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Embryonic Stem Cells |
1 INSERM U 568, IFR 50, Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France
* To whom correspondence should be addressed. E-mail: Bernard.Binetruy{at}medecine.univ-mrs.fr.
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Abstract |
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Mouse embryonic stem (ES) cells can be differentiated, in vitro, into a variety of cell types, including cardiac cells and neurons. This process is strictly controlled by the potent morphogen retinoic acid (RA). At a concentration of 10-7M, RA induces ES cell differentiation into neurons, and, conversely, inhibits cardiomyogenesis. We found that p38MAPK activity peaked spontaneously, between days 3 to 5, during ES cell differentiation and that RA completely inhibited this peak of activity. By contrast to wild type cells, that required RA treatment, p38
-/- ES cells differentiated spontaneously into neurons and did not form cardiomyocytes. Moreover, inhibition of the peak of p38MAPK activity by a specific inhibitor, PD169316, committed ES cells into the neuronal lineage and blocked cardiomyogenesis. By genetic and biochemical approaches, we demonstrate that, in two different ES cell lines, the control of p38MAPK activity constitutes an early switch, committing ES cells into either neurogenesis (p38 off) or cardiomyogenesis (p38 on).
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