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1
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Mombeek LMM, Boesmans W, Wilson DM. Genomic stress in diseases stemming from defects in the second brain. Neurogastroenterol Motil 2024:e14860. [PMID: 39004995 DOI: 10.1111/nmo.14860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 06/04/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024]
Abstract
This review discusses the less-explored realm of DNA damage and repair within the enteric nervous system (ENS), often referred to as the "second brain." While the central nervous system has been extensively studied for its DNA repair mechanisms and associated neuropathologies, the ENS, which can autonomously coordinate gastrointestinal function, experiences unique challenges and vulnerabilities related to its genome integrity. The susceptibility of the ENS to DNA damage is exacerbated by its limited protective barriers, resulting in not only endogenous genotoxic exposures, such as oxidative stress, but also exogenous threats, such as ingested environmental contaminants, local inflammatory responses, and gut dysbiosis. Here, we discuss the evidence for DNA repair defects in enteric neuropathies, most notably, the reported relationship between inherited mutations in RAD21 and LIG3 with chronic intestinal pseudo-obstruction and mitochondrial gastrointestinal encephalomyopathy disorders, respectively. We also introduce the lesser-recognized gastrointestinal complications in DNA repair syndromes, including conditions like Cockayne syndrome. The review concludes by pointing out the potential role of DNA repair defects in not only congenital disorders but also aging-related gut dysfunction, as well as the crucial need for further research to establish direct causal links between DNA damage accumulation and ENS-specific pathologic phenotypes.
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Affiliation(s)
- Lobke Marie M Mombeek
- Faculty of Medicine and Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Werend Boesmans
- Faculty of Medicine and Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, Maastricht, The Netherlands
| | - David M Wilson
- Faculty of Medicine and Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
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2
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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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3
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Kanai SM, Clouthier DE. Endothelin signaling in development. Development 2023; 150:dev201786. [PMID: 38078652 PMCID: PMC10753589 DOI: 10.1242/dev.201786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
Since the discovery of endothelin 1 (EDN1) in 1988, the role of endothelin ligands and their receptors in the regulation of blood pressure in normal and disease states has been extensively studied. However, endothelin signaling also plays crucial roles in the development of neural crest cell-derived tissues. Mechanisms of endothelin action during neural crest cell maturation have been deciphered using a variety of in vivo and in vitro approaches, with these studies elucidating the basis of human syndromes involving developmental differences resulting from altered endothelin signaling. In this Review, we describe the endothelin pathway and its functions during the development of neural crest-derived tissues. We also summarize how dysregulated endothelin signaling causes developmental differences and how this knowledge may lead to potential treatments for individuals with gene variants in the endothelin pathway.
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Affiliation(s)
- Stanley M. Kanai
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - David E. Clouthier
- Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Jacobs-Li J, Tang W, Li C, Bronner ME. Single-cell profiling coupled with lineage analysis reveals vagal and sacral neural crest contributions to the developing enteric nervous system. eLife 2023; 12:e79156. [PMID: 37877560 PMCID: PMC10627514 DOI: 10.7554/elife.79156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 10/23/2023] [Indexed: 10/26/2023] Open
Abstract
During development, much of the enteric nervous system (ENS) arises from the vagal neural crest that emerges from the caudal hindbrain and colonizes the entire gastrointestinal tract. However, a second ENS contribution comes from the sacral neural crest that arises in the caudal neural tube and populates the post-umbilical gut. By coupling single-cell transcriptomics with axial-level-specific lineage tracing in avian embryos, we compared the contributions of embryonic vagal and sacral neural crest cells to the chick ENS and the associated peripheral ganglia (Nerve of Remak and pelvic plexuses). At embryonic day (E) 10, the two neural crest populations form overlapping subsets of neuronal and glia cell types. Surprisingly, the post-umbilical vagal neural crest much more closely resembles the sacral neural crest than the pre-umbilical vagal neural crest. However, some differences in cluster types were noted between vagal and sacral derived cells. Notably, RNA trajectory analysis suggests that the vagal neural crest maintains a neuronal/glial progenitor pool, whereas this cluster is depleted in the E10 sacral neural crest which instead has numerous enteric glia. The present findings reveal sacral neural crest contributions to the hindgut and associated peripheral ganglia and highlight the potential influence of the local environment and/or developmental timing in differentiation of neural crest-derived cells in the developing ENS.
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Affiliation(s)
- Jessica Jacobs-Li
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Weiyi Tang
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Can Li
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of TechnologyPasadenaUnited States
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5
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Montalva L, Cheng LS, Kapur R, Langer JC, Berrebi D, Kyrklund K, Pakarinen M, de Blaauw I, Bonnard A, Gosain A. Hirschsprung disease. Nat Rev Dis Primers 2023; 9:54. [PMID: 37828049 DOI: 10.1038/s41572-023-00465-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/12/2023] [Indexed: 10/14/2023]
Abstract
Hirschsprung disease (HSCR) is a rare congenital intestinal disease that occurs in 1 in 5,000 live births. HSCR is characterized by the absence of ganglion cells in the myenteric and submucosal plexuses of the intestine. Most patients present during the neonatal period with the first meconium passage delayed beyond 24 h, abdominal distension and vomiting. Syndromes associated with HSCR include trisomy 21, Mowat-Wilson syndrome, congenital central hypoventilation syndrome, Shah-Waardenburg syndrome and cartilage-hair hypoplasia. Multiple putative genes are involved in familial and isolated HSCR, of which the most common are the RET proto-oncogene and EDNRB. Diagnosis consists of visualization of a transition zone on contrast enema and confirmation via rectal biopsy. HSCR is typically managed by surgical removal of the aganglionic bowel and reconstruction of the intestinal tract by connecting the normally innervated bowel down to the anus while preserving normal sphincter function. Several procedures, namely Swenson, Soave and Duhamel procedures, can be undertaken and may include a laparoscopically assisted approach. Short-term and long-term comorbidities include persistent obstructive symptoms, enterocolitis and soiling. Continued research and innovation to better understand disease mechanisms holds promise for developing novel techniques for diagnosis and therapy, and improving outcomes in patients.
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Affiliation(s)
- Louise Montalva
- Department of Paediatric Surgery, Robert-Debré Children's University Hospital, Paris, France.
- Faculty of Health, Paris-Cité University, Paris, France.
- NeuroDiderot, INSERM UMR1141, Paris, France.
| | - Lily S Cheng
- Division of Paediatric Surgery, Texas Children's Hospital, Houston, TX, USA
- Division of Paediatric Surgery, University of Virginia, Charlottesville, VA, USA
| | - Raj Kapur
- Department of Pathology, Seattle Children's Hospital, Seattle, WA, USA
| | - Jacob C Langer
- Division of Paediatric Surgery, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Dominique Berrebi
- Department of Pathology, Robert-Debré and Necker Children's University Hospital, Paris, France
| | - Kristiina Kyrklund
- Department of Paediatric Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Mikko Pakarinen
- Department of Paediatric Surgery, Helsinki University Central Hospital, Helsinki, Finland
| | - Ivo de Blaauw
- Department of Surgery, Division of Paediatric Surgery, Radboudumc-Amalia Children's Hospital, Nijmegen, Netherlands
| | - Arnaud Bonnard
- Department of Paediatric Surgery, Robert-Debré Children's University Hospital, Paris, France
- Faculty of Health, Paris-Cité University, Paris, France
- NeuroDiderot, INSERM UMR1141, Paris, France
| | - Ankush Gosain
- Department of Paediatric Surgery, Children's Hospital Colorado, Aurora, CO, USA.
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Marable SS, Bronner ME. Reprogramming of trunk neural crest to a cranial crest-like identity alters their transcriptome and developmental potential. Differentiation 2023; 131:27-37. [PMID: 37058884 PMCID: PMC10330191 DOI: 10.1016/j.diff.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 04/08/2023]
Abstract
Neural crest cells along the body axis of avian embryos differ in their developmental potential, such that the cranial neural crest forms cartilage and bone whereas the trunk neural crest is unable to do so. Previous studies have identified a cranial crest-specific subcircuit that can imbue the trunk neural crest with the ability to form cartilage after grafting to the head. Here, we examine transcriptional and cell fate changes that accompany this reprogramming. First, we examined whether reprogrammed trunk neural crest maintain the ability to form cartilage in their endogenous environment in the absence of cues from the head. The results show that some reprogrammed cells contribute to normal trunk neural crest derivatives, whereas others migrate ectopically to the forming vertebrae and express cartilage markers, thus mimicking heterotypically transplanted cranial crest cells. We find that reprogrammed trunk neural crest upregulated more than 3000 genes in common with cranial neural crest, including numerous transcriptional regulators. In contrast, many trunk neural crest genes are downregulated. Together, our findings show that reprogramming trunk neural crest with cranial crest subcircuit genes alters their gene regulatory program and developmental potential to be more cranial crest-like.
