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Human Molecular Genetics Advance Access originally published online on April 13, 2005
Human Molecular Genetics 2005 14(10):1367-1377; doi:10.1093/hmg/ddi146
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org

Fine-tuning in Ca2+ homeostasis underlies progression of cardiomyopathy in myocytes derived from genetically modified embryonic stem cells

Corinne Grey, Annabelle Méry and Michel Pucéat*

CRBM, CNRS FRE 2593, 1919, route de Mende, 34293 Montpellier, France

* To whom correspondence should be addressed. Tel: +33 467613432; Fax: 33 467521559; Email: michel.puceat{at}crbm.cnrs.fr

Received December 21, 2004; Revised March 2, 2005; Accepted April 4, 2005

Mutations of genes encoding contractile proteins are responsible for familial hypertrophic cardiomyopathies. Understanding the process of differentiation of cardiomyocytes carrying a mutated protein is a crucial step towards potential treatments of inherited cardiac disorders. Embryonic Stem (ES) cells which faithfully recapitulate in vitro the process of cardiac cell differentiation can be genetically modified to incorporate a mutation mimicking a cardiomyopathy. ES cell lines engineered to express a wild-type (MLC2vGFP) or a mutated form (R58QMLC2vGFP) of ventricular myosin light chain 2 (MLC2v) fused to GFP were differentiated into cardiomyocytes within embryoid bodies (EBs). Visualization of GFP combined with sarcomeric actinin immunofluorescence of EBs revealed that mutated MLC2v dramatically prevented myofibrillogenesis. Cardiomyocytes expressing wild-type MLC2v featured spontaneous Ca2+ spiking, but not those harboring the mutation. Expression of cardiac transcription factors Mef2c, GATAs, myocardin and Nkx2.5 was not affected by cell expression of mutated MLC2v. A dramatic decrease in expression of mRNAs encoding {alpha}-actin, MLC2a and MLC2v was observed in R58QMLC2vGFP EBs. This event was attributed to a failure of Mef2c to translocate into the nucleus, a Ca2+-dependent process. Expression in mutated cells of a constitutively active Ca2+- and calmodulin-dependent kinase II or treating EBs with ionomycin fully restored translocation of Mef2c into the nucleus and expression of mRNAs encoding sarcomeric proteins partially rescued contractile activity of EBs. Alteration of Ca2+ homeostasis in mutated cardioblasts affects the transcriptional program of cardiac cell differentiation leading to a defect in myofibrillogenesis, and, in turn, in contractility. Genetically modified ES cells provide a unique cell model to determine abnormalities in Ca2+ homeostasis underlying progression of human cardiomyopathies.


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