The EMB/ATG7-mediated autophagic process regulates neurite outgrowth and promotes enteric neuronal development.

The formation of the enteric nervous system (ENS) primarily involves the migration of enteric neural crest-derived cells (ENCCs) and the subsequent maturation of enteric neurons. The developmental dysfunction of ENCCs and enteric neurons can result in ENS disorders, such as hypoganglionosis (HG). Although neurite outgrowth is fundamental to neuronal maturation, the mechanisms by which neurite outgrowth influences neuronal maturation remain poorly defined. Here, we identified EMB as a critical regulator of enteric neuronal maturation. In EMB mutant patients, the expression of EMB is reduced in the enteric neurons of the HG-affected colon. In mice, knockdown of Emb exhibited HG-like features and defects. In vitro experiments, along with analyses using Smart-seq2 and immunoprecipitation-mass spectrometry, demonstrated that EMB is essential for autophagic flux and physically interacts with ATG7, recruiting it to the autophagosomal membrane to facilitate autophagosome formation, and then EMB/ATG7-mediated autophagy promotes neurite outgrowth. Our findings elucidate EMB-mediated autophagy as a pivotal pathway in regulating neurite outgrowth and promoting the maturation of enteric neurons, which provides a mechanistic basis for understanding ENS disorders.