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Affiliation(s)
- Sierra S Marable
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
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Halasy V, Szőcs E, Soós Á, Kovács T, Pecsenye-Fejszák N, Hotta R, Goldstein AM, Nagy N. CXCR4 and CXCL12 signaling regulates the development of extrinsic innervation to the colorectum. Development 2023; 150:dev201289. [PMID: 37039233 PMCID: PMC10263150 DOI: 10.1242/dev.201289] [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: 09/09/2022] [Accepted: 01/25/2023] [Indexed: 04/12/2023]
Abstract
The gastrointestinal tract is innervated by an intrinsic neuronal network, known as the enteric nervous system (ENS), and by extrinsic axons arising from peripheral ganglia. The nerve of Remak (NoR) is an avian-specific sacral neural crest-derived ganglionated structure that extends from the cloaca to the proximal midgut and, similar to the pelvic plexus, provides extrinsic innervation to the distal intestine. The molecular mechanisms controlling extrinsic nerve fiber growth into the gut is unknown. In vertebrates, CXCR4, a cell-surface receptor for the CXCL12 chemokine, regulates migration of neural crest cells and axon pathfinding. We have employed chimeric tissue recombinations and organ culture assays to study the role of CXCR4 and CXCL12 molecules in the development of colorectal innervation. CXCR4 is specifically expressed in nerve fibers arising from the NoR and pelvic plexus, while CXCL12 is localized to the hindgut mesenchyme and enteric ganglia. Overexpression of CXCL12 results in significantly enhanced axonal projections to the gut from the NoR, while CXCR4 inhibition disrupts nerve fiber extension, supporting a previously unreported role for CXCR4 and CXCL12 signaling in extrinsic innervation of the colorectum.
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Affiliation(s)
- Viktória Halasy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Emőke Szőcs
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Ádám Soós
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Tamás Kovács
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Nóra Pecsenye-Fejszák
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Ryo Hotta
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Allan M. Goldstein
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Nándor Nagy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
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8
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Fan Y, Hackland J, Baggiolini A, Hung LY, Zhao H, Zumbo P, Oberst P, Minotti AP, Hergenreder E, Najjar S, Huang Z, Cruz NM, Zhong A, Sidharta M, Zhou T, de Stanchina E, Betel D, White RM, Gershon M, Margolis KG, Studer L. hPSC-derived sacral neural crest enables rescue in a severe model of Hirschsprung's disease. Cell Stem Cell 2023; 30:264-282.e9. [PMID: 36868194 PMCID: PMC10034921 DOI: 10.1016/j.stem.2023.02.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 11/22/2022] [Accepted: 02/02/2023] [Indexed: 03/05/2023]
Abstract
The enteric nervous system (ENS) is derived from both the vagal and sacral component of the neural crest (NC). Here, we present the derivation of sacral ENS precursors from human PSCs via timed exposure to FGF, WNT, and GDF11, which enables posterior patterning and transition from posterior trunk to sacral NC identity, respectively. Using a SOX2::H2B-tdTomato/T::H2B-GFP dual reporter hPSC line, we demonstrate that both trunk and sacral NC emerge from a double-positive neuro-mesodermal progenitor (NMP). Vagal and sacral NC precursors yield distinct neuronal subtypes and migratory behaviors in vitro and in vivo. Remarkably, xenografting of both vagal and sacral NC lineages is required to rescue a mouse model of total aganglionosis, suggesting opportunities in the treatment of severe forms of Hirschsprung's disease.
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Affiliation(s)
- Yujie Fan
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA
| | - James Hackland
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Arianna Baggiolini
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lin Y Hung
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Huiyong Zhao
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Paul Zumbo
- Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA
| | - Polina Oberst
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Andrew P Minotti
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA
| | - Emiliano Hergenreder
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10065, USA
| | - Sarah Najjar
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Zixing Huang
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Nelly M Cruz
- Cancer Biology and Genetics and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Aaron Zhong
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; The SKI Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mega Sidharta
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; The SKI Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ting Zhou
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; The SKI Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Elisa de Stanchina
- Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Doron Betel
- Applied Bioinformatics Core, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USA
| | - Richard M White
- Cancer Biology and Genetics and Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael Gershon
- Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
| | - Kara Gross Margolis
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA; Department of Pediatrics, NYU Grossman School of Medicine, New York, NY 10010, USA
| | - Lorenz Studer
- The Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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9
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Stavely R, Hotta R, Guyer RA, Picard N, Rahman AA, Omer M, Soos A, Szocs E, Mueller J, Goldstein AM, Nagy N. A distinct transcriptome characterizes neural crest-derived cells at the migratory wavefront during enteric nervous system development. Development 2023; 150:dev201090. [PMID: 36779913 PMCID: PMC10108706 DOI: 10.1242/dev.201090] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 02/03/2023] [Indexed: 02/14/2023]
Abstract
Enteric nervous system development relies on intestinal colonization by enteric neural crest-derived cells (ENCDCs). This is driven by a population of highly migratory and proliferative ENCDCs at the wavefront, but the molecular characteristics of these cells are unknown. ENCDCs from the wavefront and the trailing region were isolated and subjected to RNA-seq. Wavefront-ENCDCs were transcriptionally distinct from trailing ENCDCs, and temporal modelling confirmed their relative immaturity. This population of ENCDCs exhibited altered expression of ECM and cytoskeletal genes, consistent with a migratory phenotype. Unlike trailing ENCDCs, the wavefront lacked expression of genes related to neuronal or glial maturation. As wavefront ENCDC genes were associated with migration and developmental immaturity, the genes that remain expressed in later progenitor populations may be particularly pertinent to understanding the maintenance of ENCDC progenitor characteristics. Dusp6 expression was specifically upregulated at the wavefront. Inhibiting DUSP6 activity prevented wavefront colonization of the hindgut, and inhibited the migratory ability of post-colonized ENCDCs from midgut and postnatal neurospheres. These effects were reversed by simultaneous inhibition of ERK signaling, indicating that DUSP6-mediated ERK inhibition is required for ENCDC migration in mouse and chick.
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Affiliation(s)
- Rhian Stavely
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Richard A. Guyer
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Nicole Picard
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Ahmed A. Rahman
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Meredith Omer
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Adam Soos
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Emoke Szocs
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Jessica Mueller
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Allan M. Goldstein
- Department of Pediatric Surgery, Pediatric Surgery Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Nandor Nagy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
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10
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Ganz J, Ratcliffe EM. Who's talking to whom: microbiome-enteric nervous system interactions in early life. Am J Physiol Gastrointest Liver Physiol 2023; 324:G196-G206. [PMID: 36625480 PMCID: PMC9988524 DOI: 10.1152/ajpgi.00166.2022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 12/22/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023]
Abstract
The enteric nervous system (ENS) is the intrinsic nervous system of the gastrointestinal tract (GI) and regulates important GI functions, including motility, nutrient uptake, and immune response. The development of the ENS begins during early organogenesis and continues to develop once feeding begins, with ongoing plasticity into adulthood. There has been increasing recognition that the intestinal microbiota and ENS interact during critical periods, with implications for normal development and potential disease pathogenesis. In this review, we focus on insights from mouse and zebrafish model systems to compare and contrast how each model can serve in elucidating the bidirectional communication between the ENS and the microbiome. At the end of this review, we further outline implications for human disease and highlight research innovations that can lead the field forward.
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Affiliation(s)
- Julia Ganz
- Department of Integrative Biology, Michigan State University, East Lansing, Michigan, United States
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11
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Sicard P, Falco A, Faure S, Thireau J, Lindsey SE, Chauvet N, de Santa Barbara P. High-resolution ultrasound and speckle tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development. Development 2022; 149:dev200625. [PMID: 35912573 PMCID: PMC10655954 DOI: 10.1242/dev.200625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 07/18/2022] [Indexed: 11/19/2023]
Abstract
Gastrointestinal motor activity has been extensively studied in adults; however, only few studies have investigated fetal motor skills. It is unknown when the gastrointestinal tract starts to contract during the embryonic period and how this function evolves during development. Here, we adapted a non-invasive high-resolution echography technique combined with speckle tracking analysis to examine the gastrointestinal tract motor activity dynamics during chick embryo development. We provided the first recordings of fetal gastrointestinal motility in living embryos without anesthesia. We found that, although gastrointestinal contractions appear very early during development, they become synchronized only at the end of the fetal period. To validate this approach, we used various pharmacological inhibitors and BAPX1 gene overexpression in vivo. We found that the enteric nervous system determines the onset of the synchronized contractions in the stomach. Moreover, alteration of smooth muscle fiber organization led to an impairment of this functional activity. Altogether, our findings show that non-invasive high-resolution echography and speckle tracking analysis allows visualization and quantification of gastrointestinal motility during development and highlight the progressive acquisition of functional and coordinated gastrointestinal motility before birth.
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Affiliation(s)
- Pierre Sicard
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
- IPAM, Biocampus Montpellier, CNRS, INSERM, University of Montpellier, 34295 Montpellier, France
| | - Amandine Falco
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
| | - Sandrine Faure
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
| | - Jérome Thireau
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
| | - Stéphanie E. Lindsey
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
- Department of Mechanical and Aerospace Engineering, University of California San Diego (UCSD), La Jolla, CA 92093, USA
| | - Norbert Chauvet
- PhyMedExp, University of Montpellier, INSERM, CNRS, 34295 Montpellier, France
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12
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Yang W, Pham J, King SK, Newgreen DF, Young HM, Stamp LA, Hao MM. A Novel Method for Identifying the Transition Zone in Long-Segment Hirschsprung Disease: Investigating the Muscle Unit to Ganglion Ratio. Biomolecules 2022; 12:biom12081101. [PMID: 36008996 PMCID: PMC9406109 DOI: 10.3390/biom12081101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Hirschsprung disease (HSCR) is characterised by the absence of enteric ganglia along variable lengths of the distal bowel. Current gold standard treatment involves the surgical resection of the defective, aganglionic bowel. Clear and reliable distinction of the normoganglionated bowel from the transition zone is key for successful resection of the entire defective bowel, and the avoidance of subsequent postoperative complications. However, the intraoperative nature of the tissue analysis and the variability of patient samples, sample preparation, and operator objectivity, make reproducible identification of the transition zone difficult. Here, we have described a novel method for using muscle units as a distinctive landmark for quantifying the density of enteric ganglia in resection specimens from HSCR patients. We show that the muscle unit to ganglion ratio is greater in the transition zone when compared with the proximal, normoganglionated region for long-segment HSCR patients. Patients with short-segment HSCR were also investigated, however, the muscle unit to ganglion ratio was not significantly different in these patients. Immunohistochemical examination of individual ganglia showed that there were no differences in the proportions of either enteric neurons or glial cells through the different regions of the resected colon. In addition, we identified that the size of enteric ganglia was smaller for patients that went on to develop HSCR associated enterocolitis; although the density of ganglia, as determined by the muscle unit to ganglia ratio, was not different when compared with patients that had no further complications. This suggests that subtle changes in the enteric nervous system, even in the “normoganglionated” colon, could be involved in changes in immune function and subsequent bacterial dysbiosis.
