Talk:Neural Crest - Enteric Nervous System

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Cite this page: Hill, M.A. (2020, February 18) Embryology Neural Crest - Enteric Nervous System. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Talk:Neural_Crest_-_Enteric_Nervous_System

2019

The enteric neural crest progressively loses capacity to form enteric nervous system

Dev Biol. 2019 Feb 1;446(1):34-42. doi: 10.1016/j.ydbio.2018.11.017. Epub 2018 Dec 7.

Zhang D1, Rollo BN1, Nagy N2, Stamp L3, Newgreen DF4. Author information 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.

Copyright © 2018 Elsevier Inc. All rights reserved.

PMID: 30529057 DOI: 10.1016/j.ydbio.2018.11.017

2018

Dev Biol. 2018 Aug 30. pii: S0012-1606(18)30441-X. doi: 10.1016/j.ydbio.2018.08.014. [Epub ahead of print] News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders. Bondurand N1, Dufour S2, Pingault V3. Author information Abstract The endothelin system is a vertebrate-specific innovation with important roles in regulating the cardiovascular system and renal and pulmonary processes, as well as the development of the vertebrate-specific neural crest cell population and its derivatives. This system is comprised of three structurally similar 21-amino acid peptides that bind and activate two G-protein coupled receptors. In 1994, knockouts of the Edn3 and Ednrb genes revealed their crucial function during development of the enteric nervous system and melanocytes, two neural-crest derivatives. Since then, human and mouse genetics, combined with cellular and developmental studies, have helped to unravel the role of this signaling pathway during development and adulthood. In this review, we will summarize the known functions of the EDN3/EDNRB pathway during neural crest development, with a specific focus on recent scientific advances, and the enteric nervous system in normal and pathological conditions. KEYWORDS: Differentiation; Endothelin; Enteric nervous system; Hirschsprung; Migration; Waardenburg PMID: 30171849 DOI: 10.1016/j.ydbio.2018.08.014

2017

Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest

Nature. 2017 Apr 6;544(7648):88-91. doi: 10.1038/nature21679. Epub 2017 Mar 20.

Green SA1, Uy BR1, Bronner ME1.

Abstract

The enteric nervous system of jawed vertebrates arises primarily from vagal neural crest cells that migrate to the foregut and subsequently colonize and innervate the entire gastrointestinal tract. Here we examine development of the enteric nervous system in the basal jawless vertebrate the sea lamprey (Petromyzon marinus) to gain insight into its evolutionary origin. Surprisingly, we find no evidence for the existence of a vagally derived enteric neural crest population in the lamprey. Rather, labelling with the lipophilic dye DiI shows that late-migrating cells, originating from the trunk neural tube and associated with nerve fibres, differentiate into neurons within the gut wall and typhlosole. We propose that these trunk-derived neural crest cells may be homologous to Schwann cell precursors, recently shown in mammalian embryos to populate post-embryonic parasympathetic ganglia, including enteric ganglia. Our results suggest that neural-crest-derived Schwann cell precursors made an important contribution to the ancient enteric nervous system of early jawless vertebrates, a role that was largely subsumed by vagal neural crest cells in early gnathostomes. PMID: 28321127 PMCID: PMC5383518 [Available on 2017-09-20] DOI: 10.1038/nature21679

Enteric nervous system development: A crest cell's journey from neural tube to colon

Semin Cell Dev Biol. 2017 Jan 10. pii: S1084-9521(17)30008-3. doi: 10.1016/j.semcdb.2017.01.006. [Epub ahead of print]

Nagy N1, Goldstein AM2.

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. Copyright © 2017 Elsevier Ltd. All rights reserved. KEYWORDS: Enteric nervous system; Gut development; Hirschsprung disease; Neural crest PMID 28087321 DOI: 10.1016/j.semcdb.2017.01.006

2016

Enteric nervous system assembly: Functional integration within the developing gut

Dev Biol. 2016 May 26. pii: S0012-1606(16)30110-5. doi: 10.1016/j.ydbio.2016.05.030. [Epub ahead of print]

Hao MM1, Foong JP2, Bornstein JC2, Li ZL1, Vanden Berghe P1, Boesmans W3.

