Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex
Heart induction by Wnt antagonists depends on the homeodomain transcription factor Hex
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DOI：
10.1101/gad.1279405
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发表时间：
2005-02-01
影响因子：
10.5
通讯作者：
Mercola, M
中科院分区：
文献类型：
--
作者：
Foley, AC;Mercola, M
Dickkopf-1 （Dkk-1）或Crescent对典型Wnt/ β -连环蛋白信号的抑制可启动脊椎动物胚胎的心脏发生。然而，对这些分泌的Writ拮抗剂的下游效应物或它们激活心脏形成的机制几乎一无所知。本研究表明，非洲爪蟾中的Wnt拮抗剂非细胞自主地刺激心脏发生，最多可刺激几个远离典型Wnt/ β -连环蛋白信号被阻断的细胞，这表明Wnt拮抗剂在心脏诱导中起间接作用。对下游介质的筛选显示，Dkk-1和典型Wnt通路的其他抑制剂诱导同源结构域转录因子Hex，该因子通常在两栖动物、鸟类和哺乳动物胚胎的内胚层中表达，其基础是假定的心脏中胚层。Hex功能的丧失可阻断内源性心脏发育和Dkk-1诱导异位心脏。与典型的Wnt通路拮抗剂一样，异位Hex诱导心脏标志物非细胞自主表达。因此，为了启动心脏发生，Wnt拮抗剂作用于内胚层上调Hex，进而控制扩散性心脏诱导因子的产生。Hex的这种新功能提示了Hex突变小鼠心脏畸形的病因学，并将使直接在中胚层诱导心脏的因素的分离成为可能。
inhibition of canonical Wnt/beta-catenin signaling by Dickkopf-1 (Dkk-1) or Crescent initiates cardiogenesis in vertebrate embryos. However, nearly nothing is known about the downstream effectors of these secreted Writ antagonists or the mechanism by which they activate heart formation. Here we show that Wnt antagonists in Xenopus stimulate cardiogenesis non-cell-autonomously, up to several cells away from those in which canonical Wnt/beta-catenin signaling is blocked, indicative of an indirect role in heart induction. A screen for downstream mediators revealed that Dkk-1 and other inhibitors of the canonical Wnt pathway induce the homeodomain transcription factor Hex, which is normally expressed in endoderm underlying the presumptive cardiac mesoderm in amphibian, bird, and mammalian embryos. Loss of Hex function blocks both endogenous heart development and ectopic heart induction by Dkk-1. As with the canonical Wnt pathway antagonists, ectopic Hex induces expression of cardiac markers non-cell-autonomously. Thus, to initiate cardiogenesis, Wnt antagonists act on endoderm to up-regulate Hex, which, in turn, controls production of a diffusible heart-inducing factor. This novel function for Hex suggests an etiology for the cardiac malformations in Hex mutant mice and will make possible the isolation of factors that induce heart directly in the mesoderm.