OBJECTIVES: Endothelin-A receptor (Ednra) signaling plays important roles in normal facial development. Ednra-/- mice are born with hypoplastic bone in the lower jaw, most of which appears to have undergone a homeotic transformation into upper jaw-like structures. Presumably, this results from loss of Ednra signaling in cephalic neural crest cells (NCCs) within the mandibular portion of the first pharyngeal arch, a transient structure from which most lower jaw and middle ear structures arise. Ednra signaling is crucial for normal gene expression within NCCs, illustrating a role for Ednra in NCC patterning. However, since Ednra is expressed by both migrating and post-migrating NCCs, it is possible that Ednra signaling is also required for migration or guidance of NCCs to the correct arch position, as well as proliferation and survival of these cells. METHODS: To examine the fate of cephalic NCCs in Ednra-/- embryos, we used the R26R;Wnt1-Cre reporter system, in which Cre expression within NCCs results in permanent b-galactosidase (b-gal) activity in NCCs and their derivatives. RESULTS: We find that loss of Ednra does not detectably alter cephalic NCC migration into the mandibular first arch. Furthermore, all bone structures derived from the mandibular arch contain b-gal-positive cells, even though these structures appear to have undergone homeosis. However, while proliferation within the pharyngeal arch is similar between wild type and Ednra-/- embryos at both E9.5 and E10.5, increased apoptosis is observed throughout the first and second arches at E9.5 and in the proximal second arch of Ednra-/- embryo at E10.5. CONCLUSIONS: Based on our studies, it appears that Ednra signaling, while not required for NCC migration, is subsequently required for survival of a subset of NCCs, with decreased survival possibly contributing to gene expression defects in Ednra-/- embryos. This work was supported by the NIH/NIDCR (DE14181 and DE14675) and the AHA (0160184B).