The broad goal of this proposal is to better understand the mechanisms of mandibular morphogenesis. The mandible develops initially from two primordia largely populated by neural crest cells (NCC) from rhombomere 2. After the two processes grow out and fuse, there is continued growth and morphogenesis subsequently leading to the formation of the mandibular skeleton. Results of rhombomere grafting experiments together with the duplicated set of mandibular skeletal elements in Hoxa-2 mutants strongly suggest that the morphogenic identity of the cranial NCC populating the mandibular arch are determined prior to their migration and local interactions within the mandibular arch determine the polarity and the pattern of skeletal elements of the mandible. A variety of studies suggest the existence of two signaling centers within the mandibular arch that regulate the patterning of the skeletal elements. Experiments in this proposal are designed to study the roles and mechanisms of action of putative signaling centers, the mesial tips of the mandibular arch and hyomandibular clefts, between the mandibular arch and hyoid arch in morphogenesis of the developing mandible. It is hypothesized that the epithelia of these regions release signals which regulate the growth and differentiation of the mesenchyme of the mandibular arch. Specific in vivo and in vitro experiments are proposed to test the following hypotheses: 1) one or more FGFs are part of the epithelial signaling in the mesial tip which regulates outgrowth of the mandible, rostral (mesial) elongation of the Meckel's cartilage, and prevents premature chondrogenesis in the mesial tips and medial region; 2) other regulatory molecules which are a part of this regulatory network include the transcription factors, Msx-1, Msx-2, and Dlx-5 and the extracellular signaling molecules FGFs, BMPs and Wnt 5a; 3) Msx-2 and Dlx-5 act together as negative and positive modulators of chondrogenesis to prevent cartilage formation in the medial region of the mandible and regulate the morphogenesis of Meckel's cartilage in the lateral region; 4) signals from the hyomandibular cleft regulate the polarity of the Meckel's cartilage and the cartilaginous elements of the middle ear and the caudal elongation of the Meckel's cartilage; 5) possible molecules involved in the signaling from the hyomandibular cleft include, FGFs, FGFRs, Msx-1, and sonic hedgehog.
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