MOLECULAR BASIS OF NORMAL AND MUTANT LIMB DEVELOPMENT

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The overall goal of the research is study the interactions between macromolecules of the cartilaginous matrix and to understand how these macromolecular interactions influence morphogenetic processes during the development of the embryonic limb. Specifically, we will investigate link protein (LP) and cartilage matrix protein (CMP) during limb morphogenesis. In cartilage, LP forms a ternary complex with aggrecan and hyaluronic acid (HA) and stabilizes the aggrecan-HA interactions. CMP is a molecular marker for post-mitotic chondrotytes and associates with the collagen fibril in cartilage. These two molecules have very different patterns of expression. LP is ubiquitously expressed and the expression of CMP is restricted to cartilage. In the growth plate of the long bones the LP gene is transcribed in both the zones of proliferation and maturation, whereas transcription of the CMP gene occurs only in the zone of maturation. We will use transgenic approaches to test several hypotheses that are based on our biochemical data. The transgenic approach to be used is the replication competent avian retrovirus with which transgenes will be delivered to chondrocytes in culture and in the intact embryo. The role of CMP will be evaluated on chondrocyte proliferation, matrix establishment and skeletal development. The role of LP in the establishment and maintenance of the integrity of the extracellular matrix will be investigated.