MECHANISMS FOR DETERMINATION AND DIFFERENTIATION OF CHONDROCYTES

这种应用是基于这样的假设： 这些因素在特定部分的形成中起着至关重要的作用。 哺乳动物骨骼和在确定和分化 软骨细胞在胚胎发育过程中。 此应用程序被细分为 分成两部分 我们最近鉴定了一本小说的DNA 含有同源结构域的蛋白质Cart 1，其选择性表达于 在前软骨细胞和软骨细胞中的特定间充质细胞。 的 本建议的第一部分是完整地检查Cart 1的功能， 通过对小鼠表型的广泛表征， 缺乏Cart 1基因的转基因小鼠， 控制Cart 1基因表达的转录机制 在前软骨细胞和软骨细胞中。 Cart-1缺陷小鼠显示出 与人类无颅综合征相似的表型。 本申请的第二部分基于以下假设： 软骨细胞特异性转录因子控制 前α 1（II）胶原蛋白基因，一种典型的终末标志物， 成熟软骨细胞的分化。 我们建议定义最小 COL 2A 1基因的内含子1中的序列，其赋予软骨细胞- 转基因中β-半乳糖苷酶报告基因的限制性表达 小鼠和胚胎，以表征软骨细胞特异性蛋白， 并克隆它们的cDNA。 本申请提出研究转录因子， 在骨骼发育的两个不同方面起着关键作用。

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.