Chondrogenesis is a specialized and regulated process of mesenchymal differentiation important in embryogenesis, growth, and homeostasis. Pathologic changes in both regulatory and structural components of this pathway affect cartilage differentiation, maintenance, and renewal with concomitant effects on the skeletal system. Studies of regulatory gene products have been hindered by the dearth of in vivo material as well as the lack of optimal in vitro systems. A basic understanding of the biologic modifiers important in chondrocyte differentiation, especially those which act on the transcriptional level, would further our understanding of developmental cartilage biology, as well as provide insight into pathologic processes including the skeletal dysplasias and osteoarthritides. In an effort to overcome some of these obstacles, a cDNA library derived from in vivo growth plate cartilage has been constructed. Two zinc finger containing human cDNA s, FC63 and FC67, have been isolated. Sequence analysis reveals multiple zinc-finger motifs and their temporal-spatial pattern of expression in both human and murine embryonic tissues suggests a role in chondrogenesis. To further delineate their role in development, functional characterization of these putative transcription factors are proposed. These include heterologous expression in dedifferentiated chondrocytes and multipotent C3H/10T1/2 cells, generation and characterization of mutant mice deficient in these components, and characterization of transgenic mice overexpressing these proteins. The human chromosomal location of FC63 is syntenic with the putative map location of an inherited acrofacial dysostosis, Nager syndrome, and mutation analysis of affected individuals is proposed. These studies should add to the rapidly increasing amount of information delineating both nuclear and extracellular components which control chondrogenesis and to our understanding of the pathological consequences of mutations in the genes which encode them.
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