Cdc42 activation by endothelin regulates neural crest cell migration in the cardiac outflow tract

Background Congenital cardiovascular malformations are the most common birth defects affecting children. Several of these defects occur in structures developing from neural crest cells. One of the key signaling pathways regulating cardiac neural crest cell (CNCC) development involves the endothelin‐A receptor (Ednra). However, the exact function of Ednra signaling in CNCC is unknown. Results The fate mapping of CNCC in Ednra embryos indicated that the migration of these cells is aberrant in the cardiac outflow tract (OFT), but not in the pharyngeal arches. This premature arrest of CNCC migration occurs independently of CNCC proliferation and apoptosis changes and major gene expression changes. Analysis of the Rho family of small GTPases in the mutant embryos revealed that Cdc42 failed to localize normally in the CNCC migrating in the OFT. The inhibition of Cdc42 activity in cultured embryos recapitulated the migratory phenotype observed in Ednra mice. Further analyses revealed that Cdc42 is part of the signaling pathway activated by endothelin specifically in OFT CNCC to control their migration. Conclusions These results indicated that the activation of Cdc42 by endothelin signaling is important for CNCC migration in the OFT but this pathway is not involved in mandibular or pharyngeal arch artery patterning. Key Findings Cardiac crest cells migrate independently of Ednra activity into the caudal pharyngeal arches but endothelin signaling is needed for cardiac neural crest cell migration once they reach the outflow tract. Endothelin signaling regulates remodeling of the pharyngeal arch arteries before day 10. Endothelin signaling activates Cdc42 activity in cardiac neural crest cells which is required for their migration in the cardiac outflow tract. Activation of Cdc42 by endothelin signaling is restricted to cardiac neural crest cells and not mandibular neural crest cells.