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Affiliation(s)
- Wendy Yang
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, Australia
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10663, Taiwan
| | - Jenny Pham
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, Australia
| | - Sebastian K. King
- Murdoch Children’s Research Institute, Parkville 3052, Australia
- Department of Paediatric Surgery, The Royal Children’s Hospital, Parkville 3052, Australia
- Department of Paediatrics, The University of Melbourne, Parkville 3010, Australia
| | | | - Heather M. Young
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, Australia
| | - Lincon A. Stamp
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, Australia
- Correspondence: (L.A.S.); (M.M.H.)
| | - Marlene M. Hao
- Department of Anatomy and Physiology, The University of Melbourne, Parkville 3010, Australia
- Correspondence: (L.A.S.); (M.M.H.)
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13
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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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14
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MacKenzie KC, Garritsen R, Chauhan RK, Sribudiani Y, de Graaf BM, Rugenbrink T, Brouwer R, van Ijcken WFJ, de Blaauw I, Brooks AS, Sloots CEJ, Meeuwsen CJHM, Wijnen RM, Newgreen DF, Burns AJ, Hofstra RMW, Alves MM, Brosens E. The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model. Int J Mol Sci 2021; 22:12354. [PMID: 34830235 PMCID: PMC8624421 DOI: 10.3390/ijms222212354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/20/2022] Open
Abstract
Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested-whole blood, dermal fibroblasts or saliva-but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to 'missing heritability' in developmental defects.
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Affiliation(s)
- Katherine C. MacKenzie
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
| | - Rhiana Garritsen
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
- Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (I.d.B.); (C.E.J.S.); (C.J.H.M.M.); (R.M.W.)
| | - Rajendra K. Chauhan
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
- Fluidigm Europe B.V., 1101 CM Amstelveen, The Netherlands
| | - Yunia Sribudiani
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Universitas of Padjadjaran, Bandung 45363, Indonesia
| | - Bianca M. de Graaf
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
| | - Tim Rugenbrink
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
| | - Rutger Brouwer
- Department of Cell Biology & Center for Biomics, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (R.B.); (W.F.J.v.I.)
| | - Wilfred F. J. van Ijcken
- Department of Cell Biology & Center for Biomics, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; (R.B.); (W.F.J.v.I.)
| | - Ivo de Blaauw
- Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (I.d.B.); (C.E.J.S.); (C.J.H.M.M.); (R.M.W.)
- Department of Paediatric Surgery, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Alice S. Brooks
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
| | - Cornelius E. J. Sloots
- Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (I.d.B.); (C.E.J.S.); (C.J.H.M.M.); (R.M.W.)
| | - Conny J. H. M. Meeuwsen
- Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (I.d.B.); (C.E.J.S.); (C.J.H.M.M.); (R.M.W.)
| | - René M. Wijnen
- Department of Pediatric Surgery, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (I.d.B.); (C.E.J.S.); (C.J.H.M.M.); (R.M.W.)
| | - Donald F. Newgreen
- Department of Cell Biology, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia;
| | - Alan J. Burns
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
- Department of Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
- Takeda Pharmaceuticals, Cambridge, MA 02139, USA
| | - Robert M. W. Hofstra
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
- Department of Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK
| | - Maria M. Alves
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children’s Hospital, 3000 CA Rotterdam, The Netherlands; (K.C.M.); (R.G.); (R.K.C.); (Y.S.); (B.M.d.G.); (T.R.); (A.S.B.); (A.J.B.); (R.M.W.H.)
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15
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Skip segment Hirschsprung's disease: report of two rare cases and management. Pediatr Surg Int 2021; 37:1563-1568. [PMID: 34398296 DOI: 10.1007/s00383-021-04981-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/06/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE Skip segment Hirschsprung's disease (SS-HSCR) is defined as the occurrence of a segment of ganglionated intestine surrounded proximally and distally by aganglionosis. The presence of the skip intestinal segment often leads to clinical misdiagnosis, missed diagnosis or inadequate resection of the lesions. The purpose was to describe two new cases of SS-HSCR with the aim of proposing questions regarding the diagnosis and treatment of this rare disease. METHODS We reported two cases of infants with SS-HSCR that were admitted to our institution within the last 3 years. RESULTS One patient had a skip segment of ganglionated intestine in the ascending colon. In the other patient, there were no ganglionic cells in the rectum and appendix, but ganglionic cells were visible in the proximal ascending colon. The entire colons in the both cases were finally resected, and a pull-through operation was performed. CONCLUSION Multipoint biopsy should be performed when the biopsy results are inconsistent with clinical manifestations. Intraoperative laparoscopic identification of the transition zone may be necessary when TCA is suspected. Multisegment biopsy is needed to as a preventative measure for SS-HSCR if TCA is indicated during surgery. Further study is required to determine the optimal length and method of retention of segments.
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16
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Abstract
Neural crest stem/progenitor cells arise early during vertebrate embryogenesis at the border of the forming central nervous system. They subsequently migrate throughout the body, eventually differentiating into diverse cell types ranging from neurons and glia of the peripheral nervous system to bones of the face, portions of the heart, and pigmentation of the skin. Along the body axis, the neural crest is heterogeneous, with different subpopulations arising in the head, neck, trunk, and tail regions, each characterized by distinct migratory patterns and developmental potential. Modern genomic approaches like single-cell RNA- and ATAC-sequencing (seq) have greatly enhanced our understanding of cell lineage trajectories and gene regulatory circuitry underlying the developmental progression of neural crest cells. Here, we discuss how genomic approaches have provided new insights into old questions in neural crest biology by elucidating transcriptional and posttranscriptional mechanisms that govern neural crest formation and the establishment of axial level identity. Expected final online publication date for the Annual Review of Genetics, Volume 55 is November 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Shashank Gandhi
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA; ,
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA; ,
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17
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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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18
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Pilon N. Treatment and Prevention of Neurocristopathies. Trends Mol Med 2021; 27:451-468. [PMID: 33627291 DOI: 10.1016/j.molmed.2021.01.009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/20/2021] [Accepted: 01/28/2021] [Indexed: 02/07/2023]
Abstract
Neurocristopathies form a heterogeneous group of rare diseases caused by abnormal development of neural crest cells. Heterogeneity of neurocristopathies directly relates to the nature of these migratory and multipotent cells, which generate dozens of specialized cell types throughout the body. Neurocristopathies are thus characterized by congenital malformations of tissues/organs that otherwise appear to have very little in common, such as the craniofacial skeleton and enteric nervous system. Treatment options are currently very limited, mainly consisting of corrective surgeries. Yet, as reviewed here, analyses of normal and pathological neural crest development in model organisms have opened up the possibility for better treatment options involving cellular and molecular approaches. These approaches provide hope that some neurocristopathies might soon be curable or preventable.
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Affiliation(s)
- Nicolas Pilon
- Molecular Genetics of Development Laboratory, Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal H3C 3P8, Québec, Canada; Centre d'Excellence en Recherche sur les Maladies Orphelines - Fondation Courtois (CERMO-FC), Université du Québec à Montréal (UQAM), Montréal H2X 3Y7, Québec, Canada; Département de Pédiatrie, Université de Montréal, Montréal H3T 1C5, Québec, Canada.
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Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung's Disease. Cell Mol Gastroenterol Hepatol 2020; 12:1-24. [PMID: 33340715 PMCID: PMC8082118 DOI: 10.1016/j.jcmgh.2020.12.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 12/14/2020] [Accepted: 12/14/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung's disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD. METHODS Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice. RESULTS After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret-/- mice, showed a high incidence rate of SSHD-like phenotypes. CONCLUSIONS mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR.
