Notch signaling is essential for ventricular chamber development.
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.
Grego-Bessa
Joaquín
J
Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, E-28049 Madrid, Spain.
Luna-Zurita
Luis
L
del Monte
Gonzalo
G
Bolós
Victoria
V
Melgar
Pedro
P
Arandilla
Alejandro
A
Garratt
Alistair N
AN
Zang
Heesuk
H
Mukouyama
Yoh-Suke
YS
Chen
Hanying
H
Shou
Weinian
W
Ballestar
Esteban
E
Esteller
Manel
M
Rojas
Ana
A
Pérez-Pomares
José María
JM
de la Pompa
José Luis
JL
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D006321:Heart / Q000196:embryology*; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D032386:Myoblasts, Cardiac / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020890:Neuregulin-1; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D036388:Ephrin-B2; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; C497762:Notch1 protein, mouse; C490581:Nrg1 protein, mouse; D051881:Receptor, Notch1; D051880:Receptors, Notch