Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation
Notch1 signaling regulates chondrogenic lineage determination through Sox9 activation
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DOI：
10.1038/cdd.2011.114
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发表时间：
2012-03-01
影响因子：
12.4
通讯作者：
Rohwedel, J.
中科院分区：
文献类型：
--
作者：
Haller, R.;Schwanbeck, R.;Rohwedel, J.
Notch信号转导参与胚胎发育过程中的几种细胞谱系决定过程。最近，我们已经表明，Sox 9是最有可能的Notch 1信号在胚胎干细胞（ESCs）的主要靶基因。通过使用我们的体外分化方案从胚胎干细胞通过胚状体（EBs）与我们的他莫昔芬诱导系统激活Notch 1的软骨形成，我们分析了Notch信号传导的功能和Sox 9的诱导在EB分化向软骨形成谱系。在EB早期阶段，当谱系确定发生时，Notch 1的暂时激活伴随着快速和短暂的Sox 9上调，并导致在EB培养后期诱导软骨形成分化。使用靶向Sox 9的siRNA，我们敲低并调整了这种早期Notch 1诱导的Sox 9表达峰至非诱导水平，这导致Notch 1诱导的软骨分化逆转。相反，在EB培养过程中连续的Notch 1激活导致软骨形成分化的完全抑制。此外，在早期Notch 1激活后在EB中观察到的心脏分化的减少和延迟并没有被siRNA介导的Sox 9敲低逆转。我们的数据表明，Notch 1信号传导在软骨形成谱系的早期阶段通过调节Sox 9的表达起着重要作用。Cell Death and Differentiation（2012）19，461-469; doi：10.1038/cdd.2011.114; 2011年8月26日在线发表
Notch signaling is involved in several cell lineage determination processes during embryonic development. Recently, we have shown that Sox9 is most likely a primary target gene of Notch1 signaling in embryonic stem cells (ESCs). By using our in vitro differentiation protocol for chondrogenesis from ESCs through embryoid bodies (EBs) together with our tamoxifen-inducible system to activate Notch1, we analyzed the function of Notch signaling and its induction of Sox9 during EB differentiation towards the chondrogenic lineage. Temporary activation of Notch1 during early stages of EB, when lineage determination occurs, was accompanied by rapid and transient Sox9 upregulation and resulted in induction of chondrogenic differentiation during later stages of EB cultivation. Using siRNA targeting Sox9, we knocked down and adjusted this early Notch1-induced Sox9 expression peak to non-induced levels, which led to reversion of Notch1-induced chondrogenic differentiation. In contrast, continuous Notch1 activation during EB cultivation resulted in complete inhibition of chondrogenic differentiation. Furthermore, a reduction and delay of cardiac differentiation observed in EBs after early Notch1 activation was not reversed by siRNA-mediated Sox9 knockdown. Our data indicate that Notch1 signaling has an important role during early stages of chondrogenic lineage determination by regulation of Sox9 expression. Cell Death and Differentiation (2012) 19, 461-469; doi: 10.1038/cdd.2011.114; published online 26 August 2011