FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine
FoxF1 and FoxL1 Link Hedgehog Signaling and the Control of Epithelial Proliferation in the Developing Stomach and Intestine
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DOI：
10.1074/jbc.m808103200
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发表时间：
2009-02-27
影响因子：
4.8
通讯作者：
Kaestner, Klaus H.
中科院分区：
文献类型：
--
作者：
Madison, Blair B.;McKenna, Lindsay B.;Kaestner, Klaus H.
刺猬（Hh）信号传导途径是脊椎动物肠道发育过程中串扰的关键组成部分，涉及内胚层分泌的Sonic（Shh）和Indian hedgehog（Ihh）蛋白，其直接向相邻的中胚层发出信号。在这里，我们表明，密切联系的间充质叉头转录因子Foxf 1和Foxl 1是这个信号级联的一部分。Foxf 1和Foxl 1周围的保守的非编码序列的分析确定了7个Gli结合位点，Foxl 1附近的两个位点在哺乳动物，鸟类，鱼类和两栖动物物种中是相同的。体外实验表明，Gli 2结合这些Gli位点，其中几个是关键的Gli 2介导的激活293细胞中的荧光素酶报告。此外，我们证明了这些元素之一的Gli蛋白在体内肠染色质免疫沉淀的占用。此外，在Gli 2/Gli 3突变体肠道中，Foxf 1和Foxl 1的表达均降低。这些结果提供了令人信服的证据表明，Foxf 1和Foxl 1是介质的Hh（内胚层）中胚层信号通路。
The hedgehog (Hh) signaling pathway is a key component of cross-talk during vertebrate gut development, involving endodermally secreted Sonic (Shh) and Indian hedgehog (Ihh) proteins that directly signal to adjacent mesoderm. Here we show that the closely linked mesenchymal forkhead transcription factors Foxf1 and Foxl1 are part of this signaling cascade. Analysis of conserved non-coding sequences surrounding Foxf1 and Foxl1 identified seven Gli binding sites, with two sites near Foxl1 being identical among mammalian, bird, fish, and amphibian species. In vitro experiments indicate that Gli2 binds to these Gli sites, several of which are critical for Gli2-mediated activation of a luciferase reporter in 293 cells. In addition, we demonstrate occupancy of one of these elements by Gli proteins in the intestine in vivo using chromatin immunoprecipitation. Furthermore, expression of both Foxf1 and Foxl1 is reduced in the Gli2/Gli3 mutant gut. These results provide compelling evidence that Foxf1 and Foxl1 are mediators of the Hh (endoderm) to mesoderm signaling pathway.