GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium.
The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.
Rojas
Anabel
A
Genentech Hall, 600 16th Street, Mail Code 2240, University of California, San Francisco, San Francisco, CA 94158-2517, USA.
Kong
Sek Won
SW
Agarwal
Pooja
P
Gilliss
Brian
B
Pu
William T
WT
Black
Brian L
BL
D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D002460:Cell Line; D049109:Cell Proliferation; D019925:Cyclin A / Q000378:metabolism; D056751:Cyclin A2; D056742:Cyclin D2; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D016213:Cyclins / Q000235:genetics*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006345:Heart Septal Defects, Ventricular / Q000201:enzymology; D006352:Heart Ventricles / Q000002:abnormalities / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology* / Q000201:enzymology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000201:enzymology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
C508184:CCNA2 protein, mouse; C486196:Ccnd2 protein, mouse; D019925:Cyclin A; D056751:Cyclin A2; D056742:Cyclin D2; D016213:Cyclins; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D015534:Trans-Activators; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4