Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification.
Notch signaling regulates Hey2 expression in a spatiotemporal dependent manner during cardiac morphogenesis and trabecular specification.
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Notch 信号在心脏形态发生和小梁规范过程中以时空依赖性方式调节 Hey2 表达。
DOI：
10.1038/s41598-018-20917-w
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发表时间：
2018-02-08
影响因子：
4.6
通讯作者：
Wu M
中科院分区：
文献类型：
--
作者：
Miao L;Li J;Li J;Tian X;Lu Y;Hu S;Shieh D;Kanai R;Zhou BY;Zhou B;Liu J;Firulli AB;Martin JF;Singer H;Zhou B;Xin H;Wu M
人类和小鼠的 Hey2 基因突变均与多种心脏缺陷有关。然而，目前报道的 Hey2 在心室致密区的定位无法解释多种心脏缺陷。此外，据报道，与其他器官相比，Notch 不调节心脏中的 Hey2。为了确定Hey2的表达模式和调控，我们使用RNAscope和Hey2CreERT2敲入系等新方法来精确确定心脏发育过程中Hey2的时空表达模式和水平。我们发现，除了在心室致密心肌中报道的表达外，Hey2 还在房室管和流出道的心内膜细胞以及小梁基部表达。通过破坏调节小梁和/或致密化的多个信号通路，我们发现，与之前的报道相反，Notch信号和Nrg1/ErbB2调节心肌和/或心内膜中Hey2的表达水平，但不调节其表达模式：小梁心肌中弱表达，致密心肌中强表达。相反，我们发现FGF信号调节早期心肌中Hey2的表达模式，并以Notch1依赖性方式调节Hey2的表达水平。
Hey2 gene mutations in both humans and mice have been associated with multiple cardiac defects. However, the currently reported localization of Hey2 in the ventricular compact zone cannot explain the wide variety of cardiac defects. Furthermore, it was reported that, in contrast to other organs, Notch doesn’t regulate Hey2 in the heart. To determine the expression pattern and the regulation of Hey2, we used novel methods including RNAscope and a Hey2CreERT2 knockin line to precisely determine the spatiotemporal expression pattern and level of Hey2 during cardiac development. We found that Hey2 is expressed in the endocardial cells of the atrioventricular canal and the outflow tract, as well as at the base of trabeculae, in addition to the reported expression in the ventricular compact myocardium. By disrupting several signaling pathways that regulate trabeculation and/or compaction, we found that, in contrast to previous reports, Notch signaling and Nrg1/ErbB2 regulate Hey2 expression level in myocardium and/or endocardium, but not its expression pattern: weak expression in trabecular myocardium and strong expression in compact myocardium. Instead, we found that FGF signaling regulates the expression pattern of Hey2 in the early myocardium, and regulates the expression level of Hey2 in a Notch1 dependent manner.
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de la Pompa JL