Foxh1 recruits Gsc to negatively regulate MixI1 expression during early mouse development
Foxh1 recruits Gsc to negatively regulate MixI1 expression during early mouse development
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DOI：
10.1038/sj.emboj.7601753
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发表时间：
2007-07-11
期刊：
影响因子：
11.4
通讯作者：
Attisano, Liliana
中科院分区：
文献类型：
--
作者：
Izzi, Luisa;Silvestri, Cristoforo;Attisano, Liliana
Mixl 1是Mix/Bix家族中的一员，是小鼠发育过程中轴向中内胚层形态发生和内胚层形成所必需的。Mix/Bix蛋白是在Nodal样信号通路中起作用的转录因子，其本身受Nodal调节。在这里，我们表明，Foxh 1形成一个DNA结合复合物与Smads调节转化生长因子β（TGF β）/Nodal依赖Mixl 1基因的表达。而Foxh 1通常被描述为一种转录激活因子，我们观察到Foxh 1-null胚胎在原肠胚形成过程中表现出扩大和增强的Mixl 1表达，表明Foxh 1在早期小鼠胚胎发生过程中负调控Mixl 1的表达。我们证明，Foxh 1与含有同源结构域的蛋白Goosecoid（GSC），这反过来又招募组蛋白去乙酰化酶抑制Mixl 1基因的表达。Gsc在胚状体中的异位表达抑制内源性Mixl 1的表达，这种作用依赖于Foxh 1。由于GSC本身以Foxh 1依赖的方式诱导，我们建议Foxh 1启动正向和负向转录回路，以改善原肠胚形成过程中的细胞命运决定。
Mixl1 is a member of the Mix/Bix family of paired-like homeodomain proteins and is required for proper axial mesendoderm morphogenesis and endoderm formation during mouse development. Mix/Bix proteins are transcription factors that function in Nodal-like signaling pathways and are themselves regulated by Nodal. Here, we show that Foxh1 forms a DNA-binding complex with Smads to regulate transforming growth factor beta (TGF beta)/ Nodal-dependent Mixl1 gene expression. Whereas Foxh1 is commonly described as a transcriptional activator, we observed that Foxh1-null embryos exhibit expanded and enhanced Mixl1 expression during gastrulation, indicating that Foxh1 negatively regulates expression of Mixl1 during early mouse embryogenesis. We demonstrate that Foxh1 associates with the homeodomain-containing protein Goosecoid (Gsc), which in turn recruits histone deacetylases to repress Mixl1 gene expression. Ectopic expression of Gsc in embryoid bodies represses endogenous Mixl1 expression and this effect is dependent on Foxh1. As Gsc is itself induced in a Foxh1-dependent manner, we propose that Foxh1 initiates positive and negative transcriptional circuits to refine cell fate decisions during gastrulation.