Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2
Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2
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DOI：
10.1038/embor.2008.7
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发表时间：
2008-04-01
期刊：
影响因子：
7.7
通讯作者：
Radtke, Freddy
中科院分区：
文献类型：
--
作者：
Riccio, Orbicia;van Gijn, Marielle E.;Radtke, Freddy
通过一系列可诱导的肠道特异性Notch突变小鼠，研究了单个Notch受体的关键作用及其维持肠隐窝祖细胞的机制。我们发现Notch1和Notch2受体在肠道中有冗余功能，因为只有同时失去这两种受体才能导致增殖的隐窝祖细胞完全转化为有丝分裂后的杯状细胞。这种转化与Hes1表达的缺失和细胞周期蛋白依赖性激酶（CDK）抑制剂p27（Kip1）和p57（Kip2）的下调有关。我们还发现，在野生型隐窝祖细胞中，两个CDK抑制基因的启动子都被Notch效应物Hes1占据。因此，我们的研究结果表明，notch介导的Hes1表达通过转录抑制两种CDK抑制剂来维持小肠的增生性隐窝腔室。
The crucial role of individual Notch receptors and the mechanism by which they maintain intestinal crypt progenitor cells were assessed by using a series of inducible gut-specific Notch mutant mice. We found that Notch1 and Notch2 receptors function redundantly in the gut, as only simultaneous loss of both receptors results in complete conversion of proliferating crypt progenitors into post-mitotic goblet cells. This conversion correlates with the loss of Hes1 expression and derepression of the cyclin-dependent kinase (CDK) inhibitors p27(Kip1) and p57(Kip2). We also found that the promoter of both CDK inhibitor genes is occupied by the Notch effector Hes1 in wild-type crypt progenitor cells. Thus, our results indicate that Notch-mediated Hes1 expression contributes to the maintenance of the proliferative crypt compartment of the small intestine by transcriptionally repressing two CDK inhibitors.