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Enteric nervous system development: what could possibly go wrong?

Nature Reviews Neuroscience volume 19, pages 552–565 (2018)Cite this article

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Abstract

The gastrointestinal tract contains its own set of intrinsic neuroglial circuits — the enteric nervous system (ENS) — which detects and responds to diverse signals from the environment. Here, we address recent advances in the understanding of ENS development, including how neural-crest-derived progenitors migrate into and colonize the bowel, the formation of ganglionated plexuses and the molecular mechanisms of enteric neuronal and glial diversification. Modern lineage tracing and transcription-profiling technologies have produced observations that simultaneously challenge and affirm long-held beliefs about ENS development. We review many genetic and environmental factors that can alter ENS development and exert long-lasting effects on gastrointestinal function, and discuss how developmental defects in the ENS might account for some of the large burden of digestive disease.

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Fig. 1: Migration of neural-crest-derived progenitors to the primordial gut.
Fig. 2: Molecular regulation of cell-type diversification in the enteric nervous system.
Fig. 3: The ‘outside-in’ development and columnar organization of the enteric plexuses.
Fig. 4: Neuroglial diversification and cellular interactions in the enteric nervous system.

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Acknowledgements

M.R. receives research support from the US National Institutes of Health (NIH; DK098903), the Paul Marks Scholars Program, the American Gastroenterological Association–Takeda Pharmaceuticals International Research Scholar Award in Neurogastroenterology, and Ivan and Phyllis Seidenberg. M.D.G. is supported by grants NS15547, NS099270 and DK093094 from the NIH and by the Einhorn Family Charitable Trust.

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Nature Reviews Neuroscience thanks R. O. Heuckeroth, V. Pachnis and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Pediatrics, Columbia University, New York, NY, USA

    Meenakshi Rao

  2. Department of Pathology and Cell Biology, Columbia University, New York, NY, USA

    Michael D. Gershon

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Glossary

Ganglionated plexuses

Nerve networks interspersed with ganglia (aggregates of neuronal cell bodies) at the internodes of connecting nerve strands.

Bilateria

Animals with bilateral symmetry.

Hirschsprung disease

(HSCR). A congenital absence of ganglia from a segment of gut that may be short or long.

Chronic intestinal pseudo-obstruction

A gut motility disorder giving rise to a functional but not mechanical obstruction to the transit of intestinal contents.

Somites

Bilaterally paired blocks of paraxial mesoderm that form along the head-to-tail axis of the developing embryo in segmented animals.

Sacral crest

Neural crest at an axial level caudal to somite 28.

Proximal gut

The region of the bowel closest to the mouth, including the oesophagus, stomach, and duodenum rostral to the ampulla of Vater (corresponding to the fetal foregut).

Neuraxis

The main axis of the CNS along the anterior–posterior dimension.

Pharyngeal arches

A series of outpouchings of mesoderm on both sides of the developing pharynx.

Mesenchyme

The embryonic connective tissue. It is of mesodermal origin in most of the body, but in the region of the head and neck it is derived from the neural crest.

Sclerotome

The portion of a somite that gives rise to bone or other skeletal tissue.

Melanocytic lineage

Neural-crest-derived precursors that commit to developing as melanin-producing cells.

Retinaldehyde dehydrogenase 2

Enzyme that catalyses the synthesis of retinoic acid from retinaldehyde.

Hindgut

Most caudal region of the fetal bowel; the region supplied by the inferior mesenteric artery.

Megacolon

Massively dilated colon, such as that which occurs proximal to the pseudo-obstruction caused by an aganglionic region of colon.

Waardenburg-Shah syndrome

Syndrome characterized by hearing loss and pigment abnormalities that can be associated with enteric aganglionosis.

Confetti transgene

A genetic multicolour-reporting system typically used in mice that enables expression of one of four different fluorescent proteins, the expression of which results from stochastic recombination in individual cells and is maintained in their progeny, allowing cell lineage to be traced.

Interstitial cells of Cajal

Connective tissue cells of the gut derived from a mesenchymal precursor common to intestinal smooth muscle. They are innervated and serve as pacemakers to intestinal smooth muscle.

Enterocytes

Simple columnar epithelial cells that constitute the majority of intestinal epithelial cells and have both absorptive and secretory functions.

Lamina propria

Loose areolar connective tissue of the intestinal mucosa. It lies under the mucosal epithelium and is demarcated from the submucosa by a thin layer of smooth muscle called the muscularis mucosa.

Dye-coupled

Relating to two cells joined by gap junctions that permit membrane-impermeant dye (and, often, electrical charge) to pass from one cell to another.

Lipopolysaccharide

(LPS). A component of the outer membrane of Gram-negative bacteria. Also known as endotoxin, it is a ligand for Toll-like receptor 4.

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Rao, M., Gershon, M.D. Enteric nervous system development: what could possibly go wrong?. Nat Rev Neurosci 19, 552–565 (2018). https://doi.org/10.1038/s41583-018-0041-0

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