Key result
14-3-3ε deletion in mice led to ventricular noncompaction resulting from a 50% decrease in cardiac proliferation and accumulation of cardiomyocytes in the G0/G1 phase.
Deletion of 14-3-3ε in mice causes ventricular noncompaction by arresting cardiomyocyte proliferation, identifying it as a novel candidate gene for human left ventricular noncompaction.
Nominate 14-3-3ε as candidate gene for human noncompaction; hypothesis-generating from animal model alone.
Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (LVNC), a cardiomyopathy characterized by increased ratios of trabecular to compact myocardium. 14-3-3ε is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3ε is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3ε deletion did not appear to induce compensation by other 14-3-3 isoforms but led to ventricular noncompaction, with features similar to LVNC, resulting from a selective reduction in compact myocardium thickness. Abnormal compaction derived from a 50% decrease in cardiac proliferation as a result of a reduced number of cardiomyocytes in G(2)/M and the accumulation of cardiomyocytes in the G(0)/G(1) phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27(Kip1), possibly through both transcriptional and posttranslational mechanisms. Our work shows that 14-3-3ε regulates cardiogenesis and growth of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via both cyclin E1 and p27(Kip1). These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3ε as a new candidate gene in congenital human cardiomyopathies.
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Kosaka et al. (2012) studied Left ventricular noncompaction. 14-3-3ε deletion vs. Wild-type mice was evaluated on Compact myocardium thickness and cardiomyocyte proliferation. 14-3-3ε deletion in mice led to ventricular noncompaction resulting from a 50% decrease in cardiac proliferation and accumulation of cardiomyocytes in the G0/G1 phase.
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