L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway
L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway
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DOI：
10.1053/joca.2001.0447
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发表时间：
2001-01-01
影响因子：
7
通讯作者：
de Crombrugghe, B
中科院分区：
文献类型：
--
作者：
Lefebvre, V;Behringer, RR;de Crombrugghe, B
目的：这项工作进行了鉴定控制间充质细胞分化成软骨细胞的转录因子。设计：我们描绘了软骨特异性增强子中的胶原蛋白2型基因（Col 2A 1），并确定了负责该增强子在软骨细胞中的活性的转录因子。然后，我们分析了这些转录因子的能力，激活特定的基因的软骨细胞分化程序和控制软骨formationinvivo.Results：一个48 bp的序列在第一个内含子的Col 2a 1驱动基因的表达，特别是在软骨中的转基因小鼠胚胎。转录因子L-Sox 5、Sox 6和Sox 9在体外结合并协同激活该增强子。它们属于HMG盒DNA结合蛋白的Sry相关家族，该家族包括许多涉及各种谱系中细胞命运决定的成员。L-Sox 5，Sox 6和Sox 9在小鼠胚胎的所有前软骨冷凝中共表达，并继续在软骨细胞中表达，直到细胞最终肥大。尽管L-Sox 5和Sox 6是高度同源的蛋白质，但它们在HMG盒结构域之外与Sox 9完全不同。这三种蛋白协同激活培养细胞中的Col 2a 1-和聚集蛋白聚糖基因。人类SOX 9的杂合突变导致肢端发育不良，这是一种严重的全身性骨骼畸形综合征。具有纯合Sox 9突变的胚胎细胞不能在体内形成软骨并激活必需的软骨细胞标记基因。初步数据表明，突变的Sox 5和Sox 6在小鼠中导致严重的骨骼畸形。结论：L-Sox 5，Sox 6，和Sox 9在软骨细胞分化中发挥重要作用，从而，在软骨形成。他们的发现将有助于进一步了解体内控制软骨发生的分子机制，揭示软骨疾病的遗传机制，并开发软骨修复的新策略。(C)2001年国际骨关节炎研究学会。
Objective: This work was carried out to identify transcription factors controlling the differentiation of mesenchymal cells into chondrocytes.Design: We delineated a cartilage-specific enhancer in the collagen type 2 gene (Col2a1) and identified transcription factors responsible for the activity of this enhancer in chondrocytes. We then analyzed the ability of these transcription factors to activate specific genes of the chondrocyte differentiation program and control cartilage formation in vivo.Results: A 48-bp sequence in the first intron of Col2a1 drove gene expression specifically in cartilage in transgenic mouse embryos. The transcription factors L-Sox5, Sox6, and Sox9 bound and cooperatively activated this enhancer in vitro. They belong to the Sry-related family of HMG box DNA-binding proteins, which includes many members implicated in cell fate determination in various lineages. L-Sox5, Sox6, and Sox9 were coexpressed in all precartilaginous condensations in mouse embryos and continued to be expressed in chondrocytes until the cells underwent final hypertrophy. Whereas L-Sox5 and Sox6 are highly homologous proteins, they are totally different from Sox9 outside the HMG box domain. The three proteins cooperatively activated the Col2a1- and aggrecan genes in cultured cells. Heterozygous mutations in SOX9 in humans lead to campomelic dysplasia, a severe and generalized skeletal malformation syndrome. Embryonic cells with a homozygous Sox9 mutation were unable to form cartilage in vivo and activate essential chondrocyte marker genes. Preliminary data indicated that the mutation of Sox5 and Sox6 in the mouse led to severe skeletal malformations.Conclusions: L-Sox5, Sox6, and Sox9 play essential roles in chondrocyte differentiation and, thereby, in cartilage formation. Their discovery will help to understand further the molecular mechanisms controlling chondrogenesis in vivo, uncover genetic mechanisms underlying cartilage diseases, and develop novel strategies for cartilage repair. (C) 2001 OsteoArthritis Research Society International.