Mechanisms of chondrocyte differentiation

软骨形成是一个多步骤的过程。软骨的形成始于间充质细胞的凝聚，然后分化为软骨细胞。我们最近的研究已经确定Sox9是所有软骨细胞分化所需的第一个主转录因子。事实上，纯合子Sox9-/-突变细胞不能分化为软骨细胞，也不能表达一系列软骨细胞特异性标记基因，如Col2a1、Collla2、Col9a2和Aggrecan。SOX9基因的杂合突变导致人类骨骼畸形综合征坎贝尔型发育不良。这项应用主要是研究Sox9在软骨形成过程中的功能。该研究建议进一步表征阻止分化为软骨细胞的Sox9-/-突变间充质样细胞的细胞表型，并从嵌合胚胎中分离这些细胞进行功能研究。它还将表征杂合Sox9+/-小鼠的异常骨骼表型，这些小鼠呈现出人类疾病camomelic Dysplasia的近乎完美的表型。它将检测环AMP对Sox9活性的作用，以及FGF途径在完整小鼠软骨形成过程中Sox9表达水平的作用。已知由这些分子控制的信号通路在生长板软骨中是活跃的。此外，本应用程序提出鉴定与Sox9和其他两个在软骨细胞中活跃的Sox家族成员相互作用的其他转录因子。

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.