Grego-Bessa Joaquín, Luna-Zurita Luis, del Monte Gonzalo, Bolós Victoria, Melgar Pedro, Arandilla Alejandro, Garratt Alistair N, Zang Heesuk, Mukouyama Yoh-Suke, Chen Hanying, Shou Weinian, Ballestar Esteban, Esteller Manel, Rojas Ana, Pérez-Pomares José María, de la Pompa José Luis
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, E-28049 Madrid, Spain.
Dev Cell. 2007 Mar;12(3):415-29. doi: 10.1016/j.devcel.2006.12.011.
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.
心室腔形态发生最初表现为小梁形成，对心脏功能和胚胎存活至关重要，且依赖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突变体表现出小梁形成受损和标志物表达减弱，EphrinB2、NRG1和BMP10表达及信号传导减弱，心肌增殖减少。功能和分子分析表明，Notch抑制会阻止EphrinB2表达，且EphrinB2是心室中在NRG1上游起作用的直接Notch靶标。然而，在小梁形成过程中发现BMP10水平独立于EphrinB2和NRG1两者。因此，外源性BMP10可挽救体外培养的RBPJk突变体的心肌增殖缺陷，而外源性NRG1可并行挽救分化。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，这两个过程精确平衡，其扰动可能导致先天性心脏病。
