Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling

• Published in: PloS one Vol. 2; no. 4; p. e398
• Main Authors: Ribeiro, Inês, Kawakami, Yasuhiko, Büscher, Dirk, Raya, Ángel, Rodríguez-León, Joaquín, Morita, Masanobu, Rodríguez Esteban, Concepción, Izpisúa Belmonte, Juan Carlos
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.04.2007; Public Library of Science (PLoS)
• Subjects: Analysis; Animals; Cardiomyocytes; Cell cycle; Cell growth; Cell Proliferation; Congenital diseases; Danio rerio; Defects; Developmental Biology; Developmental Biology/Embryology; Developmental Biology/Germ Cells; Developmental Biology/Molecular Development; Developmental Biology/Organogenesis; Developmental Biology/Pattern Formation; Developmental Biology/Stem Cells; DNA binding proteins; Embryogenesis; Embryonic development; Embryonic growth stage; Gene expression; Gene Expression Regulation, Developmental; Heart; Heart - physiology; Laboratories; Morphogenesis; Morphology; Mutation; Myocardium; Physiological aspects; Remodeling; Transcription factors; Transcription Factors - genetics; Transcription Factors - physiology; Zebrafish; La Jolla California; California; United States > US; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0000398

The heart forms from a linear tube that is subject to complex remodeling during embryonic development. Hallmarks of this remodeling are the looping of the heart tube and the regionalization into chamber and non-chamber myocardium. Cardiomyocytes in the future chamber myocardium acquire different cellular and physiological characteristics through activation of a chamber-specific genetic program, which is in part mediated by T-box genes. We characterize two new zebrafish T-box transcription factors, tbx3b and tbx2a, and analyze their role during the development of the atrioventricular canal. Loss- and gain-of-function analyses demonstrate that tbx3b and tbx2a are necessary to repress the chamber-genetic program in the non-chamber myocardium. We also show that tbx3b and tbx2a are required to control cell proliferation in the atrioventricular canal and that misregulation of cell proliferation in the heart tube influences looping. Furthermore, we characterize the heart phenotype of a novel Tbx3 mutation in mice and show that both the control of cell proliferation and the repression of chamber-specific genetic program in the non-chamber myocardium are conserved roles of Tbx3 in this species. Taken together, our results uncover an evolutionarily conserved role of Tbx2/3 transcription factors during remodeling of the heart myocardium and highlight the importance of controlling cell proliferation as a driving force of morphogenesis.