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20
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Perera SN, Kerosuo L. On the road again: Establishment and maintenance of stemness in the neural crest from embryo to adulthood. STEM CELLS (DAYTON, OHIO) 2020; 39:7-25. [PMID: 33017496 PMCID: PMC7821161 DOI: 10.1002/stem.3283] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Revised: 09/08/2020] [Accepted: 09/11/2020] [Indexed: 12/22/2022]
Abstract
Unique to vertebrates, the neural crest (NC) is an embryonic stem cell population that contributes to a greatly expanding list of derivatives ranging from neurons and glia of the peripheral nervous system, facial cartilage and bone, pigment cells of the skin to secretory cells of the endocrine system. Here, we focus on what is specifically known about establishment and maintenance of NC stemness and ultimate fate commitment mechanisms, which could help explain its exceptionally high stem cell potential that exceeds the "rules set during gastrulation." In fact, recent discoveries have shed light on the existence of NC cells that coexpress commonly accepted pluripotency factors like Nanog, Oct4/PouV, and Klf4. The coexpression of pluripotency factors together with the exceptional array of diverse NC derivatives encouraged us to propose a new term "pleistopotent" (Greek for abundant, a substantial amount) to be used to reflect the uniqueness of the NC as compared to other post-gastrulation stem cell populations in the vertebrate body, and to differentiate them from multipotent lineage restricted stem cells. We also discuss studies related to the maintenance of NC stemness within the challenging context of being a transient and thus a constantly changing population of stem cells without a permanent niche. The discovery of the stem cell potential of Schwann cell precursors as well as multiple adult NC-derived stem cell reservoirs during the past decade has greatly increased our understanding of how NC cells contribute to tissues formed after its initial migration stage in young embryos.
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Affiliation(s)
- Surangi N Perera
- Neural Crest Development and Disease Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
| | - Laura Kerosuo
- Neural Crest Development and Disease Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA
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21
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Soret R, Schneider S, Bernas G, Christophers B, Souchkova O, Charrier B, Righini-Grunder F, Aspirot A, Landry M, Kembel SW, Faure C, Heuckeroth RO, Pilon N. Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improves Colon Structure and Function in Mouse Models of Hirschsprung Disease. Gastroenterology 2020; 159:1824-1838.e17. [PMID: 32687927 DOI: 10.1053/j.gastro.2020.07.018] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/25/2020] [Accepted: 07/10/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Hirschsprung disease (HSCR) is a life-threatening birth defect in which the distal colon is devoid of enteric neural ganglia. HSCR is treated by surgical removal of aganglionic bowel, but many children continue to have severe problems after surgery. We studied whether administration of glial cell derived neurotrophic factor (GDNF) induces enteric nervous system regeneration in mouse models of HSCR. METHODS We performed studies with four mouse models of HSCR: Holstein (HolTg/Tg, a model for trisomy 21-associated HSCR), TashT (TashTTg/Tg, a model for male-biased HSCR), Piebald-lethal (Ednrbs-l//s-l, a model for EDNRB mutation-associated HSCR), and Ret9/- (with aganglionosis induced by mycophenolate). Mice were given rectal enemas containing GDNF or saline (control) from postnatal days 4 through 8. We measured survival times of mice, and colon tissues were analyzed by histology, immunofluorescence, and immunoblots. Neural ganglia regeneration and structure, bowel motility, epithelial permeability, muscle thickness, and neutrophil infiltration were studied in colon tissues and in mice. Stool samples were collected, and microbiomes were analyzed by 16S rRNA gene sequencing. Time-lapse imaging and genetic cell-lineage tracing were used to identify a source of GDNF-targeted neural progenitors. Human aganglionic colon explants from children with HSCR were cultured with GDNF and evaluated for neurogenesis. RESULTS GDNF significantly prolonged mean survival times of HolTg/Tg mice, Ednrbs-l//s-l mice, and male TashTTg/Tg mice, compared with control mice, but not Ret9/- mice (which had mycophenolate toxicity). Mice given GDNF developed neurons and glia in distal bowel tissues that were aganglionic in control mice, had a significant increase in colon motility, and had significant decreases in epithelial permeability, muscle thickness, and neutrophil density. We observed dysbiosis in fecal samples from HolTg/Tg mice compared with feces from wild-type mice; fecal microbiomes of mice given GDNF were similar to those of wild-type mice except for Bacteroides. Exogenous luminal GDNF penetrated aganglionic colon epithelium of HolTg/Tg mice, inducing production of endogenous GDNF, and new enteric neurons and glia appeared to arise from Schwann cells within extrinsic nerves. GDNF application to cultured explants of human aganglionic bowel induced proliferation of Schwann cells and formation of new neurons. CONCLUSIONS GDNF prolonged survival, induced enteric neurogenesis, and improved colon structure and function in 3 mouse models of HSCR. Application of GDNF to cultured explants of aganglionic bowel from children with HSCR induced proliferation of Schwann cells and formation of new neurons. GDNF might be developed for treatment of HSCR.
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Affiliation(s)
- Rodolphe Soret
- 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
| | - Sabine Schneider
- Department of Pediatrics, the University of Pennsylvania Perelman School of Medicine and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
| | - Guillaume Bernas
- Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
| | - Briana Christophers
- Department of Pediatrics, the University of Pennsylvania Perelman School of Medicine and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
| | - Ouliana Souchkova
- 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
| | - Baptiste Charrier
- 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
| | - Franziska Righini-Grunder
- Division de gastroentérologie, hépatologie et nutrition pédiatrique, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada
| | - Ann Aspirot
- Division de chirurgie pédiatrique, Centre hospitalier universitaire Sainte-Justine, Montréal, Québec, Canada; Département de pédiatrie, Université de Montréal, Montréal, Québec, Canada
| | - Mathieu Landry
- Département des Sciences Biologiques, Université du Québec à Montréal (UQAM), Montréal, Québec, Canada
| | - Steven W Kembel
- 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; Division de gastroentérologie, hépatologie et nutrition pédiatrique, Centre Hospitalier Universitaire Sainte-Justine, Montréal, Québec, Canada; Département de pédiatrie, Université de Montréal, Montréal, Québec, Canada
| | - Robert O Heuckeroth
- Department of Pediatrics, the University of Pennsylvania Perelman School of Medicine and The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania
| | - Nicolas Pilon
- 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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22
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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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El-Nachef WN, Bronner ME. De novo enteric neurogenesis in post-embryonic zebrafish from Schwann cell precursors rather than resident cell types. Development 2020; 147:dev186619. [PMID: 32541008 PMCID: PMC7375481 DOI: 10.1242/dev.186619] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 06/03/2020] [Indexed: 12/12/2022]
Abstract
The enteric nervous system (ENS) is essential for normal gastrointestinal function. Although the embryonic origin of enteric neurons from the neural crest is well established, conflicting evidence exists regarding postnatal enteric neurogenesis. Here, we address this by examining the origin of de novo neurogenesis in the post-embryonic zebrafish ENS. Although new neurons are added during growth and after injury, the larval intestine appears to lack resident neurogenic precursors or classical glia marked by sox10, plp1a, gfap or s100 Rather, lineage tracing with lipophilic dye or inducible Sox10-Cre suggests that post-embryonic enteric neurons arise from trunk neural crest-derived Schwann cell precursors that migrate from the spinal cord into the intestine. Furthermore, the 5-HT4 receptor agonist prucalopride increases enteric neurogenesis in normal development and after injury. Taken together, the results suggest that despite the lack of resident progenitors in the gut, post-embryonic enteric neurogenesis occurs via gut-extrinsic Schwann cell precursors during development and injury, and is promoted by serotonin receptor agonists. The absence of classical glia in the ENS further suggests that neural crest-derived enteric glia might have evolved after the teleost lineage.This article has an associated 'The people behind the papers' interview.
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Affiliation(s)
- Wael Noor El-Nachef
- Department of Medicine, Vatche and Tamar Manoukian Division of Digestive Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
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24
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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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25
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Margarido AS, Le Guen L, Falco A, Faure S, Chauvet N, de Santa Barbara P. PROX1 is a specific and dynamic marker of sacral neural crest cells in the chicken intestine. J Comp Neurol 2019; 528:879-889. [PMID: 31658363 DOI: 10.1002/cne.24801] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 08/31/2019] [Accepted: 10/16/2019] [Indexed: 01/29/2023]
Abstract
The enteric nervous system (ENS) is a complex network constituted of neurons and glial cells that ensures the intrinsic innervation of the gastrointestinal tract. ENS cells originate from vagal and sacral neural crest cells that are initially located at the border of the neural tube. In birds, sacral neural crest cells (sNCCs) first give rise to an extramural ganglionated structure (the so-called Nerve of Remak [NoR]) and to the pelvic plexus. Later, sNCCs enter the colon mesenchyme to colonize and contribute to the intrinsic innervation of the caudal part of the gut. However, no specific sNCC marker has been described. Here, we report the expression pattern of prospero-related homeobox 1 (PROX1) in the developing chick colon. PROX1 is a homeobox domain transcription factor that plays a role in cell type specification in various tissues. Using in situ hybridization and immunofluorescence techniques, we showed that PROX1 is expressed in sNCCs localized in the NoR and in the pelvic plexus. Then, using real-time quantitative PCR we found that PROX1 displays a strong and highly dynamic expression pattern during NoR development. Moreover, we demonstrated using in vivo cell tracing, that sNCCs are the source of the PROX1-positive cells within the NoR. Our results indicate that PROX1 is the first marker that specifically identifies sNCCs. This might help to better identify the role of the different neural crest cell populations in distal gut innervation, and consequently to improve the diagnosis of diseases linked to incomplete ENS formation, such as Hirschsprung's disease.
