This Program Project consists of three closely related and integrated proposals focusing on signals that regulate skeletal morphogenesis during embryonic development. The projects are highly coordinated, founded in the last 10 years of a highly successful Program Project and with a long history of collaborative efforts before that. A unique feature of this team is the exchange of expertise between laboratories whose primary focus has been either developmental skeletal biology (Tabin, McMahon) or endocrine control of skeletogenesis (Kronenberg). The high-resolution histology core extends the technical capabilities of each individual lab. All three projects are focused on dissecting the roles of key regulatory pathways in skeletal development. Project 1 will examine the mechanisms used by parathyroid hormone-related protein (PTHrP) and associated G-proteins in regulating these processes and will determine the roles of novel regulators of Chondrocyte differentiation discovered in the last grant cycle, as well as characterizing the early cells of the osteoblast lineage and their relationship with the perichondrium. PTHrP works in a feedback loop with a second secreted protein;Indian hedgehog (Ihh). Project 3 will explore the role of extracellular matrix in modulating Ihh signaling and will also study the role of the perichondrium in signaling to and controlling growth and differentiation of the cartilage elements. Project 2 is devoted to defining the regulatory networks involved in chondrogenesis and osteogenesis within the skeletal elements themselves. These projects are knit together by common themes, complimentary approaches, shared reagents, and direct collaborations. 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. RELEVANCE (provided by applicant): This Program Project focuses on the intercellular signals that control the growth of the developing skeletal tissues. Because the same regulatory networks are utilized post-natally as the skeleton grows, remodels and repairs itself, these studies will also increase understanding of medically relevant aspects of bone physiology, including regulation of the post-natal growth plate and control of bone healing and remodeling following fractures Note: The critiques below were prepared by the reviewers assigned to various components of this application. These commentaries may not necessarily reflect the position of the reviewers at the close of the group discussion or the final majority opinion of the group, although the reviewers are asked to amend their critiques if their positions changed during the discussion. The resume and other initial sections of the summary statement are the authoritative representations of the final outcome of group discussion. If there is any discrepancy between the peer reviewers'commentaries and the numerical score on the face page of this summary statement, the numerical score should be considered the most accurate representation of the final outcome of the group discussion.