Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor-deficient mice

Most of the bone and cartilage in the craniofacial region is derived from c ephalic neural crest cells, which undergo three primary developmental event s: migration from the rhombomeric neuroectoderm to the pharyngeal arches, p roliferation as the ectomesenchyme within the arches, and differentiation i nto terminal structures. Interactions between the ectomesenchymal cells and surrounding cells are required in these processes, in which defects can le ad to craniofacial malformation. We have previously shown that the G-protei n-coupled endothelin-A receptor (ETA) is expressed in the neural crest-deri ved ectomesenchyme, whereas the cognate ligand for ETA, endothelin-l (ET-1) , is expressed in arch epithelium and the paraxial mesoderm-derived arch co re; absence of either ETA or ET-1 results in numerous craniofacial defects. In this study we have attempted to define the point at which cephalic neur al crest development is disrupted in ETA-deficient embryos. We find that, w hile neural crest cell migration in the head of ETA-/- embryos appears norm al, expression of a number of transcription factors in the arch ectomesench ymal cells is either absent or significantly reduced. These ETA-dependent f actors include the transcription factors goosecoid, Dlx-2, Dlx-3, dHAND, eH AND, and Barx1, but not MHox, Hoxa-2, CRABP1, or Ufd1. In addition, the siz e of the arches in E10.5 to E11.5 ETA-/- embryos is smaller and an increase in ectomesenchymal apoptosis is observed. Thus, ETA signaling in ectomesen chymal cells appears to coordinate specific aspects of arch development by inducing expression of transcription factors in the postmigratory ectomesen chyme. Absence of these signals results in retarded arch growth, defects in proper differentiation, and, in some mesenchymal cells, apoptosis. In part icular, this developmental pathway appears distinct from the pathway that i ncludes UFD1L, implicated as a causative gene in CATCH 22 patients, and sug gests parallel complementary pathways mediating craniofacial development. ( C) 2000 Academic Press.