Transcriptional mechanisms of chondrocyte differentiation
Transcriptional mechanisms of chondrocyte differentiation
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DOI：
10.1016/s0945-053x(00)00094-9
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发表时间：
2000-09-01
期刊：
影响因子：
6.9
通讯作者：
Huang, WD
中科院分区：
文献类型：
--
作者：
de Crombrugghe, B;Lefebvre, V;Huang, WD
为了确定控制间充质细胞分化为软骨细胞的遗传程序的主转录因子，我们首先在前α 1（II）胶原（Col 2a 1）基因中描绘了一个48 bp的软骨细胞特异性增强子元件，这是软骨细胞的早期和丰富的标志物。我们的实验已经证明，含有HMG盒的转录因子Sox 9结合并激活该增强子元件，是软骨细胞分化和一系列软骨细胞特异性标记基因包括Col 2a 1、Col 9a 2、Col 11 a2和聚集蛋白聚糖表达所必需的。在缺乏Sox 9的情况下，分化的阻断发生在间充质凝聚的阶段，这表明Sox 9也可能控制间充质凝聚所需的细胞表面蛋白的表达的假设。由于Sox 9还含有一个有效的转录激活结构域，因此它是一种典型的转录因子。Sox家族的另外两个成员L-Sox 5和Sox 6也与48-bp Col 2a 1增强子结合，并与Sox 9一起激活该增强子以及内源性Col 2a 1和聚集蛋白聚糖基因。L-Sox 5和Sox 6彼此具有高度的序列同一性，并且可能具有冗余功能。除了HMG盒，L-Sox 5和Sox 6与Sox 9没有相似性，因此可能具有与Sox 9互补的功能。我们的实验表明，像Sox 9，Sox 5和Sox 6可能也需要软骨细胞分化的假设。其他实验已经提供了Sox 9多肽和Sox 9基因是已知控制软骨内骨生长板中软骨形成的离散步骤的信号分子的靶标的证据。Sox 9的蛋白激酶A（PKA）磷酸化增加其DNA结合和转录活性。由于PKA磷酸化的Sox 9存在于生长板的前肥大区，即甲状旁腺相关肽（PTHrP）受体基因表达的相同位置，并且由于PTHrP信号传导由环AMP介导，因此我们假设Sox 9是PTHrP信号传导的靶点。其他实验也表明，成纤维细胞生长因子（FGF）增加培养的软骨细胞中Sox 9的表达，并且这种激活是由促分裂原活化蛋白激酶途径介导的。这些结果支持这样的假设，即在软骨发育不全，一种由FGF受体3激活突变引起的疾病，也可能有异常高的Sox 9表达。(C)出版社：Elsevier Science B. V.国际矩阵生物学学会。All rights reserved.
With the goal of identifying master transcription factors that control the genetic program of differentiation of mesenchymal cells into chondrocytes, we first delineated a 48-bp chondrocyte-specific enhancer element in the gene for pro alpha 1(II) collagen (Col2a1), an early and abundant marker of chondrocytes. Our experiments have demonstrated that the HMG-box-containing transcription factor, Sox9 which binds and activates this enhancer element, is required for chondrocyte differentiation and for expression of a series of chondrocyte-specific marker genes including Col2a1, Col9a2, Col11a2 and Aggrecan. In the absence of Sox9 the block in differentiation occurs at the stage of mesenchymal condensation, suggesting the hypothesis that Sox9 might also control expression of cell surface proteins needed for mesenchymal condensation. Since Sox9 also contains a potent transcription activation domain, it is a typical transcription factor. Two other members of the Sox family, L-Sox5 and Sox6, also bind to the 48-bp Col2a1 enhancer and together with Sox9 activate this enhancer as well as the endogenous Col2a1 and aggrecan genes. L-Sox5 and Sox6 have a high degree of sequence identity to each other and are likely to have redundant functions. Except for the HMG-box, L-Sox5 and Sox6 have no similarity to Sox9 and, hence, are likely to have a complementary function to that of Sox9. Our experiments suggest the hypothesis that, like Sox9, Sox5 and Sox6 might also be needed for chondrocyte differentiation. Other experiments, have provided evidence that the Sox9 polypeptide and the Sox9 gene are targets of signaling molecules that are known to control discrete steps of chondrogenesis in the growth plate of endochondral bones. Protein kinase A (PKA) phosphorylation of Sox9 increases its DNA binding and transcriptional activity. Since PKA-phosphorylated-Sox9 is found in the prehypertrophic zone of the growth plate, the same location where the gene for the receptor of the parathyroid hormone-related peptide (PTHrP) is expressed and since PTHrP signaling is mediated by cyclic AMP, we have hypothesized that Sox9 is a target for PTHrP signaling. Other experiments have also shown that fibroblast growth factors (FGFs) increase the expression of Sox9 in chondrocytes in culture and that this activation is mediated by the mitogen-activated protein kinase pathway. These results favor the hypothesis that in achondroplasia, a disease caused by activating mutations in FGF receptor 3, there might also be an abnormally high Sox9 expression. (C) 2000 Published by Elsevier Science B.V./International Society of Matrix Biology. All rights reserved.