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

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.

Keywords: Enteric nervous system; Gut development; Hirschsprung disease; Neural crest.

Fig. 1

Migration, patterning, and differentiation of enteric neural crest-derived cells (ENCCs) in the mouse embryo. NCCs (orange dots) delaminate from the neural tube and migrate through the somites, where they are exposed to retinoic acid (ra) and begin to express Ret prior to entering the foregut mesenchyme (A). Serial sections through an E10.5 mouse embryo show vagal (B) and sacral (C) p75+ NCCs (red) migrating from the neural tube to the gut (white arrows show migratory path). The schematic illustration (D) shows vagal- and sacral-derived (arrows) contributions to the ENS. Red dots represent migrating ENCCs and shaded areas in the stomach, ceca, and cloaca denote high concentrations of ET3 and GDNF [,,–195]. At E10.5, ENCCs are present in the foregut (E), and 1 day later they have reached the distal midgut (F).

Fig. 2

Differentiation of enteric neurons and glia. Vagal neural crest-derived cells undergo progressive lineage restriction from NCC to ENCC to enteric neurons and glial cells. At each stage, specific markers label these cells. Commonly used markers for each cell type are shown. Based on functional and morphologic analyses, four general types of neurons and glial cells have been described in the gut [5,196]. *NC, neural crest cell; ENCC, enteric neural crest cell