tbx2 and tbx3 regulate the dynamics of cell proliferation during heart remodelingtbx2和tbx3调节细胞增殖的动态心脏重塑.pdf

Tbx2 and Tbx3 Regulate the Dynamics of Cell Proliferation during Heart Remodeling ˆ 1¤a 1 ¨ 1¤b ´ 1¤c,d ´ ´ ´ 2¤d 1 ´ ´ Ines Ribeiro , Yasuhiko Kawakami , Dirk Buscher , Angel Raya , Joaquın Rodrıguez-Leon , Masanobu Morita , Concepcion Rodrıguez 1 ´ 1 Esteban , Juan Carlos Izpisua Belmonte * 1 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America, 2 Unidade de Desenvolvimento, ˆ Instituto Gulbenkian de Ciencia, Oeiras, Portugal Background. 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. Methodology/Principal Finding. 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 T