title: Notch signaling is essential for ventricular chamber development.
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.
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología/CSIC, Darwin 3, Campus de Cantoblanco, E-28049 Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Grego-Bessa
authors.forename: Luis
authors.initials: L
authors.lastname: Luna-Zurita
authors.forename: Gonzalo
authors.initials: G
authors.lastname: del Monte
authors.forename: Victoria
authors.initials: V
authors.lastname: Bolós
authors.forename: Pedro
authors.initials: P
authors.lastname: Melgar
authors.forename: Alejandro
authors.initials: A
authors.lastname: Arandilla
authors.forename: Alistair N
authors.initials: AN
authors.lastname: Garratt
authors.forename: Heesuk
authors.initials: H
authors.lastname: Zang
authors.forename: Yoh-Suke
authors.initials: YS
authors.lastname: Mukouyama
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
authors.forename: Esteban
authors.initials: E
authors.lastname: Ballestar
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Ana
authors.initials: A
authors.lastname: Rojas
authors.forename: José María
authors.initials: JM
authors.lastname: Pérez-Pomares
authors.forename: José Luis
authors.initials: JL
authors.lastname: de la Pompa
mesh_terms: 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*
chemical_list: 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