Abstract

Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells. Copyright © 2016 Elsevier Inc. All rights reserved. KEYWORDS: Enteric nervous system; Gastrointestinal tract; Gut motility; Neural crest; Neuronal circuits

PMID 27235816

Altered expression of retinoblastoma 1 in Hirschsprung's disease

J Pediatr Surg. 2016 Aug 12. pii: S0022-3468(16)30224-X. doi: 10.1016/j.jpedsurg.2016.07.020. [Epub ahead of print]

O'Donnell AM1, Coyle D1, Puri P2.

Abstract

PURPOSE: The retinoblastoma 1 (RB1) tumor suppressor is a critical regulator of cell cycle progression and development, and has been widely documented to be inactivated in human cancer. A recent study using RB1 knockout mice suggested a new role for RB1 in the normal regulation of the enteric nervous system (ENS), because of knockout mice showing ENS abnormalities and severe intestinal dysmotility. The aim of our study was to investigate the expression of RB1 in the normal human colon and in Hirschsprung's disease (HD). MATERIALS AND METHODS: HD tissue specimens (n=10) were collected at the time of pull-through surgery, while colonic control samples were obtained at the time of colostomy closure in patients with imperforate anus (n=10). Immunolabeling of RB1 was visualized using confocal microscopy to assess protein distribution, while western blot analysis was undertaken to quantify RB1 protein expression. RESULTS: Immunohistochemistry revealed RB1 co-localized with platelet derived growth factor receptor alpha-positive (PDGFRα+) cells, nitrergic neurons and glia in controls and the ganglionic region of HD, with a marked reduction in the aganglionic HD specimens. Western blotting revealed a marked decrease in RB1 protein expression in the aganglionic region of HD colon compared to ganglionic and normal controls. CONCLUSION: We provide evidence of the presence of RB1 expression in the human colon in HD. As RB1 is known to colocalize with nitrergic neurons, the decreased expression of RB1 in the aganglionic bowel is most likely a secondary phenomenon because of the deficient nitrergic innervation in HD. Copyright © 2016 Elsevier Inc. All rights reserved. KEYWORDS: Colonic aganglionosis; Enteric nervous; Hirschsprung's disease; Retinoblastoma 1 PMID 27567306

Fluorescence Visualization of the Enteric Nervous Network in a Chemically Induced Aganglionosis Model

PLoS One. 2016 Mar 4;11(3):e0150579. doi: 10.1371/journal.pone.0150579. eCollection 2016.

Fujimura T1,2, Shibata S2, Shimojima N1, Morikawa Y1,3, Okano H2, Kuroda T1.

Abstract

Gastrointestinal motility disorders, severe variants in particular, remain a therapeutic challenge in pediatric surgery. Absence of enteric ganglion cells that originate from neural crest cells is a major cause of dysmotility. However, the limitations of currently available animal models of dysmotility continue to impede the development of new therapeutics. Indeed, the short lifespan and/or poor penetrance of existing genetic models of dysmotility prohibit the functional evaluation of promising approaches, such as stem cell replacement strategy. Here, we induced an aganglionosis model using topical benzalkonium chloride in a P0-Cre/GFP transgenic mouse in which the neural crest lineage is labeled by green fluorescence. Pathological abnormalities and functional changes in the gastrointestinal tract were evaluated 2-8 weeks after chemical injury. Laparotomy combined with fluorescence microscopy allowed direct visualization of the enteric neural network in vivo. Immunohistochemical evaluation further confirmed the irreversible disappearance of ganglion cells, glial cells, and interstitial cell of Cajal. Remaining stool weight and bead expulsion time in particular supported the pathophysiological relevance of this chemically-induced model of aganglionosis. Interestingly, we show that chemical ablation of enteric ganglion cells is associated with a long lifespan. By combining genetic labeling of neural crest derivatives and chemical ablation of enteric ganglion cells, we developed a newly customized model of aganglionosis. Our results indicate that this aganglionosis model exhibits decreased gastrointestinal motility and shows sufficient survival for functional evaluation. This model may prove useful for the development of future therapies against motility disorders.

PMID 26943905

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150579

2015

Enteric neural crest cells regulate vertebrate stomach patterning and differentiation

Development. 2015 Jan 15;142(2):331-42. doi: 10.1242/dev.118422. Epub 2014 Dec 17.

Faure S1, McKey J2, Sagnol S2, de Santa Barbara P1.

