(from the application): The long term goal of this program is to understand the molecular mechanisms controlling skeletogenesis and to characterize genes involved in embryonic skeletal patterning with the belief that such knowledge may ultimately aid in the prevention, detection and treatment of skeletal disorders. In Drosophila, certain of the major mesodermal lineages are specified by the bagpipe homeobox gene, which is a DNA-binding transcriptional regulator. We have recently isolated from mouse and human, homologues of the bagpipe gene designated Bapxl and BAPX1, respectively. We have mapped murine Bapxl to the proximal end of mouse chromosome 5 and human BAPX1 to 4p16, a region containing loci for several skeletal disorders. Bapxl encodes a predicted protein of 333 amino acids and expression of Bapxl RNA is first detectable in E8.0 embryos in the mesoderm of the most newly formed somites in the group of cells corresponding to the presclerotome, the precursor of the vertebrae. Thus Bapxl is one of the earliest developmental markers for the sclerotome portion of the somite. Bapxl continues to be expressed well into organogenesis in essentially all cartilaginous condensations which will subsequently undergo endochondral bone formation of the axial, appendicular and facial skeleton. The expression pattern of Bapxl in murine embryos suggests that there are evolutionary conserved mechanisms of mesoderm specification and differentiation and that the mammalian Bapxl gene has likely acquired an important developmental role in chondrogenesis and skeletal patterning. To investigate the developmental role of the Bapxl gene, we will undertake the following specific aims: (I) To complete the characterization of the genomic organization, chromosomal localization, and embryonic expression pattern of the Bapxl homeobox gene in both mouse and human. (II) To investigate the developmental role of the Bapxl gene in chondrogenesis and embryonic skeletal patterning, by generating a loss-of-function null mutation (gene knockout) of the Bapxl gene in mice.