vagal neural crest cells migrate into the midgut, we demonstrated a late temporal requirement for Foxd3 during ENS development. Lineage labeling of Ednrb-iCre expressing cells in Foxd3 mutant embryos revealed a reduction of ENPs throughout the gut and loss of Ednrb-iCre lineage cells in the distal colon. Although mutant mice were viable, defects in patterning and distribution of ENPs were associated with reduced proliferation and severe reduction of glial cells derived from the Ednrb-iCre lineage. Analyses of ENS-lineage and differentiation in mutant embryos suggested activation of a compensatory population of Foxd3-positive ENPs that did not express the Ednrb-iCre transgene. Our findings highlight the crucial roles played by Foxd3 during ENS development including progenitor proliferation, neural patterning, and glial differentiation and may help delineate distinct molecular programs controlling vagal versus sacral neural crest development.
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Affiliation(s)
- Nathan A Mundell
- Center for Stem Cell Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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Swamydas M, Nguyen D, Allen LD, Eddy J, Dréau D. Progranulin stimulated by LPA promotes the migration of aggressive breast cancer cells. ACTA ACUST UNITED AC 2011; 18:119-30. [PMID: 22176685 DOI: 10.3109/15419061.2011.641042] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Activator and inhibitor roles for the 88-kDa-secreted glycoprotein progranulin (PGRN) have been demonstrated in ovarian cancer cells. Here, we investigated the effects of PGRN in breast cancer migration. Testing MCF7, MDA-MB-453, and MDA-MB-231 human breast cancer cells and the MCF10A breast epithelial cell line, we demonstrate that LPA-induced PGRN stimulation led to a significant increase in cell invasion of MDA-MB-453 and MDA-MB-231 cells only (p<0.05). Moreover, incubation with an anti-PGRN antibody, an inhibitor of the ERK pathway (PD98059) or both in combination inhibited the ability of MDA-MB-231 cells to invade. Furthermore, the expression of focal adhesion kinases promoted by LPA-induced PGRN was also inhibited by PD98059 alone or in combination with an anti-PGRN antibody (p<0.05). Taken together, these results suggest that the LPA activation of PGRN involving the ERK pathway is critical to promote MDA-MB-231 breast cancer cell invasion.
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Affiliation(s)
- Muthulekha Swamydas
- Cellular and Molecular Division, Department of Biology, University of North Carolina-Charlotte, University City Blvd, Charlotte, NC 28223, USA
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Wallace AS, Anderson RB. Genetic interactions and modifier genes in Hirschsprung's disease. World J Gastroenterol 2011; 17:4937-44. [PMID: 22174542 PMCID: PMC3236992 DOI: 10.3748/wjg.v17.i45.4937] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 06/09/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung’s disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung’s disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung’s disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung’s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung’s disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.
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Wallace AS, Tan MX, Schachner M, Anderson RB. L1cam acts as a modifier gene for members of the endothelin signalling pathway during enteric nervous system development. Neurogastroenterol Motil 2011; 23:e510-22. [PMID: 21395909 DOI: 10.1111/j.1365-2982.2011.01692.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND The enteric nervous system originates from neural crest cells that migrate into the embryonic foregut and then sequentially colonize the midgut and hindgut. Defects in neural crest migration result in regions of the gut that lack enteric ganglia, a condition in humans called Hirschsprung's disease. The high degree of phenotypic variability reported in Hirschsprung's disease suggests the involvement of modifier genes. METHODS We used a two-locus complementation approach to screen for genetic interactions between L1cam and members of the endothelin signalling pathway. Immunohistochemistry was used to label PGP9.5(+) enteric neurons and Sox10(+) neural crest-derived cells in wholemount preparations of embryonic gut. Key Results Loss or haploinsufficiency of L1cam significantly increased the severity of aganglionosis in Et-3 and Ednrb null mutant embryos. Furthermore, the colonization of the developing gut by neural crest-derived cells was significantly delayed in L1cam(-/y) ; Et-3(-/-) and L1cam(-/y) ;Ednrb(sl/sl) embryos. CONCLUSIONS & INFERENCES We have identified the X-linked gene, L1cam, as the first modifier gene for members of the endothelin signalling pathway during development of the enteric nervous system. Mutations in L1CAM may act to modulate the severity of aganglionosis in some cases of Hirschsprung's disease.
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Affiliation(s)
- A S Wallace
- Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Melbourne, Victoria, Australia
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Chaoui A, Watanabe Y, Touraine R, Baral V, Goossens M, Pingault V, Bondurand N. Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. Hum Mutat 2011; 32:1436-49. [PMID: 21898658 DOI: 10.1002/humu.21583] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Accepted: 07/28/2011] [Indexed: 11/09/2022]
Abstract
Waardenburg syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action.
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Affiliation(s)
- Asma Chaoui
- INSERM U955, Hôpital Henri Mondor, Créteil, France
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