Abstract

In vertebrates, the digestive tract develops from a uniform structure where reciprocal epithelial-mesenchymal interactions pattern this complex organ into regions with specific morphologies and functions. Concomitant with these early patterning events, the primitive GI tract is colonized by the vagal enteric neural crest cells (vENCCs), a population of cells that will give rise to the enteric nervous system (ENS), the intrinsic innervation of the GI tract. The influence of vENCCs on early patterning and differentiation of the GI tract has never been evaluated. In this study, we report that a crucial number of vENCCs is required for proper chick stomach development, patterning and differentiation. We show that reducing the number of vENCCs by performing vENCC ablations induces sustained activation of the BMP and Notch pathways in the stomach mesenchyme and impairs smooth muscle development. A reduction in vENCCs also leads to the transdifferentiation of the stomach into a stomach-intestinal mixed phenotype. In addition, sustained Notch signaling activity in the stomach mesenchyme phenocopies the defects observed in vENCC-ablated stomachs, indicating that inhibition of the Notch signaling pathway is essential for stomach patterning and differentiation. Finally, we report that a crucial number of vENCCs is also required for maintenance of stomach identity and differentiation through inhibition of the Notch signaling pathway. Altogether, our data reveal that, through the regulation of mesenchyme identity, vENCCs act as a new mediator in the mesenchymal-epithelial interactions that control stomach development. © 2015. Published by The Company of Biologists Ltd. KEYWORDS: Chick; Enteric neural crest cells; Gut development; Mesenchymal-epithelial interactions; Notch pathway; Smooth muscle differentiation

PMID 25519241


Ion channel expression in the developing enteric nervous system

PLoS One. 2015 Mar 23;10(3):e0123436. doi: 10.1371/journal.pone.0123436. eCollection 2015.

Hirst CS1, Foong JP2, Stamp LA1, Fegan E1, Dent S1, Cooper EC3, Lomax AE4, Anderson CR1, Bornstein JC5, Young HM1, McKeown SJ1.

Abstract

The enteric nervous system arises from neural crest-derived cells (ENCCs) that migrate caudally along the embryonic gut. The expression of ion channels by ENCCs in embryonic mice was investigated using a PCR-based array, RT-PCR and immunohistochemistry. Many ion channels, including chloride, calcium, potassium and sodium channels were already expressed by ENCCs at E11.5. There was an increase in the expression of numerous ion channel genes between E11.5 and E14.5, which coincides with ENCC migration and the first extension of neurites by enteric neurons. Previous studies have shown that a variety of ion channels regulates neurite extension and migration of many cell types. Pharmacological inhibition of a range of chloride or calcium channels had no effect on ENCC migration in cultured explants or neuritogenesis in vitro. The non-selective potassium channel inhibitors, TEA and 4-AP, retarded ENCC migration and neuritogenesis, but only at concentrations that also resulted in cell death. In summary, a large range of ion channels is expressed while ENCCs are colonizing the gut, but we found no evidence that ENCC migration or neuritogenesis requires chloride, calcium or potassium channel activity. Many of the ion channels are likely to be involved in the development of electrical excitability of enteric neurons.

PMID 25798587

Gas1 is a receptor for sonic hedgehog to repel enteric axons

Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):E73-80. doi: 10.1073/pnas.1418629112. Epub 2014 Dec 22.

Jin S1, Martinelli DC1, Zheng X1, Tessier-Lavigne M2, Fan CM3.

Abstract

The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gαi proteins that can couple with Smo, G protein α Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance. KEYWORDS: Gas1; Hedgehog; axon guidance; chemorepellent; enteric neuron

PMID 25535338

2014

Appearance of cholinergic myenteric neurons during enteric nervous system development: comparison of different ChAT fluorescent mouse reporter lines

Neurogastroenterol Motil. 2014 Apr 8. doi: 10.1111/nmo.12343. [Epub ahead of print]

Erickson CS1, Lee SJ, Barlow-Anacker AJ, Druckenbrod NR, Epstein ML, Gosain A. Author information

