AbstractThe endothelin/endothelin receptor system plays a critical role in the differentiation and terminal migration of particular neural crest cell subpopulations. Targeted deletion of the G-protein-coupled endothelin receptors ETA and ETB was shown to result in characteristic developmental defects of derivatives of cephalic and cardiac neural crest and of neural crest-derived melanocytes and enteric neurons, respectively. Since both endothelin receptors are coupled to G-proteins of the Gq/G11- and G12/G13-families, we generated mouse lines lacking Gαq/Gα11 or Gα12/Gα13 in neural crest cells to study their roles in neural crest development. Mice lacking Gαq/Gα11 in a neural crest cell-specific manner had craniofacial defects similar to those observed in mice lacking the ETA receptor or endothelin-1 (ET-1). However, in contrast to ET-1/ETA mutant animals, cardiac outflow tract morphology was intact. Surprisingly, neither Gαq/Gα11- nor Gα12/Gα13-deficient mice showed developmental defects seen in animals lacking either the ETB receptor or its ligand endothelin-3 (ET-3). Interestingly, Gα12/Gα13 deficiency in neural crest cell-derived cardiac cells resulted in characteristic cardiac malformations. Our data show that Gq/G11- but not G12/G13-mediated signaling processes mediate ET-1/ETA-dependent development of the cephalic neural crest. In contrast, ET-3/ETB-mediated development of neural crest-derived melanocytes and enteric neurons appears to involve G-proteins different from Gq/G11/G12/G13.