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Affiliation(s)
| | - Ludovic Le Guen
- PHYMEDEXP, Université de Montpellier, INSERM, CNRS, Montpellier, France
| | - Amandine Falco
- PHYMEDEXP, Université de Montpellier, INSERM, CNRS, Montpellier, France
| | - Sandrine Faure
- PHYMEDEXP, Université de Montpellier, INSERM, CNRS, Montpellier, France
| | - Norbert Chauvet
- PHYMEDEXP, Université de Montpellier, INSERM, CNRS, Montpellier, France
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Shenoy A, De Los Santos Y, Johnson KN, Petroze R. Distal rectal skip segment Hirschsprung disease: Case report and review of literature. Fetal Pediatr Pathol 2019; 38:437-443. [PMID: 31032690 DOI: 10.1080/15513815.2019.1608606] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Background: Lack of ganglion cells on adequate suction rectal biopsy is the gold standard for diagnosis of neonatal Hirschsprung disease (HD), and the presence of ganglion cells precludes such a diagnosis. Case report: A 10-day old male neonate presented with clinical symptoms concerning for HD. However, suction rectal biopsies demonstrated submucosal ganglion cells on the distal suction rectal biopsies (2 cm from anal verge) and not on the proximal (3 cm from anal verge), with similar findings on repeat biopsies. Clinical suspicion remained high, and diagnostic laparoscopy with intraoperative biopsies confirmed aganglionosis with a sigmoid transition. A pull through resection confirmed the diagnosis of distal rectal skip segment HD (SSHD) with a ∼6 cm length of circumferential aganglionosis extending into the proximal sigmoid. Conclusions: Discordant results on suction rectal biopsies should raise the possibility of SSHD. Awareness of the entity can facilitate timely definitive management in neonatal period.
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Affiliation(s)
- Archana Shenoy
- University of Florida College of Medicine , Gainesville , USA
| | | | - Kevin Neil Johnson
- Division of Pediatric Surgery, Department of Surgery, University of Florida College of Medicine , Gainesville , USA
| | - Robin Petroze
- Division of Pediatric Surgery, Department of Surgery, University of Florida College of Medicine , Gainesville , USA
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27
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Huycke TR, Tabin CJ. Chick midgut morphogenesis. THE INTERNATIONAL JOURNAL OF DEVELOPMENTAL BIOLOGY 2019; 62:109-119. [PMID: 29616718 DOI: 10.1387/ijdb.170325ct] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The gastrointestinal tract is an essential system of organs required for nutrient absorption. As a simple tube early in development, the primitive gut is patterned along its anterior-posterior axis into discrete compartments with unique morphologies relevant to their functions in the digestive process. These morphologies are acquired gradually through development as the gut is patterned by tissue interactions, both molecular and mechanical in nature, involving all three germ layers. With a focus on midgut morphogenesis, we review work in the chick embryo demonstrating how these molecular signals and mechanical forces sculpt the developing gut tube into its mature form. In particular, we highlight two mechanisms by which the midgut increases its absorptive surface area: looping and villification. Additionally, we review the differentiation and patterning of the intestinal mesoderm into the layers of smooth muscle that mechanically drive peristalsis and the villification process itself. Where relevant, we discuss the mechanisms of chick midgut morphogenesis in the context of experimental data from other model systems.
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Affiliation(s)
- Tyler R Huycke
- Department of Genetics, Harvard Medical School, Boston, MA, USA.
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28
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Simkin JE, Zhang D, Stamp LA, Newgreen DF. Fine scale differences within the vagal neural crest for enteric nervous system formation. Dev Biol 2019; 446:22-33. [DOI: 10.1016/j.ydbio.2018.11.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 11/13/2018] [Indexed: 12/24/2022]
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29
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Zhang D, Rollo BN, Nagy N, Stamp L, Newgreen DF. The enteric neural crest progressively loses capacity to form enteric nervous system. Dev Biol 2018; 446:34-42. [PMID: 30529057 DOI: 10.1016/j.ydbio.2018.11.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/09/2018] [Accepted: 11/29/2018] [Indexed: 01/18/2023]
Abstract
Cells of the vagal neural crest (NC) form most of the enteric nervous system (ENS) by a colonising wave in the embryonic gut, with high cell proliferation and differentiation. Enteric neuropathies have an ENS deficit and cell replacement has been suggested as therapy. This would be performed post-natally, which raises the question of whether the ENS cell population retains its initial ENS-forming potential with age. We tested this on the avian model in organ culture in vitro (3 days) using recipient aneural chick midgut/hindgut combined with ENS-donor quail midgut or hindgut of ages QE5 to QE10. ENS cells from young donor tissues (≤ QE6) avidly colonised the aneural recipient, but this capacity dropped rapidly 2-3 days after the transit of the ENS cell wavefront. This loss in capability was autonomous to the ENS population since a similar decline was observed in ENS cells isolated by HNK1 FACS. Using QE5, 6, 8 and 10 midgut donors and extending the time of assay to 8 days in chorio-allantoic membrane grafts did not produce 'catch up' colonisation. NC-derived cells were counted in dissociated quail embryo gut and in transverse sections of chick embryo gut using NC, neuron and glial marker antibodies. This showed that the decline in ENS-forming ability correlated with a decrease in proportion of ENS cells lacking both neuronal and glial differentiation markers, but there were still large numbers of such cells even at stages with low colonisation ability. Moreover, ENS cells in small numbers from young donors were far superior in colonisation ability to larger numbers of apparently undifferentiated cells from older donors. This suggests that the decline of ENS-forming ability has both quantitative and qualitative aspects. In this case, ENS cells for cell therapies should aim to replicate the embryonic ENS stage rather than using post-natal ENS stem/progenitor cells.
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Affiliation(s)
- Dongcheng Zhang
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, Australia
| | - Benjamin N Rollo
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, Australia
| | - Nandor Nagy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary
| | - Lincon Stamp
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville 3010, Victoria, Australia
| | - Donald F Newgreen
- Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, Australia.
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30
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Kim H, Langohr IM, Faisal M, McNulty M, Thorn C, Kim J. Ablation of Ezh2 in neural crest cells leads to aberrant enteric nervous system development in mice. PLoS One 2018; 13:e0203391. [PMID: 30169530 PMCID: PMC6118393 DOI: 10.1371/journal.pone.0203391] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 08/20/2018] [Indexed: 11/19/2022] Open
Abstract
In the current study, we examined the role of Ezh2 as an epigenetic modifier for the enteric neural crest cell development through H3K27me3. Ezh2 conditional null mice were viable up to birth, but died within the first hour of life. In addition to craniofacial defects, Ezh2 conditional null mice displayed reduced number of ganglion cells in the enteric nervous system. RT-PCR and ChIP assays indicated aberrant up-regulation of Zic1, Pax3, and Sox10 and loss of H3K27me3 marks in the promoter regions of these genes in the myenteric plexus. Overall, these results suggest that Ezh2 is an important epigenetic modifier for the enteric neural crest cell development through repression of Zic1, Pax3, and Sox10.
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Affiliation(s)
- Hana Kim
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Ingeborg M. Langohr
- School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Mohammad Faisal
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Margaret McNulty
- School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Caitlin Thorn
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America
| | - Joomyeong Kim
- Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, United States of America
- * E-mail:
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31
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Rothstein M, Bhattacharya D, Simoes-Costa M. The molecular basis of neural crest axial identity. Dev Biol 2018; 444 Suppl 1:S170-S180. [PMID: 30071217 DOI: 10.1016/j.ydbio.2018.07.026] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 07/27/2018] [Accepted: 07/27/2018] [Indexed: 10/28/2022]
Abstract
The neural crest is a migratory cell population that contributes to multiple tissues and organs during vertebrate embryonic development. It is remarkable in its ability to differentiate into an array of different cell types, including melanocytes, cartilage, bone, smooth muscle, and peripheral nerves. Although neural crest cells are formed along the entire anterior-posterior axis of the developing embryo, they can be divided into distinct subpopulations based on their axial level of origin. These groups of cells, which include the cranial, vagal, trunk, and sacral neural crest, display varied migratory patterns and contribute to multiple derivatives. While these subpopulations have been shown to be mostly plastic and to differentiate according to environmental cues, differences in their intrinsic potentials have also been identified. For instance, the cranial neural crest is unique in its ability to give rise to cartilage and bone. Here, we examine the molecular features that underlie such developmental restrictions and discuss the hypothesis that distinct gene regulatory networks operate in these subpopulations. We also consider how reconstructing the phylogeny of the trunk and cranial neural crest cells impacts our understanding of vertebrate evolution.
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Affiliation(s)
- Megan Rothstein
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
| | | | - Marcos Simoes-Costa
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA.
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32
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Migration and diversification of the vagal neural crest. Dev Biol 2018; 444 Suppl 1:S98-S109. [PMID: 29981692 DOI: 10.1016/j.ydbio.2018.07.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 07/03/2018] [Accepted: 07/03/2018] [Indexed: 12/17/2022]
Abstract
Arising within the neural tube between the cranial and trunk regions of the body axis, the vagal neural crest shares interesting similarities in its migratory routes and derivatives with other neural crest populations. However, the vagal neural crest is also unique in its ability to contribute to diverse organs including the heart and enteric nervous system. This review highlights the migratory routes of the vagal neural crest and compares them across multiple vertebrates. We also summarize recent advances in understanding vagal neural crest ontogeny and discuss the contribution of this important neural crest population to the cardiovascular system and endoderm-derived organs, including the thymus, lungs and pancreas.