Abstract

BACKGROUND: Cholinergic neurons have been identified with the acetylcholine synthetic enzyme choline acetyltransferase (ChAT). However, ChAT is difficult to localize in newly differentiated peripheral neurons making the study of cholinergic neuronal development problematic. Consequently, researchers have used mouse reporter lines to indicate the presence of ChAT. METHODS: Our objective was to determine which ChAT reporter line was the most sensitive indicator of ChAT expression. We utilized two different fluorescent ChAT reporter lines (ChAT-GFP and ChAT-Cre;R26R:floxSTOP:tdTomato) together with immunolocalization of ChAT protein (ChAT-IR) to characterize the spatial and temporal expression of ChAT in myenteric neurons throughout enteric nervous system (ENS) development. KEY RESULTS: ChAT-IR cells were first seen in the intestine at E10.5, even within the migration wavefront of neural precursors. Myenteric neurons within the distal small intestine (dSI) and proximal colon were first labeled by ChAT-IR, then ChAT-GFP, and finally ChAT-Cre tdTomato. The percentage of ChAT-IR neurons is equivalent to adult levels in the dSI by E13.5 and proximal colon by P0. After these stages, the percentages remained relatively constant throughout development despite dramatic changes in neuronal density. CONCLUSIONS & INFERENCES: These observations indicate that neurotransmitter expression occurs early and there is only a brief gap between neurogenesis and neurotransmitter expression. Our finding that the proportion of ChAT myenteric neurons reached adult levels during embryonic development suggests that the fate of cholinergic neurons is tightly regulated and that their differentiation might influence further neuronal development. ChAT-GFP is a more accurate indicator of early ENS cholinergic neuronal differentiation than the ChAT-Cre;R26R:floxSTOP:tdTomato reporter mouse. © 2014 John Wiley & Sons Ltd. KEYWORDS: ChAT, ChAT-Cre tdTomato, ChAT-GFP, cholinergic neurogenesis, enteric nervous system

PMID 24712519

Involvement of DNMT3B in the pathogenesis of Hirschsprung disease and its possible role as a regulator of neurogenesis in the human enteric nervous system

Genet Med. 2014 Feb 27. doi: 10.1038/gim.2014.17. [Epub ahead of print]

Torroglosa A1, Enguix-Riego MV1, Fernández RM1, Román-Rodriguez FJ1, Moya-Jiménez MJ2, de Agustín JC2, Antiñolo G1, Borrego S1. Author information

Abstract

Purpose:Hirschsprung disease (OMIM 142623) is a neurocristopathy attributed to a failure of cell proliferation or migration and/or failure of the enteric precursors along the gut to differentiate during embryonic development. Although some genes involved in this pathology are well characterized, many aspects remain poorly understood. In this study, we aimed to identify novel genes implicated in the pathogenesis of Hirschsprung disease.Methods:We compared the expression patterns of genes involved in human stem cell pluripotency between enteric precursors from controls and Hirschsprung disease patients. We further evaluated the role of DNMT3B in the context of Hirschsprung disease by inmunocytochemistry, global DNA methylation assays, and mutational screening.Results:Seven differentially expressed genes were identified. We focused on DNMT3B, which encodes a DNA methyltransferase that performs de novo DNA methylation during embryonic development. DNMT3B mutational analysis in our Hirschsprung disease series revealed the presence of potentially pathogenic mutations (p.Gly25Arg, p.Arg190Cys, and p.Gly198Trp).Conclusion:DNMT3B may be regulating enteric nervous system development through DNA methylation in the neural crest cells, suggesting that aberrant methylation patterns could have a relevant role in Hirschsprung disease. Moreover, the synergistic effect of mutations in both DNMT3B and other Hirschsprung disease-related genes may be contributing to a more severe phenotype in our Hirschsprung disease patients.Genet Med advance online publication 27 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.17.

PMID 24577265

2013

Building a brain in the gut: development of the enteric nervous system

Clin Genet. 2013 Apr;83(4):307-16. doi: 10.1111/cge.12054. Epub 2012 Nov 27.

Goldstein AM, Hofstra RM, Burns AJ. Source Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Abstract The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is an essential component of the gut neuromusculature and controls many aspects of gut function, including coordinated muscular peristalsis. The ENS is entirely derived from neural crest cells (NCC) which undergo a number of key processes, including extensive migration into and along the gut, proliferation, and differentiation into enteric neurons and glia, during embryogenesis and fetal life. These mechanisms are under the molecular control of numerous signaling pathways, transcription factors, neurotrophic factors and extracellular matrix components. Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies, arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR), or aganglionic megacolon. This review focuses on the molecular and genetic factors regulating ENS development from NCC, the clinical genetics of HSCR and its associated syndromes, and recent advances aimed at improving our understanding and treatment of enteric neuropathies. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.

