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Mutations in  GATA4  and  TBX5  are associated with congenital heart defects in humans. Interaction between GATA4 and TBX5 is important for normal cardiac septation, but the underlying molecular mechanisms are not well understood. Here, we show that Gata4 and Tbx5 are co-expressed in the embryonic atria and ventricle, but after E15.5, ventricular expression of Tbx5 decreases. Co-localization and co-immunoprecipitation studies demonstrate an interaction of Gata4 and Tbx5 in the developing atria and ventricles, but the ventricular interaction declines after E14.5.  Gata4 +/− ;Tbx5 +/−   mouse embryos display decreased atrial and ventricular myocardial thickness at E11.5, prior to cardiac septation. To determine the cell lineage in which the interaction was functionally significant  in vivo , mice heterozygous for  Gata4  in the myocardium or endocardium and heterozygous for  Tbx5  ( Gata4 MyoDel/wt ;Tbx5 +/−   and  Gata4 EndoDel/wt ;Tbx5 +/−  , respectively) were generated.  Gata4 MyoDel/wt ;Tbx5 +/−   mice displayed embryonic lethality, thin myocardium with reduced cell proliferation, and atrioventricular septation defects similar to  Gata4;Tbx5  compound heterozygotes while  Gata4 EndoDel/wt ;Tbx5 +/−   embryos were normal.  Cdk4  and  Cdk2 , cyclin-dependent kinases required for myocardial development and septation were reduced in  Gata4 +/− ;Tbx5 +/−   hearts. Cdk4 is a known direct target of Gata4 and the regulation of Cdk2 in the developing heart has not been studied. Chromatin immunoprecipitation and transactivation studies demonstrate that Gata4 and Tbx5 directly regulate Cdk4 while only Tbx5 activates Cdk2 expression. These findings highlight the mechanisms by which disruption of the Gata4 and Tbx5 interaction in the myocardium contributes to cardiac septation defects in humans.

Disruption of myocardial Gata4 and Tbx5 results in defects in cardiomyocyte proliferation and atrioventricular septation