Neuronal Differentiation in Schwann Cell Lineage Underlies Postnatal Neurogenesis in the Enteric Nervous System

Abstract

Elucidation of the cellular identity of neuronal precursors provides mechanistic insights into the development and pathophysiology of the nervous system. In the enteric nervous system (ENS), neurogenesis persists from midgestation to the postnatal period. Cellular mechanism underlying the long-term neurogenesis in the ENS has remained unclear. Using genetic fate mapping in mice, we show here that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate in the postnatal period and contributes to the ENS. We found SCP-derived neurogenesis in the submucosal region of the small intestine in the absence of vagal neural crest-derived ENS precursors. Under physiological conditions, SCPs comprised up to 20% of enteric neurons in the large intestine and gave rise mainly to restricted neuronal subtypes, calretinin-expressing neurons. Genetic ablation of Ret, the signaling receptor for glial cell line-derived neurotrophic factor, in SCPs caused colonic oligoganglionosis, indicating that SCP-derived neurogenesis is essential to ENS integrity. Identification of Schwann cells as a physiological neurogenic source provides novel insight into the development and disorders of neural crest-derived tissues.

Dual origin of enteric neurons in vagal Schwann cell precursors and the sympathetic neural crest

“…A fourth, recently discovered source of enteric neurons are Schwann cell precursors at a later differentiation stage than the vagal ones we describe here, which travel along the mesenteric and pelvic nerves and become enteric neurons after birth (36). Many of them are presumably born in the thoracolumbar neural crest and it thus appears that the trunk crest has been co-opted in all of its regions (cervical, thoracolumbar, and sacral) to invade the gut, but at different stages of development, according to a variety of mechanisms and intermediates, in a seemingly opportunistic fashion.…”

“…Quantification of esophageal neurons and measurements of the , that contributes to most para-and prevertebral sympathetic ganglia (C: celiac; M: mesenteric) and the adrenal medulla (AM); (ii) sympatho-enteric (green) from somite 3-7 and caudal to somite 28, that contributes to the superior cervical ganglion (SCG) and forms the pelvic ganglion (P) [as well as the ganglion of Remak in chicken (RG)], and most of the ENS; and (iii) parasympatho-enteric (blue), from preotic levels to somite 2, that forms parasympathetic ganglia and contributes to the foregut nervous system. Gray dots represent postnatal contribution of Schwann cell precursors of enteric extrinsic nerves to the ENS (36).…”

Bidirectional brain-gut interactions and chronic pathological changes after traumatic brain injury in mice

“…Astrocytes and EGCs both upregulate the expression of glial fibrillary acidic protein (GFAP) upon activation. Peripherally, varying isoforms of GFAP are expressed among glial cells; within the intestinal mucosa, GFAP is a specific marker for EGCs 43 . Immunofluorescent quantification of GFAP-positive cells in mucosa of colon sections revealed a significant decrease in mucosal GFAP expression at 24 hours post-injury relative to shams (Figure 3A,B,D).…”

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies

“…post-natal) enteric neurogenesis from Schwann cell precursors in the mouse (Uesaka et al, 2015). The importance of this population for supply of enteric neurons will need to be evaluated in other animal, and human, models.…”