Nicolas R. Chevalier, Fanny Gayda, Nadège Bondurand, Ze Chi Chan, Thierry Savy, Monique Frain, Amira El Merhie, Lenuta Canta, Monica Dicu, Isabelle Le Parco, Léna Zig
Abstract Enteric neural crest cells (ENCCs) colonize the gut during embryogenesis and migration defects give rise to Hirschsprung disease (HD). Mutations in GDNF/RET and EDN3/EDNRB are known to be causal in HD. Here, we show that migrating ENCCs in mice exhibit endogenous EDN3/EDNRB-gated calcium activity, mediated by chloride channels, T-type Ca 2+ channels and inositol trisphosphate-sensitive intracellular-store release. We find that inhibiting Ca 2+ activity results in ENCC migration defects, while exciting it promotes migration by increasing ENCC contractility and traction force to the extracellular matrix. Our study demonstrates that embryonic endothelin-mediated neural crest migration and adult endothelin-mediated vasoconstriction is one and the same phenomenon, taking place in different cell types. Our results suggest a functional link between rare mutations of CACNA1H (the gene encoding CaV3.2) and HD, and pave the way for understanding neurocristopathies in terms of neural crest cell bioelectric activity deficits.