Izzi Luisa, Silvestri Cristoforo, von Both Ingo, Labbé Etienne, Zakin Lise, Wrana Jeffrey L, Attisano Liliana
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
EMBO J. 2007 Jul 11;26(13):3132-43. doi: 10.1038/sj.emboj.7601753. Epub 2007 Jun 14.
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 (TGFbeta)/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.
Mixl1是配对样同源结构域蛋白的Mix/Bix家族成员，在小鼠发育过程中，对于正确的轴向中内胚层形态发生和内胚层形成是必需的。Mix/Bix蛋白是在类Nodal信号通路中起作用的转录因子，其自身受Nodal调控。在此，我们表明Foxh1与Smads形成DNA结合复合物，以调节转化生长因子β（TGFβ）/Nodal依赖性的Mixl1基因表达。虽然Foxh1通常被描述为转录激活因子，但我们观察到Foxh1基因敲除的胚胎在原肠胚形成期间表现出Mixl1表达的扩展和增强，表明Foxh1在小鼠早期胚胎发育过程中对Mixl1的表达起负调控作用。我们证明Foxh1与含同源结构域的蛋白Goosecoid（Gsc）相关联，而Gsc又募集组蛋白去乙酰化酶来抑制Mixl1基因表达。在胚状体中异位表达Gsc可抑制内源性Mixl1表达，且这种效应依赖于Foxh1。由于Gsc本身是以Foxh1依赖的方式被诱导的，我们提出Foxh1启动正、负转录回路，以在原肠胚形成期间优化细胞命运决定。
