Mechanisms of chondrocyte differentiation

软骨细胞分化机制

• 批准号: 6590723
• 负责人: Benoit de Crombrugghe
• 金额: $ 18.82万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590723
• 关键词: cartilage development; cell differentiation; chondrocytes; cyclic AMP; developmental genetics; embryo /fetus; embryogenesis; fibroblast growth factor; gene expression; genetic regulatory element; genetically modified animals; laboratory mouse; mesenchyme; molecular cloning; nucleic acid sequence; phenotype; tissue /cell culture; tissue mosaicism; transcription factor

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.

软骨发生是软骨形成的多步骤过程。软骨形成开始于间充质细胞的凝聚，然后分化成软骨细胞。我们最近的研究已经确定Sox 9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Sox 9-/-突变细胞无法分化为软骨细胞，也无法表达一系列软骨细胞特异性标记基因，例如Col 2a 1、Collla 2、Col 9a 2和聚集蛋白聚糖。SOX 9基因的杂合突变导致人类骨骼畸形综合征--畸形肢发育不良。本申请集中于研究Sox 9在软骨形成过程中的功能。它提出进一步表征Sox 9-/-突变间充质样细胞的细胞表型，所述细胞被阻止分化成软骨细胞，并从嵌合胚胎中分离这些细胞用于功能研究。它还将表征杂合Sox 9 +/-小鼠的异常骨骼表型，其呈现人类疾病Campomelic发育不良的几乎完美的表型。它将检查环AMP对Sox 9活性的作用，以及在完整小鼠软骨形成过程中FGF途径对Sox 9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，本申请提出鉴定与Sox 9和与在软骨细胞中有活性的另外两个Sox家族成员相互作用的其它转录因子。