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33
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Uribe RA, Hong SS, Bronner ME. Retinoic acid temporally orchestrates colonization of the gut by vagal neural crest cells. Dev Biol 2018; 433:17-32. [PMID: 29108781 PMCID: PMC5722660 DOI: 10.1016/j.ydbio.2017.10.021] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 10/23/2017] [Indexed: 02/06/2023]
Abstract
The enteric nervous system arises from neural crest cells that migrate as chains into and along the primitive gut, subsequently differentiating into enteric neurons and glia. Little is known about the mechanisms governing neural crest migration en route to and along the gut in vivo. Here, we report that Retinoic Acid (RA) temporally controls zebrafish enteric neural crest cell chain migration. In vivo imaging reveals that RA loss severely compromises the integrity and migration of the chain of neural crest cells during the window of time window when they are moving along the foregut. After loss of RA, enteric progenitors accumulate in the foregut and differentiate into enteric neurons, but subsequently undergo apoptosis resulting in a striking neuronal deficit. Moreover, ectopic expression of the transcription factor meis3 and/or the receptor ret, partially rescues enteric neuron colonization after RA attenuation. Collectively, our findings suggest that retinoic acid plays a critical temporal role in promoting enteric neural crest chain migration and neuronal survival upstream of Meis3 and RET in vivo.
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Affiliation(s)
- Rosa A Uribe
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Department of Biosciences, Rice University, Houston, TX 77005, USA.
| | - Stephanie S Hong
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA
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Radenkovic G, Radenkovic D, Velickov A. Development of interstitial cells of Cajal in the human digestive tract as the result of reciprocal induction of mesenchymal and neural crest cells. J Cell Mol Med 2017; 22:778-785. [PMID: 29193736 PMCID: PMC5783873 DOI: 10.1111/jcmm.13375] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 08/08/2017] [Indexed: 01/02/2023] Open
Abstract
Neural crest cells (NCC) can migrate into different parts of the body and express their strong inductive potential. In addition, they are multipotent and are able to differentiate into various cell types with diverse functions. In the primitive gut, NCC induce differentiation of muscular structures and interstitial cells of Cajal (ICC), and they themselves differentiate into the elements of the enteric nervous system (ENS), neurons and glial cells. ICC develop by way of mesenchymal cell differentiation in the outer parts of the primitive gut wall around the myenteric plexus (MP) ganglia, with the exception of colon, where they appear simultaneously also at the submucosal border of the circular muscular layer around the submucosal plexus (SMP) ganglia. However, in a complex process of reciprocal induction of NCC and local mesenchyma, c‐kit positive precursors are the first to differentiate, representing probably the common precursors of ICC and smooth muscle cells (SMC). C‐kit positive precursors could represent a key impact factor regarding the final differentiation of NCC into neurons and glial cells with neurons subsequently excreting stem cell factor (SCF) and other signalling molecules. Under the impact of SCF, a portion of c‐kit positive precursors lying immediately around the ganglia differentiate into ICC, while the rest differentiate into SMC.
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Affiliation(s)
- Goran Radenkovic
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia
| | - Dina Radenkovic
- UCL Medical School, University College London (UCL), London, UK
| | - Aleksandra Velickov
- Department of Histology and Embryology, Faculty of Medicine, University of Nis, Nis, Serbia
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35
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Espinosa-Medina I, Jevans B, Boismoreau F, Chettouh Z, Enomoto H, Müller T, Birchmeier C, Burns AJ, Brunet JF. Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest. Proc Natl Acad Sci U S A 2017; 114:11980-11985. [PMID: 29078343 PMCID: PMC5692562 DOI: 10.1073/pnas.1710308114] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Most of the enteric nervous system derives from the "vagal" neural crest, lying at the level of somites 1-7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the "vagal crest" subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3-7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.
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Affiliation(s)
- Isabel Espinosa-Medina
- Institut de Biologie de l'École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Ben Jevans
- Stem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom
| | - Franck Boismoreau
- Institut de Biologie de l'École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Zoubida Chettouh
- Institut de Biologie de l'École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France
| | - Hideki Enomoto
- Laboratory for Neural Differentiation and Regeneration, Graduate School of Medicine, Kobe University, 650-0017 Kobe City, Japan
| | - Thomas Müller
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz-Association, 13125 Berlin, Germany
| | - Carmen Birchmeier
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz-Association, 13125 Berlin, Germany
| | - Alan J Burns
- Stem Cells and Regenerative Medicine, Birth Defects Research Centre, University College London Great Ormond Street Institute of Child Health, WC1N 1EH London, United Kingdom
- Department of Clinical Genetics, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands
| | - Jean-François Brunet
- Institut de Biologie de l'École Normale Supérieure (IBENS), École Normale Supérieure, CNRS, INSERM, PSL Research University, 75005 Paris, France;
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36
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Stamp LA. Cell therapy for GI motility disorders: comparison of cell sources and proposed steps for treating Hirschsprung disease. Am J Physiol Gastrointest Liver Physiol 2017; 312:G348-G354. [PMID: 28209600 DOI: 10.1152/ajpgi.00018.2017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 02/02/2017] [Accepted: 02/08/2017] [Indexed: 01/31/2023]
Abstract
Cell therapeutic approaches to treat a range of congenital and degenerative neuropathies are under intense investigation. There have been recent significant advancements in the development of cell therapy to treat disorders of the enteric nervous system (ENS), enteric neuropathies. These advances include the efficient generation of enteric neural progenitors from pluripotent stem cells and the rescue of a Hirschsprung disease model mouse following their transplantation into the bowel. Furthermore, a recent study provides evidence of functional innervation of the bowel muscle by neurons derived from transplanted ENS-derived neural progenitors. This mini-review discusses these recent findings, compares endogenous ENS-derived progenitors and pluripotent stem cell-derived progenitors as a cell source for therapy, and proposes the key steps for cell therapy to treat Hirschsprung disease.
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Affiliation(s)
- Lincon A Stamp
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
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37
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Charrier B, Pilon N. Toward a better understanding of enteric gliogenesis. NEUROGENESIS 2017; 4:e1293958. [PMID: 28352645 DOI: 10.1080/23262133.2017.1293958] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 02/03/2017] [Indexed: 12/12/2022]
Abstract
Most of gastrointestinal functions are controlled by the enteric nervous system (ENS), which contains a vast diversity of neurons and glial cells. In accordance with its key role, defective ENS formation is the cause of several diseases that affect quality of life and can even be life-threatening. Treatment of these diseases would greatly benefit from a better understanding of the molecular mechanisms underlying ENS formation. In this regard, although several important discoveries have been made over the years, how the full spectrum of enteric neuronal and glial cell subtypes is generated from neural crest cells during development still remains enigmatic. Because they also have stem cell properties, such knowledge would be especially important for the enteric glial cell lineage. In a recent study, we identified the NR2F1 transcription factor as a new key regulator of enteric gliogenesis. Here we discuss our recent findings and briefly review what is already known about the mechanisms and signaling pathways involved in enteric gliogenesis, with an emphasis on Hedgehog and Notch signaling.
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Affiliation(s)
- Baptiste Charrier
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal, Montreal, Quebec, Canada; Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
| | - Nicolas Pilon
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, Faculty of Sciences, University of Quebec at Montreal , Montreal, Quebec, Canada
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38
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Colonic mesenchyme differentiates into smooth muscle before its colonization by vagal enteric neural crest-derived cells in the chick embryo. Cell Tissue Res 2017; 368:503-511. [DOI: 10.1007/s00441-017-2577-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 01/13/2017] [Indexed: 01/09/2023]
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39
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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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40
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Cheng LS, Graham HK, Pan WH, Nagy N, Carreon-Rodriguez A, Goldstein AM, Hotta R. Optimizing neurogenic potential of enteric neurospheres for treatment of neurointestinal diseases. J Surg Res 2016; 206:451-459. [PMID: 27884342 DOI: 10.1016/j.jss.2016.08.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 06/30/2016] [Accepted: 08/04/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND Enteric neurospheres derived from postnatal intestine represent a promising avenue for cell replacement therapy to treat Hirschsprung disease and other neurointestinal diseases. We describe a simple method to improve the neuronal yield of spontaneously formed gut-derived neurospheres. MATERIALS AND METHODS Enteric neurospheres were formed from the small and large intestines of mouse and human subjects. Neurosphere size, neural crest cell content, cell migration, neuronal differentiation, and neuronal proliferation in culture were analyzed. The effect of supplemental neurotrophic factors, including glial cell line-derived neurotrophic factor (GDNF) and endothelin-3, was also assessed. RESULTS Mouse small intestine-derived neurospheres contained significantly more P75-expressing neural crest-derived cells (49.9 ± 15.3% versus 21.6 ± 11.9%, P < 0.05) and gave rise to significantly more Tuj1-expressing neurons than colon-derived neurospheres (69.9 ± 8.6% versus 46.2 ± 15.6%, P < 0.05). A similar pattern was seen in neurospheres isolated from human small and large intestine (32.6 ± 17.5% versus 10.2 ± 8.2% neural crest cells, P < 0.05; 29.7 ± 16.4% versus 16.0 ± 13.5% enteric neurons, P < 0.05). The addition of GDNF to the culture media further improved the neurogenic potential of small intestinal neurospheres (75.9 ± 4.0% versus 67.8 ± 5.8%, P < 0.05) whereas endothelin-3 had no effect. CONCLUSIONS Enteric neurospheres formed from small intestine and supplemented with GDNF yield an enriched population of neural crest-derived progenitor cells and give rise to a high density of enteric neurons.
