Enteric nervous system development: migration, differentiation, and disease

Abstract

The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.

Changes in Enteric Neurons of Small Intestine in a Rat Model of Irritable Bowel Syndrome with Diarrhea

“…Malfunction of the ENS is recognized in disorders such as neuropathic pseudoobstruction and autoimmune enteric neuropathy, for example Hirschsprung's disease. 4 Most preclinical, morphological, and functional studies of the ENS have focused on the normal bowel.…”

Toward a better understanding of enteric gliogenesis

“…20,21 However, much less is known regarding the mechanisms underlying the associated cell fate decisions. 22 As seen in other developmental systems, cell fate decisions in the ENS are believed to be orchestrated by the combination of extrinsic factors from the gut mesenchyme and direct cell-cell communication between adjacent enteric NCCs. Pertaining to gliogenesis, such a combination is well exemplified by the functional interaction between Hedgehog and Notch signaling pathways.…”

Regenerative Medicine: Advances from Developmental to Degenerative Diseases

“…Unless there is surgical intervention to remove non-innervated part of the gut within 24 hours of birth, Hirschsprung's disease is fatal 51 . Given that the disease is underpinned by an absence of a particular cell type -enteric neurons -cell replacement therapies have been thought to be the ideal treatment for Hirschsprung's disease 52 .…”