Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1.
Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1.
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DOI：
10.1016/j.mce.2015.01.015
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发表时间：
2015-03-05
影响因子：
4.1
通讯作者：
Dong, Yufeng
中科院分区：
文献类型：
--
作者：
Tian, Ye;Xu, Ying;Fu, Qin;Chang, Martin;Wang, Yongjun;Shang, Xifu;Wan, Chao;Marymont, John V.;Dong, Yufeng
虽然Notch信号传导在软骨形成的调节中起着关键作用，但其下游靶点尚不清楚。为了解决这个问题，我们进行了功能获得和丧失实验，并证明Notch抑制软骨形成通过上调转录因子Twist 1起作用。在Notch激活后，微团培养中的小鼠肢芽间充质祖细胞显示出对软骨形成的抑制。Twist 1被发现在Notch激活过程中软骨形成的起始阶段仅在间充质祖细胞中表达。在这些细胞中抑制Notch信号显著降低Twist 1的蛋白表达。此外，敲低Twist 1可显著降低NICD 1对MPC软骨形成的抑制作用。组成性激活的Notch信号显著增强Twist 1启动子活性;而突变研究表明，Twist 1启动子的Notch响应性需要启动子区域中的推定NICD/RBPjK结合元件。最后，染色质免疫沉淀试验进一步证实，Notch细胞内结构域影响Twist 1通过直接结合到Twist 1启动子。这些数据为理解Notch抑制软骨发生的分子机制提供了新的见解。
While Notch signaling plays a critical role in the regulation of cartilage formation, its downstream targets are unknown. To address this we performed gain and losses of function experiments and demonstrate that Notch inhibition of chondrogenesis acts via up-regulation of the transcription factor Twist1. Upon Notch activation, murine limb bud mesenchymal progenitor cells in micromass culture displayed an inhibition of chondrogenesis. Twist1 was found to be exclusively expressed in mesenchymal progenitor cells at the onset stage of chondrogenesis during Notch activation. Inhibition of Notch signaling in these cells significantly reduced protein expression of Twist1. Furthermore, the inhibition effect of NICD1 on MPC chondrogenesis was markedly reduced by knocking down of Twist1. Constitutively active Notch signaling significantly enhanced Twist1 promoter activity; whereas mutation studies indicated that a putative NICD/RBPjK binding element in the promoter region is required for the Notch-responsiveness of the Twist1 promoter. Finally, chromatin immunoprecipitation assays further confirmed that the Notch intracellular domain influences Twist1 by directly binding to the Twist1 promoter. These data provide a novel insight into understanding the molecular mechanisms behind Notch inhibition of the onset of chondrogenesis.
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影响因子：
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作者：
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