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A more recent version of this article appeared on July 1, 2003
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Submitted on September 5, 2002
Revised on February 13, 2003
Accepted on February 25, 2003
1 Centre de Recherches de Biochimie Macromoléculaire, CNRS UPR 1086, IFR24, Montpellier, France
2 Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT, USA
* Corresponding author. E-mail address: puceat{at}crbm.cnrs-mop.fr.
The function of the GTPase Rac1, a molecular switch transducing intracellular signals from growth factors, in differentiation of a specific cell type during early embryogenesis has not been investigated. To address the question, we used ES cells differentiated into cardiomyocytes, a model which faithfully recapitulates early stages of cardiogenesis. Overexpression in ES cells of a constitutively active Rac (RacV12) but not of an active mutant (RacL61D38) which does not activate the NADPH oxydase generating ROS, prevented MEF2C expression and severely compromised cardiac cell differentiation. This resulted in poor expression of ventricular myosin light chain 2 (MLC2v) and its lack of insertion into sarcomeres. Thus ES-derived cardiomyocytes featured impaired myofibrillogenesis and contractility. Overexpression of MEF2C or addition of catalase in the culture medium rescued the phenotype of racV12 cells. In contrast, RacV12 specifically expressed in ES-derived ventricular cells improved the propensity of cardioblasts to differentiate into beating cardiomyocytes. This was attributed to both a facilitation of myofibrillogenesis and a prolongation in their proliferation. The dominant negative mutant RacN17 early or lately expressed in ES-derived cells prevented myofibrillogenesis and in turn beating of cardiomyocytes. We thus suggest a stage-dependent function of the GTPase during early embryogenesis.
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