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The Wnt/β-catenin pathway regulates cardiac valve formation

机译:Wnt /β-catenin途径调节心脏瓣膜的形成

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Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/β-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear β-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear β-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/β-catenin signalling in determining endocardial cell fate.
机译:截断肿瘤抑制性腺瘤性息肉病大肠杆菌(Apc)组成性激活Wnt /β-catenin信号通路。 Apc在发育中起一定作用:例如,截短的Apc的小鼠胚胎不能完全形成胃泌尿。为了更充分地了解这一作用,我们研究了截短的Apc对斑马鱼发育的影响。在这里,我们表明,与小鼠相反,斑马鱼可以完全消化。但是,突变的心脏无法循环并形成过多的心内膜垫。相反,分泌的Wnt抑制剂Apc或Dickkopf 1(Dkk1)的过表达会阻止缓冲形成。在野生型心脏中,核β-连环蛋白(活化的经典Wnt信号转导的标志)仅在瓣膜形成细胞中积聚,在那里它可以激活Tcf记者。在突变型心脏中,所有细胞均显示核β-连环蛋白和Tcf报告基因活性,而瓣膜标记物明显上调。伴随地,通常限于心内膜垫的增殖和上皮-间充质转变发生在整个心内膜。我们的发现确定了Wnt /β-catenin信号传导在确定心内膜细胞命运方面的新作用。

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