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  • Review Article
  • Published:

Development and developmental disorders of the enteric nervous system

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.

Key Points

  • Enteric neural crest-derived cells (ENCCs) mostly migrate within the gut mesenchyme; a subpopulation, however, migrates across the mesentery to the postcaecal hindgut, forming the colonic enteric nervous system (ENS)

  • Precise spatiotemporal regulation of ENCC proliferation, differentiation and migration is essential for ENS development

  • ENCC proliferation is influenced by their density, and studies of mice have shown that ENCCs have some ability to act collectively to adapt to prevailing conditions

  • Enteric neurogenesis occurs over a protracted period of time during prenatal and postnatal development, but does not seem to occur in adults, except after injury or activation of 5-HT4 receptors

  • Hirschsprung disease is the best characterized developmental disorder of the ENS and is caused by a failure of neural crest-derived cells to colonize the distal bowel

  • Transplantation of ENS progenitors, activation of the neurogenic potential of glia and 5-HT4 receptor activation are potential ways of generating enteric neurons in patients with enteric neuropathies

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Figure 1: Morphological and microscopic characteristics of a mouse model of Hirschsprung disease.
Figure 2: Signalling pathways involved in ENS development.
Figure 3: Timetable and migratory pathway of ENCCs along the embryonic mouse gut.
Figure 4: Proliferation of ENCCs in zebrafish and mice.

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Acknowledgements

F. Obermayr is supported by a Research Fellowship from the German Research Foundation (DFG, OB 381/1-1), H. Enomoto is supported by RIKEN and Scientific Research on Innovative Areas 'Cellular and Molecular Basis for Neuro-Vascular Wiring' (22122005) from the Ministry of Education, Science, Sports and Culture, Japan, and H. M. Young is supported by NHMRC Fellowship 1002506 and NHMRC Project Grants 628349 and 1019931. The authors would also like to thank Annette Bergner for processing material for immunohistochemistry for the figures.

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All authors researched data for the article, substantially contributed to the discussion of content and reviewed and/or edited the manuscript before submission. In addition, F. Obermayr and H. M. Young wrote the article.

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Obermayr, F., Hotta, R., Enomoto, H. et al. Development and developmental disorders of the enteric nervous system. Nat Rev Gastroenterol Hepatol 10, 43–57 (2013). https://doi.org/10.1038/nrgastro.2012.234

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