14-3-3ε plays a role in cardiac ventricular compaction by regulating the cardiomyocyte cell cycle.
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.
Departments of Pediatrics, The University of Utah School of Medicine, Salt Lake City, Utah, USA.
Yasuhiro
Y
Kosaka
Katarzyna A
KA
Cieslik
Ling
L
Li
George
G
Lezin
Colin T
CT
Maguire
Yukio
Y
Saijoh
Kazuhito
K
Toyo-oka
Michael J
MJ
Gambello
Matteo
M
Vatta
Anthony
A
Wynshaw-Boris
Antonio
A
Baldini
H Joseph
HJ
Yost
Luca
L
Brunelli
D048948:14-3-3 Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle / Q000502:physiology; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005318:Fetal Heart / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism
D048948:14-3-3 Proteins; C530105:Ccnd1 protein, mouse; C493961:Cdkn1b protein, mouse; D019927:Cyclin E; D017931:DNA Primers; D015513:Oncogene Proteins; C568314:cyclin E1, mouse; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27