PMID 23167617


Development and developmental disorders of the enteric nervous system

Nat Rev Gastroenterol Hepatol. 2013 Jan;10(1):43-57. doi: 10.1038/nrgastro.2012.234. Epub 2012 Dec 11.

Obermayr F, Hotta R, Enomoto H, Young HM. Source Department of Pediatric Surgery, University Children's Hospital, University of Tübingen, Hoppe-Seyler Straße 3, Tübingen 72076, Germany.

Abstract

The enteric nervous system (ENS) arises from neural crest-derived cells that migrate into and along the gut, leading to the formation of a complex network of neurons and glial cells that regulates motility, secretion and blood flow. This Review summarizes the progress made in the past 5 years in our understanding of ENS development, including the migratory pathways of neural crest-derived cells as they colonize the gut. The importance of interactions between neural crest-derived cells, between signalling pathways and between developmental processes (such as proliferation and migration) in ensuring the correct development of the ENS is also presented. The signalling pathways involved in ENS development that were determined using animal models are also described, as is the evidence for the involvement of the genes encoding these molecules in Hirschsprung disease-the best characterized paediatric enteric neuropathy. Finally, the aetiology and treatment of Hirschsprung disease in the clinic and the potential involvement of defects in ENS development in other paediatric motility disorders are outlined.

PMID 23229326


Enteric neurons show a primary cilium

J Cell Mol Med. 2013 Jan;17(1):147-53. doi: 10.1111/j.1582-4934.2012.01657.x. Epub 2012 Dec 4.

Luesma MJ, Cantarero I, Castiella T, Soriano M, Garcia-Verdugo JM, Junquera C. Source Department of Human Anatomy and Histology, Faculty of Medicine, University of Zaragoza, Zaragoza, Spain. mjluesma@unizar.es

Abstract

The primary cilium is a non-motile cilium whose structure is 9+0. It is involved in co-ordinating cellular signal transduction pathways, developmental processes and tissue homeostasis. Defects in the structure or function of the primary cilium underlie numerous human diseases, collectively termed ciliopathies. The presence of single cilia in the central nervous system (CNS) is well documented, including some choroid plexus cells, neural stem cells, neurons and astrocytes, but the presence of primary cilia in differentiated neurons of the enteric nervous system (ENS) has not yet been described in mammals to the best of our knowledge. The enteric nervous system closely resembles the central nervous system. In fact, the ultrastructure of the ENS is more similar to the CNS ultrastructure than to the rest of the peripheral nervous system. This research work describes for the first time the ultrastructural characteristics of the single cilium in neurons of rat duodenum myenteric plexus, and reviews the cilium function in the CNS to propose the possible role of cilia in the ENS cells. © 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PMID 23205631


Balancing on the crest - Evidence for disruption of the enteric ganglia via inappropriate lineage segregation and consequences for gastrointestinal function

Dev Biol. 2013 Jan 31. pii: S0012-1606(13)00042-0. doi: 10.1016/j.ydbio.2013.01.024. [Epub ahead of print]

Musser MA, Michelle Southard-Smith E. Source Division of Genetic Medicine, Department of Medicine and the PhD Program in Human Genetics, Center for Human Genetic Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Abstract Normal enteric nervous system (ENS) development relies on numerous factors, including appropriate migration, proliferation, differentiation, and maturation of neural crest (NC) derivatives. Incomplete rostral to caudal migration of enteric neural crest-derived progenitors (ENPs) down the gut is at least partially responsible for the absence of enteric ganglia that is a hallmark feature of Hirschsprung disease (HSCR). The thought that ganglia proximal to aganglionosis are normal has guided surgical procedures for HSCR patients. However, chronic gastrointestinal dysfunction suffered by a subset of patients after surgery as well as studies in HSCR mouse models suggest that aberrant NC segregation and differentiation may be occurring in ganglionated regions of the intestine. Studies in mouse models that possess enteric ganglia throughout the length of the intestine (non-HSCR) have also found that certain genetic alterations affect neural crest lineage balance and interestingly many of these mutants also have functional gastrointestinal (GI) defects. It is possible that many GI disorders can be explained in part by imbalances in NC-derived lineages. Here we review studies evaluating ENS defects in HSCR and non-HSCR mouse models, concluding with clinical implications while highlighting areas requiring further study. Copyright © 2013 Elsevier Inc. All rights reserved.

