14-3-3ε plays a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle

Yasuhiro Kosaka, Katarzyna A. Cieslik, Ling Li, George Lezin, Colin T. Maguire, Yukio Saijoh, Kazuhito Toyo-oka, Michael J. Gambello, Matteo Vatta, Anthony Wynshaw-Boris, Antonio Baldini, H. Joseph Yost, Luca Brunelli

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24 Scopus citations

Abstract

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 14-3-3ε 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 G2/M and the accumulation of cardiomyocytes in the G0/G1 phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27kip1, 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 p27kip1. 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.

Original languageEnglish (US)
Pages (from-to)5089-5102
Number of pages14
JournalMolecular and cellular biology
Volume32
Issue number24
DOIs
StatePublished - Dec 1 2012

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Kosaka, Y., Cieslik, K. A., Li, L., Lezin, G., Maguire, C. T., Saijoh, Y., Toyo-oka, K., Gambello, M. J., Vatta, M., Wynshaw-Boris, A., Baldini, A., Yost, H. J., & Brunelli, L. (2012). 14-3-3ε plays a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle. Molecular and cellular biology, 32(24), 5089-5102. https://doi.org/10.1128/MCB.00829-12