The transcrintion factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6
The transcrintion factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6
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DOI：
10.1101/gad.1017802
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发表时间：
2002-11-01
影响因子：
10.5
通讯作者：
de Crombrugghe, B
中科院分区：
文献类型：
--
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
为了研究转录因子Sox 9是否在软骨细胞分化的连续步骤中具有重要作用，我们使用Cre/loxP重组系统产生小鼠胚胎，其中Sox 9从肢芽的未分化间充质细胞中缺失，或者Sox-9基因在软骨形成间充质凝聚后失活。在间充质凝聚之前，Sox 9在肢芽中的失活导致软骨和骨的完全缺失，但肢体发育的不同轴的标记物显示出正常的表达模式。发育肢体内的凋亡域扩大，表明Sox 9抑制凋亡。Sox 5和Sox 6，另外两个参与软骨形成的Sox基因的表达，不再检测到。此外，Runx 2，成骨细胞分化所需的转录因子的表达，也被取消。胚胎，其中Sox-9被删除后，间充质凝聚，表现出严重的全身性软骨发育不良，类似于Sox-5，Sox 6双无效突变小鼠。大多数细胞作为浓缩的间充质细胞被逮捕，并没有经历明显的分化为软骨细胞。此外，软骨细胞增殖受到严重抑制，关节形成有缺陷。虽然印度刺猬，Patched 1，甲状旁腺相关肽（Pthrp），和Pth/Pthrp受体的表达，他们的表达下调。我们的实验进一步表明，还需要Sox 9来防止增殖的软骨细胞转化为肥大的软骨细胞。我们的结论是，Sox 9是需要在软骨细胞分化途径的连续步骤。
To examine whether the transcription factor Sox9 has an essential role during the sequential steps of chondrocyte differentiation, we have used the Cre/loxP recombination system to generate mouse embryos in which either Sox9 is missing from undifferentiated mesenchymal cells of limb buds or the Sox-9 gene is inactivated after chondrogenic mesenchymal condensations. Inactivation of Sox9 in limb buds before mesenchymal condensations resulted in a complete absence of both cartilage and bone, but markers for the different axes of limb development showed a normal pattern of expression. Apoptotic domains within the developing limbs were expanded, suggesting that Sox9 suppresses apoptosis. Expression of Sox5 and Sox6, two other Sox genes involved in chondrogenesis, was no longer detected. Moreover, expression of Runx2, a transcription factor needed for osteoblast differentiation, was also abolished. Embryos, in which Sox-9 was deleted after mesenchymal condensations, exhibited a severe generalized chondrodysplasia, similar to that in Sox-5; Sox6 double-null mutant mice. Most cells were arrested as condensed mesenchymal cells and did not undergo overt differentiation into chondrocytes. Furthermore, chondrocyte proliferation was severely inhibited and joint formation was defective. Although Indian hedgehog, Patched1, parathyroid hormone-related peptide (Pthrp), and Pth/Pthrp receptor were expressed, their expression was down-regulated. Our experiments further suggested that Sox9 is also needed to prevent conversion of proliferating chondrocytes into hypertrophic chondrocytes. We conclude that Sox9 is required during sequential steps of the chondrocyte differentiation pathway.