PMID 23376538

Building a brain in the gut: development of the enteric nervous system

Clin Genet. 2013 Apr;83(4):307-16. doi: 10.1111/cge.12054. Epub 2012 Nov 27.

Goldstein A, Hofstra R, Burns A. Source Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Abstract The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is an essential component of the gut neuromusculature and controls many aspects of gut function, including coordinated muscular peristalsis. The ENS is entirely derived from neural crest cells (NCC) which undergo a number of key processes, including extensive migration into and along the gut, proliferation, and differentiation into enteric neurons and glia, during embryogenesis and fetal life. These mechanisms are under the molecular control of numerous signaling pathways, transcription factors, neurotrophic factors and extracellular matrix components. Failure in these processes and consequent abnormal ENS development can result in so-called enteric neuropathies, arguably the best characterized of which is the congenital disorder Hirschsprung disease (HSCR), or aganglionic megacolon. This review focuses on the molecular and genetic factors regulating ENS development from NCC, the clinical genetics of HSCR and its associated syndromes, and recent advances aimed at improving our understanding and treatment of enteric neuropathies. © 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd. PMID 23167617

2012

The enteric nervous system

Dev Biol. 2012 Jun 1;366(1):64-73. doi: 10.1016/j.ydbio.2012.01.012. Epub 2012 Jan 24.

Sasselli V, Pachnis V, Burns AJ. Source Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. Abstract The enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, consists of numerous types of neurons, and glial cells, that are distributed in two intramuscular plexuses that extend along the entire length of the gut and control co-ordinated smooth muscle contractile activity and other gut functions. All enteric neurons and glia are derived from neural crest cells (NCC). Vagal (hindbrain) level NCC provide the majority of enteric precursors along the entire length of the gut, while a lesser contribution, that is restricted to the hindgut, arises from the sacral region of the neuraxis. After leaving the dorsal neural tube NCC undergo extensive migration, proliferation, survival and differentiation in order to form a functional ENS. This article reviews the molecular mechanisms underlying these key developmental processes and highlights the major groups of molecules that affect enteric NCC proliferation and survival (Ret/Gdnf and EdnrB/Et-3 pathways, Sox10 and Phox2b transcription factors), cell migration (Ret and EdnrB signalling, semaphorin 3A, cell adhesion molecules, Rho GTPases), and the development of enteric neuronal subtypes and morphologies (Mash1, Gdnf/neurturin, BMPs, Hand2, retinoic acid). Finally, looking to the future, we discuss the need to translate the wealth of data gleaned from animal studies to the clinical area and thus better understand, and develop treatments for, congenital human diseases affecting the ENS. Copyright © 2012 Elsevier Inc. All rights reserved.

PMID 22290331


2006

Neural crest and the development of the enteric nervous system

Adv Exp Med Biol. 2006;589:181-96.

Anderson RB1, Newgreen DF, Young HM. Author information Abstract The formation of the enteric nervous system (ENS) is a particularly interesting example of the migratory ability of the neural crest and of the complexity of structures to which neural crest cells contribute. The distance that neural crest cells migrate to colonize the entire length of the gastrointestinal tract exceeds that of any other neural crest cell population. Furthermore, this migration takes a long time--over 25% of the gestation period for mice and around 3 weeks in humans. After colonizing the gut, neural crest-derived cells within the gut wall then differentiate into glial cells plus many different types of neurons, and generate the most complex part of the peripheral nervous system. PMID 17076282

2004

Embryonic development of the ganglion plexuses and the concentric layer structure of human gut: a topographical study

Anat Embryol (Berl). 2004 Apr;208(1):33-41. Epub 2004 Feb 27.

