MECHANISMS FOR DETERMINATION AND DIFFERENTIATION OF CHONDROCYTES

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This application is based on the hypothesis that specific transcription factors play a critical role in the formation of specific parts of the mammalian skeleton and in the determination and differentiation of chondrocytes during embryonic development. This application is subdivided in two different parts. We have recently identified the DNA for a novel homeodomain containing protein, Cart1, which is selectively expressed in specific mesenchymal cells, in prechondrocytes and chondrocytes. The first part of this proposal is to examine the function of Cart1 in intact mice and embryos by an extensive characterization of the phenotype of mice that are deficient in Cart1 and to study in transgenic mice the transcriptional mechanisms which control the expression of the Cart1 gene in prechondrocytes and chondrocytes. Cart-1 deficient mice show a phenotype that is similar to a human acrania syndrome. The second part of this application is based on the hypothesis that other chondrocyte-specific transcription factors(s) control the activation of the gene for proalpha1(II) collagen, a typical marker of terminal differentiation of mature chondrocytes. We propose to define the minimal sequence in intron 1 of the COL2A1 gene which confers chondrocyte- restricted expression to a beta-galactosidase reporter gene in transgenic mice and embryos, to characterize chondrocyte-specific proteins which bind to this minimal functionally active sequence and to clone their cDNAs. This application proposes to study transcription factors that play a critical role in two different aspects of skeletogenesis.