Notch signaling is essential for ventricular chamber development
Notch signaling is essential for ventricular chamber development
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DOI：
10.1016/j.devcel.2006.12.011
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发表时间：
2007-03-01
影响因子：
11.8
通讯作者：
de la Pompa, Jose Luis
中科院分区：
文献类型：
--
作者：
Grego-Bessa, Joaquin;Luna-Zurita, Luis;de la Pompa, Jose Luis
心室形态发生首先表现为小梁形成，对于心脏功能和胚胎活力至关重要，并且取决于心内膜和心肌之间的细胞相互作用。我们发现心室 Notch1 活性在假定的小梁心内膜处最高。 RBPJk 和 Notch1 突变体显示小梁形成和标记物表达受损，EphrinB2、NRG1 和 BMP10 表达和信号传导减弱，心肌增殖减少。功能和分子分析表明，Notch 抑制可阻止 EphrinB2 表达，并且 EphrinB2 是作用于心室中 NRG1 上游的直接 Notch 靶标。然而，在小梁形成过程中，BMP10 水平被发现与 EphrinB2 和 NRG1 无关。因此，外源BMP10可以挽救体外培养的RBPJk突变体的心肌增殖缺陷，而外源NRG1同时可以挽救分化。我们认为，在小梁形成过程中，Notch 独立调节心肌细胞、增殖和分化，这是两个微妙平衡的过程，其扰动可能导致先天性心脏病。
Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses show that Notch inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch target acting upstream of NRG1 in the ventricles. However, BMP10 levels are found to be independent of both EphrinB2 and NRG1 during trabeculation. Accordingly, exogenous BMP10 rescues the myocardial proliferative defect of in vitro-cultured RBPJk mutants, while exogenous NRG1 rescues differentiation in parallel. We suggest that during trabeculation Notch independently regulates cardiomyocyte, proliferation and differentiation, two exquisitely balanced processes whose perturbation may result in congenital heart disease.