Fu M1, Tam PK, Sham MH, Lui VC. Author information

Abstract

In this study, we performed a detailed topographical study on the development of ganglion plexuses and the smooth muscle layers of human embryonic and fetal gut. Neuron and glia differentiation was investigated with anti-PGP9.5 and anti-S100 antibodies respectively. The differentiation of smooth muscle and interstitial cells of Cajal (ICC) was studied with anti-smooth muscle alpha-actin and anti-C-Kit antibodies respectively. By week 7, rostro-caudal neural crest cell (NCC) colonization of the gut was complete, and NCCs have differentiated into neurons and glia. At the foregut, neurons and glia were aggregated into ganglion plexus in the myenteric region, and the longitudinal and circular muscle layers have started to differentiate; however, neurons and glia were not found in the submucosa. At the hindgut, neurons and glia were dispersed within the mesenchyme. Myenteric plexus, longitudinal and circular muscle layers formed along the entire gut by week 9. Scattered and individual neurons and glia, and small ganglion plexuses were detected in the foregut and midgut submucosa by week 12. Ganglion plexus was not seen in the hindgut submucosa until week 14. Muscularis mucosae was formed at the foregut and midgut by week 12 but was only discernible at the hindgut 2 weeks later. As the gut wall developed, ganglion plexus increased in size with more neurons and glia, and the formation of intra-plexus nerve fascicle. ICCs were localized in the ganglion plexus as early as week 7. ICCs were initially dispersed in the plexus and were preferentially localized at the periphery of the plexus by week 20. The specification of the annular layers of human embryonic and fetal gut follows a strict spatio-temporal pattern in a rostro-caudal and centripetal manner suggesting that interaction between (1) homotypic and/or heterotypic cells; and (2) cells and the extracellular matrix is critical for the embryonic development of the gut mesenchyme and the enteric nervous system.

PMID 14991401

2000

Types of neurons in the enteric nervous system

J Auton Nerv Syst. 2000 Jul 3;81(1-3):87-96.

Furness JB. Source Department of Anatomy and Cell Biology, University of Melbourne, VIC 3010, Parkville, Australia. john.furness@anatomy.unimelb.edu.au

Abstract

This paper, written for the symposium in honour of more than 40 years' contribution to autonomic research by Professor Geoffrey Burnstock, highlights the progress made in understanding the organisation of the enteric nervous system over this time. Forty years ago, the prevailing view was that the neurons within the gut wall were post-ganglionic neurons of parasympathetic pathways. This view was replaced as evidence accrued that the neurons are part of the enteric nervous system and are involved in reflex and integrative activities that can occur even in the absence of neuronal influence from extrinsic sources. Work in Burnstock's laboratory led to the discovery of intrinsic inhibitory neurons with then novel pharmacology of transmission, and precipitated investigation of neuron types in the enteric nervous system. All the types of neurons in the enteric nervous system of the small intestine of the guinea-pig have now been identified in terms of their morphologies, projections, primary neurotransmitters and physiological identification. In this region there are 14 functionally defined neuron types, each with a characteristic combination of morphological, neurochemical and biophysical properties. The nerve circuits underlying effects on motility, blood flow and secretion that are mediated through the enteric nervous system are constructed from these neurons. The circuits for simple motility reflexes are now known, and progress has been made in analysing those involved in local control of blood flow and transmucosal fluid movement in the small intestine.

PMID 10869706

1991

Enteric glia

Glia. 1991;4(2):195-204.

Gershon MD1, Rothman TP. Author information

Abstract

The structure of the enteric nervous system (ENS) is different from that of extraenteric peripheral nerve. Collagen is excluded from the enteric plexuses and support for neuronal elements is provided by astrocyte-like enteric glial cells. Enteric glia differ from Schwann cells in that they do not form basal laminae and they ensheath axons, not individually, but in groups. Although enteric glia are rich in the S-100 and glial fibrillary acidic proteins, it has been difficult to find a single chemical marker that distinguishes enteric glia from non-myelinating Schwann cells. Nevertheless, two monoclonal antibodies have been obtained that recognize antigens that are expressed on Schwann cells (Ran-1 in rats and SMP in avians) but not enteric glia. Functional differences between enteric glia and non-myelinating Schwann cells, including responses to gliotoxins and in vitro proliferative rates, have also been observed. Developmentally, enteric glia, like Schwann cells, are derived from the neural crest. In both mammals and birds the precursors of the ENS appear to migrate to the bowel from sacral as well as vagal levels of the crest. These crest-derived emigrés give rise to both enteric glia and neurons; however, analyses of the ontogeny of the enteric innervation in a mutant mouse (the ls/ls), in which the original colonizing waves of crest-derived precursor cells are unable to invade the terminal colon, suggest that enteric glia can also arise from Schwann cells that enter the gut with the extrinsic innervation. When induced to leave back-transplanted segments of avian bowel, enteric crest-derived cells migrate into peripheral nerves and form Schwann cells. Enteric glia and Schwann cells thus appear to be different cell types, but ones that derive from lineages that diverge relatively late in ontogeny. PMID 1827778