Tracing the enteric neural crest cell pathway from origin to colonization: insights into Hirschsprung’s disease

The enteric nervous system (ENS) is a highly organized network of neurons and glial cells within the intestinal wall, which orchestrates the precise regulation of gastrointestinal motility, nutrient absorption, and mucosal barrier function through interconnected ganglia and plexuses. Originating from enteric neural crest cells (ENCCs), the ENS develops as ENCCs undergo a coordinated migratory process to colonize the entire gastrointestinal tract. Defective migration of ENCCs leads to neurodevelopmental disorders, such as Hirschsprung's disease (HSCR), in which the distal intestine remains aganglionic. In recent years, breakthroughs in single-cell RNA sequencing and spatial transcriptomics have significantly advanced our ability to resolve gut cellular networks, uncovering spatiotemporal heterogeneity and lineage diversification during ENS development. Nevertheless, the inherent complexity of intestinal tissues-including diverse cell types, microenvironmental interactions, and multiscale regulatory networks-continues to impede mechanistic insights and precision therapeutics for enteric neurodevelopmental disorders. This review provides a comprehensive synthesis of molecular mechanisms underlying ENS migration, encompassing critical signaling pathways, migratory dynamics, and multicellular regulatory networks. We further discuss emerging technologies and unresolved questions in this rapidly evolving field.