Neuron-Glia Interaction in the Developing and Adult Enteric Nervous System

Abstract

The enteric nervous system (ENS) constitutes the largest part of the peripheral nervous system. In recent years, ENS development and its neurogenetic capacity in homeostasis and allostasishave gained increasing attention. Developmentally, the neural precursors of the ENS are mainly derived from vagal and sacral neural crest cell portions. Furthermore, Schwann cell precursors, as well as endodermal pancreatic progenitors, participate in ENS formation. Neural precursorsenherite three subpopulations: a bipotent neuron-glia, a neuronal-fated and a glial-fated subpopulation. Typically, enteric neural precursors migrate along the entire bowel to the anal end, chemoattracted by glial cell-derived neurotrophic factor (GDNF) and endothelin 3 (EDN3) molecules. During migration, a fraction undergoes differentiation into neurons and glial cells. Differentiation is regulated by bone morphogenetic proteins (BMP), Hedgehog and Notch signalling. The fully formed adult ENS may react to injury and damage with neurogenesis and gliogenesis. Nevertheless, the origin of differentiating cells is currently under debate. Putative candidates are an embryonic-like enteric neural progenitor population, Schwann cell precursors and transdifferentiating glial cells. These cells can be isolated and propagated in culture as adult ENS progenitors and may be used for cell transplantation therapies for treating enteric aganglionosis in Chagas and Hirschsprung's diseases.

Keywords: BMP; EDN3; GDNF; Notch; enteric nervous system; gastrointestinal system; gut; hedgehog; neural crest cells; neuron-glia interaction.

Figure 1

Enteric nervous system (ENS) precursors colonize the gut in two waves. (a) Enteric ganglia form the myenteric plexus (MP) between the circular (CM) and longitudinal muscle (LM) layers and the submucosal plexus (SMP) in the mucosa. (b) The majority of neural precursors are derived from the vagal neural crest, adjacent to somites 1 to 7 (orange). They migrate along the bowel in an oral to anal direction. A second group originates from sacral neural crest cells (in mice behind somite 24), forms the pelvic ganglia (pg) and migrates in an anal to oral direction (red). Further enteric neural precursors are descendants of Schwann cell precursors (SCP, green) or pancreatic progenitors (blue). (c) Neural-fated enteric neural crest-derived cells (ENCCs) (N) differentiate in the myenteric region (grey). In parallel, neuron-glia bipotent (N-G) and glial-fated ENCCs (G) migrate into the mucosal area (yellow) and differentiate further into neurons and glial cells.; h heart; ld liver diverticulum, pd pancreatic diverticulum, c caecum.

Figure 2

Time intervals in which different neuronal subtypes form. These are characterized by the expression of specific neurotransmitters.

Figure 3

Schematic of enteric neural differentiation showing regulatory signalling pathways and marker gene expression. Several signalling pathways promote or inhibit key processes like ENCC (purple) migration, proliferation and differentiation of neuronal- and glial-fated progenitors (blue and green). Generally accepted markers for each cellular subpopulation are indicated in blue.

Figure 4

Suggested identities of multipotent neural progenitors. (a) Neurosphere-forming multipotent cells may be isolated from theintestinal system in human and mouse. (b) Glial cells may transdifferentiate into neurons directly after injury. (c) Adult ENCC-like neural progenitors with stem cell character may differentiate into neurons and glia during homeostasis and after injury. (d) Schwann cell precursor cells may differentiate into neurons and glial cells after injury.