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

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.

Fig. 1

Schematic showing formation of enteric nervous system (ENS) from neural crest-derived precursors. (a) Vagal neural crest-derived cells enter the proximal (oral) end of the embryonic gut and migrate along its entire length giving rise to the majority of the neurons and glia of the ENS. Sacral neural crest-derived cells enter the hindgut and migrate in an oral direction to form neurons and glia in the distal portion of the gut. (b) In the post-natal gut, the ENS is organized in web-like plexuses that are located between the muscle layers: the myenteric plexus is situated between the longitudinal and circular muscle layers, and the submucosal plexus between the circular muscle and the mucosa. (c) The enteric plexuses contain small groupings of enteric neurons and glia. FG, foregut; MD, midgut; HD, hindgut.

Fig. 2

Flow diagram showing potential experimental approaches for gaining insight to the molecular mechanisms underlying enteric neuropathies, and development of novel therapies for their treatment.