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EMBRYONIC STEM CELLS: CHARACTERIZATION SERIES

p38 Mitogen-Activated Protein Kinase Activity Commits Embryonic Stem Cells to Either Neurogenesis or Cardiomyogenesis

Institut National de la Santé et de la Recherche Médicale U568, Institut Fédératif de Recherches 50, Faculté de Médecine, Université de Nice Sophia Antipolis, Nice, France

Key Words. Embryonic stem cells • p38 mitogen-activated protein kinase • Neurogenesis • Cardiomyogenesis

Correspondence: Bernard Binétruy, Ph.D., INSERM U626, Faculté de Médecine, Université de Marseille II, 27 Bld J Moulin, 13385 Marseille, France. Telephone: (33) 4-91-32-44-06; Fax: (33) 4-91-25-43-36; e-mail: bernard.binetruy{at}medecine.univ-mrs.fr

Received August 17, 2005; accepted for publication January 7, 2006.
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^–7 M, RA induces ES cell differentiation into neurons and, conversely, inhibits cardiomyogenesis. We found that p38 mitogen-activated protein kinase (p38MAPK) activity peaked spontaneously, between day 3 and day 5, during ES cell differentiation and that RA completely inhibited this peak of activity. In contrast to wild-type cells, which required RA treatment, p38 ^–1– 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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