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首页> 外文期刊>Journal of Cardiovascular Development and Disease >Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality
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Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality

机译：Nfatc1谱系心内膜祖细胞中的异位头蛋白诱导胚胎致死率。

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The initial heart is composed of a myocardial tube lined by endocardial cells. The TGFβ superfamily is known to play an important role, as BMPs from the myocardium signal to the overlying endocardium to create an environment for EMT. Subsequently, BMP and TGFβ signaling pathways synergize to form primitive valves and regulate myocardial growth. In this study, we investigated the requirement of BMP activity by transgenic over-expression of extracellular BMP antagonist Noggin. Using Nfatc1Cre to drive lineage-restricted Noggin within the endocardium, we show that ectopic Noggin arrests cardiac development in E10.5-11 embryos, resulting in small hearts which beat poorly and die by E12.5. This is coupled with hypoplastic endocardial cushions, reduced trabeculation and fewer mature contractile fibrils in mutant hearts. Moreover, Nfatc1Cre-mediated diphtheria toxin fragment-A expression in the endocardium resulted in genetic ablation and a more severe phenotype with lethality at E11 and abnormal linear hearts. Molecular analysis demonstrated that endocardial Noggin resulted in a specific alteration of TGFβ/BMP-mediated signal transduction, in that, both Endoglin and ALK1 were downregulated in mutant endocardium. Combined, these results demonstrate the cell-autonomous requirement of the endocardial lineage and function of unaltered BMP levels in facilitating endothelium-cardiomyocyte cross-talk and promoting endocardial cushion formation.
机译：初始心脏由衬有心内膜细胞的心肌管组成。众所周知，TGFβ超家族起着重要的作用，因为BMP从心肌信号传递到上覆的心内膜，从而为EMT创建环境。随后，BMP和TGFβ信号通路协同作用，形成原始瓣膜并调节心肌生长。在这项研究中，我们调查了细胞外BMP拮抗剂Noggin转基因过表达对BMP活性的需求。使用Nfatc1 Cre 在心内膜内驱动谱系受限的Noggin，我们发现异位Noggin阻止了E10.5-11胚胎的心脏发育，导致小心脏跳动较弱，并死于E12.5。这与发育不良的心内膜垫层，小梁减少和突变心脏中较少的成熟收缩原纤维相结合。此外，Nfatc1 介导的白喉毒素片段-A在心内膜中的表达导致遗传性消融和更严重的表型，在E11和异常线性心脏具有致死性。分子分析表明，心内膜Noggin导致TGFβ/ BMP介导的信号转导发生特定变化，因为Endoglin和ALK1在突变型心内膜中均被下调。结合起来，这些结果证明了心内膜谱系的细胞自主性要求和BMP水平未改变的功能在促进内皮-心肌细胞串扰和促进心内膜垫形成中的作用。

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