Cells that form the skeleton first become patterned into specific shapes, and then differentiate to form stiff, supporting, structural elements. Cleft palate, one of the most common birth defects, arises from disruptions in the patterning phase of skeletogenesis, and osteoarthritis, which will affect nearly one in five Americans during the coming decade, stem from disturbed control of skeletal tissue differentiation and histogenesis. Both disorders can appear with improper functioning of developmental regulatory genes that control reciprocal signaling between cells that govern skeletal development. Our project investigates early developmental stages of zebrafish to understand reciprocal signaling in skeletogenesis. We hypothesize that a pathway patterning the palatal skeleton involves specific interactions among Sonic hedgehog, Platelet- derived growth factor, and other signals. We hypothesize that a pathway controlling histogenesis of cartilage and cartilage-replacement bone involves specific interactions among Bone morphogenetic proteins, Indian hedgehog, and Parathyroid hormone related protein. To test these hypotheses, we will examine the detailed abnormal developmental and skeletal phenotypes that arise by perturbing functions of genes in these pathways. We also propose to carry out forward and reverse genetic screens to identify new skeletal mutants. Our findings will improve our knowledge of signaling pathways between cranial epithelia and mesenchyme, and between cartilage and bone progenitors, and thereby inform our understanding of the pathogenesis of cleft palate and osteoarthritis.