(Taken directly from the application) This program project consists of four closely related and integrated projects focusing on signals that regulate skeletal morphogenesis during embryonic development. Because the same regulatory network is utilized postnatally as the skeleton grows, remodels, and repairs itself, these studies will increase understanding of medically important problems. Moreover the unique tools available for developmental studies will provide insights not obtained as readily by other approaches. The four projects are highly coordinated because they have grown out of a long history of collaborative efforts. The program project will encourage the exchange of expertise between laboratories whose primary focus has been either developmental biology or bone biology. By establishing core facilities for morphologic analysis and transgenic mice, the technical capabilities of each individual laboratory will be extended. In Project 1 the physiologic roles of the parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP), Indian hedgehog (Ihh) and bone morphogenic protein (BMP) secreted signals will be explored in mice, by studying targeted deletions and chimeric embryos. The dual role of the PTH/PTHrP receptor as a regulator of bone development and calcium homeostasis will be explored. In Project 2, genetic interactions between the Ihh and PTHrP pathways will be studied; the cell-autonomy of Ihh signaling, the modulation of BMP signaling by antagonistic factors such as Noggin, and the modulation of signaling by Hox gene products will be analyzed; and the function of an additional class of secreted signals, exemplified by Wnt5a, will be studied in mouse skeletal development. In Project 3, the strengths of the chick embryo system for gene misexpression will be utilized in studying the possible role of the secreted factor Autotaxin in initiation of chondrogenesis, the function of two additional Wnt genes, Wnt5b, and Wnt14, in regulation of bone growth, differentiation and segmentation, and the role of Hox genes in modulating signals to achieve bone patterning. In Project 4, signals involved in segmentation of the forming skeletal elements will be studied taking advantage of a unique insertional mouse mutation, and studying the relationship of the signals studied in the other three projects to the segmentation of individual bones. Together these highly related projects will achieve a new level of understanding of the regulation of bone morphogenesis, which could not be attained by independent efforts.
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