Foxl1 controls the Wnt/β-catenin pathway by modulating the expression of proteoglycans in the gut
Foxl1 controls the Wnt/β-catenin pathway by modulating the expression of proteoglycans in the gut
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DOI：
10.1074/jbc.m104366200
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发表时间：
2001-11-16
影响因子：
4.8
通讯作者：
Kaestner, KH
中科院分区：
文献类型：
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作者：
Perreault, N;Katz, JP;Kaestner, KH
Foxl 1是一种在胃肠道间质中表达的翼状螺旋转录因子。Foxl 1基因敲除小鼠在胃、十二指肠和空肠的上皮细胞中显示出严重的结构缺陷。在这里，我们解决了Foxl 1控制胃肠道分化的分子机制。首先，我们发现在无效小鼠的上皮中发现的异常是增殖细胞数量增加的结果，而不是细胞迁移速率的变化。接下来，我们研究了受Foxl 1影响的调节回路。我们关注Wnt/β-连环蛋白信号通路作为Foxl 1的可能靶点，因为它已被证明在胃肠道增殖中起核心作用。我们证明了Foxl 1通过增加细胞外蛋白聚糖激活Wnt/β-连环蛋白途径，所述蛋白聚糖充当Wnt的共受体。因此，我们确定Foxl 1参与Wnt/β-连环蛋白通路的调节，提供了肠道间充质/上皮细胞串扰的新联系。此外，我们提供了第一个例子暗示蛋白多糖在胃肠道细胞增殖的调节。
Foxl1 is a winged helix transcription factor expressed in the mesenchyme of the gastrointestinal tract. Foxl1 null mice display severe structural defects in the epithelia of the stomach, duodenum, and jejunum. Here we addressed the molecular mechanisms by which Foxl1 controls gastrointestinal differentiation. First we showed that the abnormalities found in the epithelia of the null mice are the result of an increase in the number of proliferating cells and not a change in the rate of cell migration. Next we investigated the regulatory circuits affected by Foxl1. We focused on the Wnt/beta -catenin signaling pathway as a possible target of Foxl1 as it has been shown to play a central role in gastrointestinal proliferation. We demonstrated that Foxl1 activates the Wnt/beta -catenin pathway by increasing extracellular proteoglycans, which act as co-receptors for Wnt. Thus we establish that Foxl1 is involved in the regulation of the Wnt/beta -catenin pathway, providing a novel link in mesenchymal/epithelial cross-talk in the gut. Moreover, we provide the first example implicating proteoglycans in the regulation of cellular proliferation in the gastrointestinal tract.