期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 32, 期 24, 页码 5089-5102出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00829-12
关键词
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资金
- Division of Neonatology (Pediatrics), University of Utah School of Medicine
- Children's Health Research Center, University of Utah School of Medicine
- Primary Children's Medical Center Foundation Innovative Grant at the University of Utah School of Medicine
- Department of Pediatrics (Neonatology), The University of Texas Medical School at Houston
- American Heart Association
- National Institute of Child Health and Human Development
- National Center for Research Resources, National Institutes of Health [8UL1TR000105]
- National Center for Advancing Translational Sciences, National Institutes of Health [8UL1TR000105]
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. 14-3-3 epsilon is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3 epsilon is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3 epsilon 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 14-3-3 epsilon 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 14-3-3 epsilon as a new candidate gene in congenital human cardiomyopathies.
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