Role of Neuronal signaling pathways in promoting intestinal smooth muscle maturation – NeuroPIMM

Gastrointestinal (GI) motility, i.e. the coordinated muscular contraction of the gut, is essential to the health and well-being of individuals of all ages. These movements originate from layers of smooth muscles that rhythmically contract through the coordination of the enteric nervous system (ENS) and the interstitial cells of Cajal (ICCs). During development, the GI tract is being colonized by the vagal enteric neural crest cells (vENCCs) that will give rise to the ENS. The ENS, or “second brain”, is an integrated neuronal network that monitors the complex behaviors of the gut by controlling smooth muscle contractions (or peristalsis) and changing the blood flow and secretions of water and electrolytes. Whilst the ENS regulation of GI physiology is well established, its role during development is underappreciated. Our consortium recently demonstrated that inductive signals from vENCCs control mesenchymal patterning and differentiation. However, the cellular and molecular mechanisms governing the interplay between ENS and muscle progenitor cells regarding smooth muscle development and function remain unknown in humans. Hirschsprung’s Disease (HSCR) is a rare disease (1/5000) characterized by the absence of enteric neurons in the distal GI tract (colon). Infants with HSCR often have severe constipations, growth failure and are at risk of dying from the complications of toxic megacolon. This syndrome, which reflects an embryological malformation of the GI tract, is regarded as the consequence of the premature arrest in migration of vENCCs in the hindgut between the 5th and 12th week of gestation. Interestingly, anomalies of the adjacent digestive musculature have been revealed in patients with HSCR. Despite its crucial functional role in the adult GI tract, we hypothesize that the ENS network regulate intestinal smooth muscle development and maturation in health and during Hirschsprung’s diseases (HSCR). To that end, we will characterize and test the mechanisms of ENS-mediated smooth muscle patterning with a focus on the BMP signaling pathway. Finally, we will study the impact of the ENS on muscle development in HSCR. This proposal will expand our knowledge on the effect of vENCCs on intestinal smooth muscle differentiation and growth in health and during functional disorders.