# Endothelin-3 and T-type Ca2+ channels drive enteric neural crest cell calcium activity, contractility and migration

## TL;DR

Researchers discovered that endothelin-3 and T-type calcium channels help gut nerve cells migrate by creating electrical activity and contractions.

## Contribution

The study reveals a novel mechanism where endothelin-3 and T-type Ca2+ channels regulate neural crest cell migration through calcium activity and contractility.

## Key findings

- Endothelin-3 activates calcium activity in migrating gut nerve cells via chloride channels and T-type Ca2+ channels.
- Inhibiting calcium activity impairs cell migration, while stimulating it enhances contractility and movement.
- The findings link CACNA1H gene mutations to Hirschsprung disease through disrupted neural crest cell bioelectric activity.

## 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 Ca2+ channels and inositol trisphosphate-sensitive intracellular-store release. We find that inhibiting Ca2+ 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.

Neural crest cells migrate in the embryo to form the gut’s nervous system. Researchers found that endothelin-3 triggers electrical oscillations via T-type calcium channels, enabling these cells to contract like ‘mini muscles’ and colonize organs.