RNA sequencing of the zebrafish larval intestine and dissociated ENCCs of mice

The enteric nervous system , which arises from neural crest cells, plays important roles in many aspects of the gastrointestinal tract function, including motility, secretions, blood flow and hormone release. Here, we identify EMB as an evolutionarily conserved regulator of ENS development. In zebrafish, loss of emb leads to decreased number of enteric neurons and impaired GI transit ability by affecting the neural crest cell migration. In mice, knockout of emb causes HSCR-like phenotypes and defects in ENS development. Using in vitro cell and tissue culture, we show that EMB is required for both the proliferation and migration of enteric neural crest cells . Mechanistically, EMB binds to and recruits the phosphatase complex PP2A to the cellular membrane to facilitate the activation of PI3K-AKt pathway, thereby promoting the ENCC development. Indeed, application of PI3K or Akt agonists could partially restore the ENS developmental defects in zebrafish emb mutants. Furthermore, rare variants of EMB may potentially contribute to the pathology of Hirschsprung's disease in humans. In summary, our results demonstrate the essential role of EMB during ENS development.