Division of Developmental Biology, Cincinnati Children's Research Foundation and Department of Pediatrics, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Dev Biol. 2011 Mar 15;351(2):297-310. doi: 10.1016/j.ydbio.2010.11.037. Epub 2011 Jan 4.
The homeobox gene hhex is one of the earliest markers of the anterior endoderm, which gives rise to foregut organs such as the liver, ventral pancreas, thyroid, and lungs. The regulatory networks controlling hhex transcription are poorly understood. In an extensive cis-regulatory analysis of the Xenopus hhex promoter, we determined how the Nodal, Wnt, and BMP pathways and their downstream transcription factors regulate hhex expression in the gastrula organizer. We show that Nodal signaling, present throughout the endoderm, directly activates hhex transcription via FoxH1/Smad2 binding sites in the proximal -0.44 Kb promoter. This positive action of Nodal is suppressed in the ventral-posterior endoderm by Vent 1 and Vent2, homeodomain repressors that are induced by BMP signaling. Maternal Wnt/β-catenin on the dorsal side of the embryo cooperates with Nodal and indirectly activates hhex expression via the homeodomain activators Siamois and Twin. Siamois/Twin stimulate hhex transcription through two mechanisms: (1) they induce the expression of Otx2 and Lim1 and together Siamois, Twin, Otx2, and Lim1 appear to promote hhex transcription through homeobox sites in a Wnt-responsive element located between -0.65 to -0.55 Kb of the hhex promoter. (2) Siamois/Twin also induce the expression of the BMP-antagonists Chordin and Noggin, which are required to exclude Vents from the organizer allowing hhex transcription. This study reveals a complex network regulating anterior endoderm transcription in the early embryo.
同源盒基因 hhex 是前内胚层最早的标记物之一，它产生前肠器官，如肝脏、腹侧胰腺、甲状腺和肺。控制 hhex 转录的调控网络知之甚少。在对非洲爪蟾 hhex 启动子的广泛顺式调控分析中，我们确定了 Nodal、Wnt 和 BMP 途径及其下游转录因子如何在原肠胚组织者中调节 hhex 的表达。我们表明，存在于整个内胚层中的 Nodal 信号通过 FoxH1/Smad2 结合位点直接激活近端 -0.44 Kb 启动子中的 hhex 转录。这种 Nodal 的正调控作用被 BMP 信号诱导的同源域抑制因子 Vent1 和 Vent2 在腹后侧内胚层中抑制。胚胎背侧的母体 Wnt/β-catenin 与 Nodal 合作，通过同源域激活因子 Siamois 和 Twin 间接激活 hhex 表达。Siamois/Twin 通过两种机制刺激 hhex 转录：（1）它们诱导 Otx2 和 Lim1 的表达，并且 Siamois、Twin、Otx2 和 Lim1 一起似乎通过位于 hhex 启动子的-0.65 至-0.55 Kb 之间的 Wnt 反应元件中的同源盒位点促进 hhex 转录。（2）Siamois/Twin 还诱导 BMP 拮抗剂 Chordin 和 Noggin 的表达，这对于将 Vent 从组织者中排除以允许 hhex 转录是必需的。这项研究揭示了一个调节早期胚胎前内胚层转录的复杂网络。
