The Spatiotemporal Expression of Notch1 and Numb and Their Functional Interaction during Cardiac Morphogenesis.
The Spatiotemporal Expression of Notch1 and Numb and Their Functional Interaction during Cardiac Morphogenesis.
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作者：
Miao L;Lu Y;Nusrat A;Abdelnasser HY;Datta S;Zhou B;Schwartz RJ;Wu M
Numb家族蛋白（NFP），包括Numb和Numblike（Numbl），通常已知其作为多种类型祖细胞的细胞命运决定因素的作用，主要是由于其作为Notch抑制剂的功能。先前的研究表明，心肌NFP双敲除（MDKO）心脏显示上调的Notch激活和心脏祖细胞分化和心脏形态发生的各种缺陷。增强的Notch激活是否导致MDKO中的这些缺陷尚不完全清楚。为了回答这个问题，我们使用多种方法，包括RNAScope，Numb和Notch报告小鼠系，研究了Notch 1表达，Notch激活和Numb表达在小鼠胚胎心脏中的时空模式。为了进一步询问NFP和Notch信号传导激活之间的相互作用，我们在MDKO中缺失Notch 1或RBPJk等位基因。我们检查并比较了Notch 1敲除、NFPs双敲除、Notch 1; Numb; Numbl和RBPJk; Numb; Numbl三敲除的表型。我们的研究表明，Notch 1在心肌中的表达和激活的几个阶段，和Numb的心外膜富集，并没有显示在心肌中的不对称分布。心脏特异性Notch 1缺失导致多种结构缺陷和胚胎致死MDKO中Notch 1或RBPJk缺失不能挽救MDKO中的结构缺陷，但部分挽救了心脏祖细胞分化、心肌细胞增殖和小梁形态发生的缺陷。我们的研究得出结论，NFP调节祖细胞分化，心肌细胞增殖，小梁形态发生部分通过Notch 1和发挥更多的作用，而不是抑制Notch 1信号在心脏形态发生。
Numb family proteins (NFPs), including Numb and Numblike (Numbl), are commonly known for their role as cell fate determinants for multiple types of progenitor cells, mainly due to their function as Notch inhibitors. Previous studies have shown that myocardial NFP double knockout (MDKO) hearts display an up-regulated Notch activation and various defects in cardiac progenitor cell differentiation and cardiac morphogenesis. Whether enhanced Notch activation causes these defects in MDKO is not fully clear. To answer the question, we examined the spatiotemporal patterns of Notch1 expression, Notch activation, and Numb expression in the murine embryonic hearts using multiple approaches including RNAScope, and Numb and Notch reporter mouse lines. To further interrogate the interaction between NFPs and Notch signaling activation, we deleted both Notch1 or RBPJk alleles in the MDKO. We examined and compared the phenotypes of Notch1 knockout, NFPs double knockout, Notch1; Numb; Numbl and RBPJk; Numb; Numbl triple knockouts. Our study showed that Notch1 is expressed and activated in the myocardium at several stages, and Numb is enriched in the epicardium and did not show the asymmetric distribution in the myocardium. Cardiac-specific Notch1 deletion causes multiple structural defects and embryonic lethality. Notch1 or RBPJk deletion in MDKO did not rescue the structural defects in the MDKO but partially rescued the defects of cardiac progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis. Our study concludes that NFPs regulate progenitor cell differentiation, cardiomyocyte proliferation, and trabecular morphogenesis partially through Notch1 and play more roles than inhibiting Notch1 signaling during cardiac morphogenesis.
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