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Affiliation(s)
- Lily S Cheng
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA.,Department of Surgery, University of California San Francisco, 500 Parnassus Ave., San Francisco, CA, 94143, USA
| | - Hannah K Graham
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA
| | - Wei Hua Pan
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA.,Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, 280 Chongqing S Rd, Huangpu, Shanghai, China
| | - Nandor Nagy
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA.,Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Tuzolto St. 58, Budapest 1094, Hungary
| | - Alfonso Carreon-Rodriguez
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA.,Laboratorio de Genética y Biomarcadores, Instituto Nacional de Salud Pública, Av Universidad 655, Santa María Ahuacatitlán, 62100 Cuernavaca, Mor., Mexico
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St., Boston, MA, 02114, USA
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41
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Heanue TA, Shepherd IT, Burns AJ. Enteric nervous system development in avian and zebrafish models. Dev Biol 2016; 417:129-38. [PMID: 27235814 DOI: 10.1016/j.ydbio.2016.05.017] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 05/10/2016] [Accepted: 05/12/2016] [Indexed: 01/10/2023]
Abstract
Our current understanding of the developmental biology of the enteric nervous system (ENS) and the genesis of ENS diseases is founded almost entirely on studies using model systems. Although genetic studies in the mouse have been at the forefront of this field over the last 20 years or so, historically it was the easy accessibility of the chick embryo for experimental manipulations that allowed the first descriptions of the neural crest origins of the ENS in the 1950s. More recently, studies in the chick and other non-mammalian model systems, notably zebrafish, have continued to advance our understanding of the basic biology of ENS development, with each animal model providing unique experimental advantages. Here we review the basic biology of ENS development in chick and zebrafish, highlighting conserved and unique features, and emphasising novel contributions to our general understanding of ENS development due to technical or biological features.
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Affiliation(s)
| | | | - Alan J Burns
- Stem Cells and Regenerative Medicine, UCL Institute of Child Health, London, UK; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
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42
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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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43
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Barnes KJ, Spencer NJ. Can colonic migrating motor complexes occur in mice lacking the endothelin-3 gene? Clin Exp Pharmacol Physiol 2016; 42:485-95. [PMID: 25708159 DOI: 10.1111/1440-1681.12380] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Revised: 02/14/2015] [Accepted: 02/16/2015] [Indexed: 01/21/2023]
Abstract
In mammals, colonic migrating motor complexes (CMMC) are a major propulsive contraction responsible for the expulsion of faecal content. Mice with a mutation of the endothelin-3 gene raised on a 129SL background strain have ~70% colonic aganglionosis, lack CMMC, and are lethal within 12 days postpartum. In contrast, endothelin-3 mutant mice raised and maintained on a C57BL6 background strain (lethal-spotted (ls/ls) mice) can live for much longer, but it is unclear whether CMMC generation is preserved in these mice also lacking the endothelin-3 gene. The aim of this study was to determine whether CMMC exist in ls/ls mouse colon and, if so, whether their existence and frequency are related to the length of aganglionosis. Spatiotemporal mapping and mechanical recordings of colonic wall movements were made from isolated whole colons obtained from wild-type and ls/ls mice. Although ls/ls mice had a megacolon, they still generated CMMC in the ganglionic segment, which on some occasions could propagate short distances into the aganglionic region. There was large variability in aganglionosis length, which showed a weak correlation with the existence or frequency of CMMC. Interestingly, CMMC propagation velocity was slower in ls/ls mice when evoked by intraluminal fluid. A myogenic motor pattern was identified in the aganglionic region that was maintained under tonic inhibition. We show that despite megacolon, ls/ls mice still generate CMMC in the ganglionic region. These offspring have sufficient propulsive motility in the ganglionic segment to live a normal murine lifespan and rarely die of bowel obstruction.
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Affiliation(s)
- Kyra J Barnes
- Discipline of Human Physiology, Center for Neuroscience, School of Medicine, Flinders University of South Australia, Adelaide, SA, Australia
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Stathopoulou A, Natarajan D, Nikolopoulou P, Patmanidi AL, Lygerou Z, Pachnis V, Taraviras S. Inactivation of Geminin in neural crest cells affects the generation and maintenance of enteric progenitor cells, leading to enteric aganglionosis. Dev Biol 2015; 409:392-405. [PMID: 26658318 DOI: 10.1016/j.ydbio.2015.11.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 11/27/2015] [Accepted: 11/27/2015] [Indexed: 11/25/2022]
Abstract
Neural crest cells comprise a multipotent, migratory cell population that generates a diverse array of cell and tissue types, during vertebrate development. Enteric Nervous System controls the function of the gastrointestinal tract and is mainly derived from the vagal and sacral neural crest cells. Deregulation on self-renewal and differentiation of the enteric neural crest cells is evident in enteric nervous system disorders, such as Hirschsprung disease, characterized by the absence of ganglia in a variable length of the distal bowel. Here we show that Geminin is essential for Enteric Nervous System generation as mice that lacked Geminin expression specifically in neural crest cells revealed decreased generation of vagal neural crest cells, and enteric neural crest cells (ENCCs). Geminin-deficient ENCCs showed increased apoptosis and decreased cell proliferation during the early stages of gut colonization. Furthermore, decreased number of committed ENCCs in vivo and the decreased self-renewal capacity of enteric progenitor cells in vitro, resulted in almost total aganglionosis resembling a severe case of Hirschsprung disease. Our results suggest that Geminin is an important regulator of self-renewal and survival of enteric nervous system progenitor cells.
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Affiliation(s)
| | - Dipa Natarajan
- Division of Molecular Neurobiology, MRC/National Institute for Medical Research, London, United Kingdom
| | | | | | - Zoi Lygerou
- Department of Biology, Medical School, University of Patras, Patras, Greece
| | - Vassilis Pachnis
- Division of Molecular Neurobiology, MRC/National Institute for Medical Research, London, United Kingdom
| | - Stavros Taraviras
- Department of Physiology, Medical School, University of Patras, Patras, Greece.
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Rollo BN, Zhang D, Stamp LA, Menheniott TR, Stathopoulos L, Denham M, Dottori M, King SK, Hutson JM, Newgreen DF. Enteric Neural Cells From Hirschsprung Disease Patients Form Ganglia in Autologous Aneuronal Colon. Cell Mol Gastroenterol Hepatol 2015; 2:92-109. [PMID: 28174705 PMCID: PMC4980742 DOI: 10.1016/j.jcmgh.2015.09.007] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 09/17/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Hirschsprung disease (HSCR) is caused by failure of cells derived from the neural crest (NC) to colonize the distal bowel in early embryogenesis, resulting in absence of the enteric nervous system (ENS) and failure of intestinal transit postnatally. Treatment is by distal bowel resection, but neural cell replacement may be an alternative. We tested whether aneuronal (aganglionic) colon tissue from patients may be colonized by autologous ENS-derived cells. METHODS Cells were obtained and cryopreserved from 31 HSCR patients from the proximal resection margin of colon, and ENS cells were isolated using flow cytometry for the NC marker p75 (nine patients). Aneuronal colon tissue was obtained from the distal resection margin (23 patients). ENS cells were assessed for NC markers immunohistologically and by quantitative reverse-transcription polymerase chain reaction, and mitosis was detected by ethynyl-2'-deoxyuridine labeling. The ability of human HSCR postnatal ENS-derived cells to colonize the embryonic intestine was demonstrated by organ coculture with avian embryo gut, and the ability of human postnatal HSCR aneuronal colon muscle to support ENS formation was tested by organ coculture with embryonic mouse ENS cells. Finally, the ability of HSCR patient ENS cells to colonize autologous aneuronal colon muscle tissue was assessed. RESULTS ENS-derived p75-sorted cells from patients expressed multiple NC progenitor and differentiation markers and proliferated in culture under conditions simulating Wnt signaling. In organ culture, patient ENS cells migrated appropriately in aneural quail embryo gut, and mouse embryo ENS cells rapidly spread, differentiated, and extended axons in patient aneuronal colon muscle tissue. Postnatal ENS cells derived from HSCR patients colonized autologous aneuronal colon tissue in cocultures, proliferating and differentiating as neurons and glia. CONCLUSIONS NC-lineage cells can be obtained from HSCR patient colon and can form ENS-like structures in aneuronal colonic muscle from the same patient.
