Craniofacial malformations arise when development does not work correctly. Learning about head skeletal development, including the regulatory genes that control development, is essential for our understanding of what goes wrong in human inherited disorders. Developmental mechanisms are broadly shared among animals. The jaws of diverse vertebrates come from the same embryonic tissues, and depend on correct function of the same genes. E.g., mutation of the Endothelin 1 gene, encoding a cell-cell signal, causes a prominent reduction of the jaw in mice and in zebrafish, a valuable animal model on which this proposal focuses because of favorable attributes for study. Three projects are proposed to test predictions of hypotheses about the mechanisms underlying formation of bones and cartilages. The first investigation is to use precise cell marking procedures to learn arrangements of embryonic facial skeleton-forming cells, and to learn by time-lapse recordings in intact embryos, how the cells rearrange as they develop cartilages that differ from one another in shape. A further goal is to learn, by the same methods, how the cell arrangements and rearrangements are disrupted when critical pattern-determining genes, Hox genes and the Endothelin 1 gene, do not function. The second investigation is to use molecular methods to examine the cellular responses to Endothelin 1 signaling. This will be accomplished by learning what gene activities change in skeleton-forming cells receiving an Endothelin 1 signal, and what are the functional consequences of these changes. The third investigation is use a skeletal screen with larvae derived from mutagenized fish to discover new genes required for craniofacial patterning, and, by analyzing the mutants, to learn how the genes function.
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