Notch Signaling Is Essential for Ventricular Chamber Development

Joaquín Grego-Bessa, Luis Luna-Zurita, Gonzalo del Monte, Victoria Bolós, Pedro Melgar, Alejandro Arandilla, Alistair N. Garratt, Heesuk Zang, Yoh suke Mukouyama, Hanying Chen, Weinian Shou, Esteban Ballestar, Manel Esteller, Ana Rojas, José María Pérez-Pomares, José Luis de la Pompa

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Abstract

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.

Original languageEnglish
Pages (from-to)415-429
Number of pages15
JournalDevelopmental Cell
Volume12
Issue number3
DOIs
Publication statusPublished - 1 Mar 2007

Keywords

  • DEVBIO

Cite this

Grego-Bessa, J., Luna-Zurita, L., del Monte, G., Bolós, V., Melgar, P., Arandilla, A., Garratt, A. N., Zang, H., Mukouyama, Y. S., Chen, H., Shou, W., Ballestar, E., Esteller, M., Rojas, A., Pérez-Pomares, J. M., & de la Pompa, J. L. (2007). Notch Signaling Is Essential for Ventricular Chamber Development. Developmental Cell, 12(3), 415-429. https://doi.org/10.1016/j.devcel.2006.12.011