Dominance of SOX9 function over RUNX2 during skeletogenesis
Dominance of SOX9 function over RUNX2 during skeletogenesis
复制标题
DOI：
10.1073/pnas.0605170103
复制
发表时间：
2006-12-12
影响因子：
11.1
通讯作者：
Lee, Brendan
中科院分区：
文献类型：
--
作者：
Zhou, Guang;Zheng, Qiping;Lee, Brendan
间充质干细胞来源的骨软骨祖细胞在骨骼原基凝结过程中表达两种主转录因子 SOX9 和 RUNX2。它们分别对软骨形成和成骨至关重要，它们的单倍体不足会导致人类骨骼发育不良。我们证明 SOX9 直接与 RUNX2 相互作用，并通过其进化上保守的高迁移率组和矮域抑制其活性。小鼠成骨细胞中全长 SOX9 或其 RUNX2 相互作用结构域的异位表达会导致骨发育不良，其特征是严重骨质减少和成骨细胞分化标记物下调。因此，即使在已建立的成骨细胞谱系中，SOX9 也可以在体内抑制 RUNX2 功能。最后，我们证明 SOX9 的这种显着抑制功能与人类 Campomelic 发育不良具有生理相关性。在 Campomelic 发育不良中，SOX9 的单倍体不足导致 RUNX2 转录靶标 COL10A1 以及 RUNX 基因家族的所有三个成员上调。总之，在软骨内骨化过程中注定要形成软骨谱系的间充质前体中，SOX9 的功能优于 RUNX2。
Mesenchymal stem cell-derived osteochondroprogenitors express two master transcription factors, SOX9 and RUNX2, during condensation of the skeletal anlagen. They are essential for chondrogenesis and osteogenesis, respectively, and their haploinsufficiency causes human skeletal dysplasias. We show that SOX9 directly interacts with RUNX2 and represses its activity via their evolutionarily conserved high-mobility-group and runt domains. Ectopic expression of full-length SOX9 or its RUNX2-interacting domain in mouse osteoblasts results in an osteodysplasia characterized by severe osteopenia and down-regulation of osteoblast differentiation markers. Thus, SOX9 can inhibit RUNX2 function in vivo even in established osteoblastic lineage. Finally, we demonstrate that this dominant inhibitory function of SOX9 is physiologically relevant in human campomelic dysplasia. In campomelic dysplasia, haploinsufficiency of SOX9 results in up-regulation of the RUNX2 transcriptional target COL10A1 as well as all three members of RUNX gene family. in summary, SOX9 is dominant over RUNX2 function in mesenchymal precursors that are destined for a chondrogenic lineage during endochondral ossification.