Mechanisms of chondrocyte differentiation

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Chondrogenesis is a multistep process by which cartilages are formed. Cartilage formation begins with condensations of mesenchymal cells followed by their differentiation into chondrocytes. Our recent studies have identified Sox9 as the first master transcription factor that is required for differentiation of all chondrocytes. Indeed, homozygous Sox9-/- mutant cells are unable to differentiate into chondrocytes and to express a series of chondrocyte-specific marker genes such as Col2a1, Collla2, Col9a2 and Aggrecan. Heterozygous mutations in the SOX9 gene cause the human skeletal malformation syndrome Campomelic Dysplasia. This application is centered on the study of the function of Sox9 during chondrogenesis. It proposes to further characterize the cellular phenotype of Sox9-/- mutant mesenchymal like cells that are blocked from differentiation into chondrocytes and to isolate these cells from chimeric embryos for functional studies. It will also characterize the abnormal skeletal phenotype of heterozygous Sox9+/- mice that present an almost perfect phenocopy of the human disease Campomelic Dysplasia. It will examine the role of cyclic AMP on the activity of Sox9 and that of the FGF pathway on the level of expression of Sox9 during chondrogenesis in intact mice. Signaling pathways controlled by these molecules are known to be active in growth plate cartilages. In addition, this application proposes to identify other transcription factors that interact with Sox9 and with two other Sox family members that are active in chondrocytes.