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Key Words
- Aganglionosis
- CHIR-99021, 6-[2-[[4-(2,4-dichlorophenyl)-5-(5-methyl-1H-imidazol-2-yl)pyrimidin-2-yl]amino]ethylamino]pyridine-3-carbonitrile
- Cell Therapy
- ENC, enteric neural crest
- ENS, enteric nervous system
- EdU, ethynyl-2′-deoxyuridine
- Enteric Nervous System
- FBS, fetal bovine serum
- GFAP, glial fibrillary acidic protein
- GSK3, glycogen synthase kinase 3
- HNK1, human natural killer-1
- HSCR, Hirschsprung disease
- Hirschsprung Disease
- MTR, MitoTracker Red
- Megacolon
- NC, neural crest
- PBS, phosphate-buffered saline
- PFA, paraformaldehyde
- RCH, Royal Children’s Hospital
- SMA, smooth muscle actin
- SOX10, sex-determining region Y–box 10
- TUJ1, neuron-specific class III β-tubulin
- eGFP, enhanced green fluorescent protein
- nNOS, neuronal nitric oxide synthase
- nTCM, neural tissue culture medium
- qRT-PCR, quantitative reverse transcription and polymerase chain reaction
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Affiliation(s)
- Benjamin N. Rollo
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia,Correspondence Address correspondence to: Benjamin N. Rollo, PhD, Murdoch Children’s Research Institute, The Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia. fax: +61-3-9348-1391.Murdoch Children’s Research InstituteThe Royal Children’s HospitalFlemington RoadParkvilleVictoria 3052Australia
| | - Dongcheng Zhang
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Lincon A. Stamp
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia
| | - Trevelyan R. Menheniott
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Lefteris Stathopoulos
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Mark Denham
- Stem Cell Laboratory, Department of Biomedicine, Danish Research Institute of Translational Neuroscience, Aarhus University, Aarhus, Denmark
| | - Mirella Dottori
- Centre for Neural Engineering, NICTA, University of Melbourne, Australia
| | - Sebastian K. King
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia,Royal Children’s Hospital, Parkville, Victoria, Australia
| | - John M. Hutson
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia,Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia,Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Donald F. Newgreen
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
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Uribe RA, Bronner ME. Meis3 is required for neural crest invasion of the gut during zebrafish enteric nervous system development. Mol Biol Cell 2015; 26:3728-40. [PMID: 26354419 PMCID: PMC4626059 DOI: 10.1091/mbc.e15-02-0112] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 09/02/2015] [Indexed: 01/02/2023] Open
Abstract
Loss of Meis3 leads to defects in enteric neural crest cell migration, number, and proliferation during colonization of the gut. This leads to colonic aganglionosis, in which the hindgut is devoid of neurons, identifying it as a novel candidate factor in the etiology of Hirschsprung’s disease during enteric nervous system development. During development, vagal neural crest cells fated to contribute to the enteric nervous system migrate ventrally away from the neural tube toward and along the primitive gut. The molecular mechanisms that regulate their early migration en route to and entry into the gut remain elusive. Here we show that the transcription factor meis3 is expressed along vagal neural crest pathways. Meis3 loss of function results in a reduction in migration efficiency, cell number, and the mitotic activity of neural crest cells in the vicinity of the gut but has no effect on neural crest or gut specification. Later, during enteric nervous system differentiation, Meis3-depleted embryos exhibit colonic aganglionosis, a disorder in which the hindgut is devoid of neurons. Accordingly, the expression of Shh pathway components, previously shown to have a role in the etiology of Hirschsprung’s disease, was misregulated within the gut after loss of Meis3. Taken together, these findings support a model in which Meis3 is required for neural crest proliferation, migration into, and colonization of the gut such that its loss leads to severe defects in enteric nervous system development.
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Affiliation(s)
- Rosa A Uribe
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
| | - Marianne E Bronner
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125
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Mesenchymal-epithelial interactions during digestive tract development and epithelial stem cell regeneration. Cell Mol Life Sci 2015; 72:3883-96. [PMID: 26126787 DOI: 10.1007/s00018-015-1975-2] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 06/17/2015] [Accepted: 06/18/2015] [Indexed: 12/16/2022]
Abstract
The gastrointestinal tract develops from a simple and uniform tube into a complex organ with specific differentiation patterns along the anterior-posterior and dorso-ventral axes of asymmetry. It is derived from all three germ layers and their cross-talk is important for the regulated development of fetal and adult gastrointestinal structures and organs. Signals from the adjacent mesoderm are essential for the morphogenesis of the overlying epithelium. These mesenchymal-epithelial interactions govern the development and regionalization of the different gastrointestinal epithelia and involve most of the key morphogens and signaling pathways, such as the Hedgehog, BMPs, Notch, WNT, HOX, SOX and FOXF cascades. Moreover, the mechanisms underlying mesenchyme differentiation into smooth muscle cells influence the regionalization of the gastrointestinal epithelium through interactions with the enteric nervous system. In the neonatal and adult gastrointestinal tract, mesenchymal-epithelial interactions are essential for the maintenance of the epithelial regionalization and digestive epithelial homeostasis. Disruption of these interactions is also associated with bowel dysfunction potentially leading to epithelial tumor development. In this review, we will discuss various aspects of the mesenchymal-epithelial interactions observed during digestive epithelium development and differentiation and also during epithelial stem cell regeneration.
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Delalande JM, Thapar N, Burns AJ. Dual labeling of neural crest cells and blood vessels within chicken embryos using Chick(GFP) neural tube grafting and carbocyanine dye DiI injection. J Vis Exp 2015:e52514. [PMID: 26065540 PMCID: PMC4542995 DOI: 10.3791/52514] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
All developing organs need to be connected to both the nervous system (for sensory and motor control) as well as the vascular system (for gas exchange, fluid and nutrient supply). Consequently both the nervous and vascular systems develop alongside each other and share striking similarities in their branching architecture. Here we report embryonic manipulations that allow us to study the simultaneous development of neural crest-derived nervous tissue (in this case the enteric nervous system), and the vascular system. This is achieved by generating chicken chimeras via transplantation of discrete segments of the neural tube, and associated neural crest, combined with vascular DiI injection in the same embryo. Our method uses transgenic chickGFP embryos for intraspecies grafting, making the transplant technique more powerful than the classical quail-chick interspecies grafting protocol used with great effect since the 1970s. ChickGFP-chick intraspecies grafting facilitates imaging of transplanted cells and their projections in intact tissues, and eliminates any potential bias in cell development linked to species differences. This method takes full advantage of the ease of access of the avian embryo (compared with other vertebrate embryos) to study the co-development of the enteric nervous system and the vascular system.
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Affiliation(s)
- Jean-Marie Delalande
- Birth Defects Research Centre, UCL Institute of Child Health; Blizard Institute, Centre for Digestive Diseases, Queen Mary University of London, Barts and The London School of Medicine and Dentistry
| | - Nikhil Thapar
- Birth Defects Research Centre, UCL Institute of Child Health
| | - Alan J Burns
- Birth Defects Research Centre, UCL Institute of Child Health; Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam;
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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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Bergeron KF, Cardinal T, Touré AM, Béland M, Raiwet DL, Silversides DW, Pilon N. Male-biased aganglionic megacolon in the TashT mouse line due to perturbation of silencer elements in a large gene desert of chromosome 10. PLoS Genet 2015; 11:e1005093. [PMID: 25786024 PMCID: PMC4364714 DOI: 10.1371/journal.pgen.1005093] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 02/23/2015] [Indexed: 01/13/2023] Open
Abstract
Neural crest cells (NCC) are a transient migratory cell population that generates diverse cell types such as neurons and glia of the enteric nervous system (ENS). Via an insertional mutation screen for loci affecting NCC development in mice, we identified one line—named TashT—that displays a partially penetrant aganglionic megacolon phenotype in a strong male-biased manner. Interestingly, this phenotype is highly reminiscent of human Hirschsprung’s disease, a neurocristopathy with a still unexplained male sex bias. In contrast to the megacolon phenotype, colonic aganglionosis is almost fully penetrant in homozygous TashT animals. The sex bias in megacolon expressivity can be explained by the fact that the male ENS ends, on average, around a “tipping point” of minimal colonic ganglionosis while the female ENS ends, on average, just beyond it. Detailed analysis of embryonic intestines revealed that aganglionosis in homozygous TashT animals is due to slower migration of enteric NCC. The TashT insertional mutation is localized in a gene desert containing multiple highly conserved elements that exhibit repressive activity in reporter assays. RNAseq analyses and 3C assays revealed that the TashT insertion results, at least in part, in NCC-specific relief of repression of the uncharacterized gene Fam162b; an outcome independently confirmed via transient transgenesis. The transcriptional signature of enteric NCC from homozygous TashT embryos is also characterized by the deregulation of genes encoding members of the most important signaling pathways for ENS formation—Gdnf/Ret and Edn3/Ednrb—and, intriguingly, the downregulation of specific subsets of X-linked genes. In conclusion, this study not only allowed the identification of Fam162b coding and regulatory sequences as novel candidate loci for Hirschsprung’s disease but also provides important new insights into its male sex bias. Hirschsprung’s disease (also known as aganglionic megacolon) is a severe congenital defect of the enteric nervous system (ENS) resulting in complete failure to pass stools. It is characterized by the absence of neural ganglia (aganglionosis) in the distal gut due to incomplete colonization of the embryonic intestines by neural crest cells (NCC), the ENS precursors. Hirschsprung’s disease has an incidence of 1 in 5000 newborns and a 4:1 male sex bias. Although many genes have been associated with this complex genetic disease, most of its heritability as well as its male sex bias remain unexplained. Here, we describe an insertional mutant mouse line (“TashT”) in which virtually all homozygotes display colonic aganglionosis due to defective migration of enteric NCC, but in which only a subset of homozygotes develops megacolon. Surprisingly, this group is almost exclusively male. The TashT ENS defect stems, at least in part, from the disruption of long-range interactions between evolutionarily conserved elements with silencer activity and Fam162b, resulting in NCC-specific upregulation of this uncharacterized protein coding gene. Global analysis of gene expression further revealed that several hundreds of genes are significantly deregulated in TashT enteric NCC. Interestingly, this dataset includes multiple X-linked candidate genes potentially underlying the male sex bias. Taken together, our data pave the way for a clearer understanding of the intriguing male sex bias of Hirschsprung’s disease.
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Affiliation(s)
- Karl-F. Bergeron
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
| | - Tatiana Cardinal
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
| | - Aboubacrine M. Touré
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
| | - Mélanie Béland
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
| | - Diana L. Raiwet
- Veterinary Genetics Laboratory, Faculty of Veterinary Medicine, University of Montreal, Quebec, Canada
| | - David W. Silversides
- Veterinary Genetics Laboratory, Faculty of Veterinary Medicine, University of Montreal, Quebec, Canada
| | - Nicolas Pilon
- Molecular Genetics of Development Laboratory, Department of Biological Sciences and BioMed Research Center, University of Quebec at Montreal (UQAM), Quebec, Canada
- * E-mail:
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