Endothelin-3 and T-type Ca2+ channels drive enteric neural crest cell calcium activity, contractility and migration
- 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
2026-01-20
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.