p38 mitogen activated protein kinase controls two successive-steps during the early mesodermal commitment of embryonic stem cells.
Embryonic stem (ES) cells differentiate in vitro into all cell lineages. We previously found that the p38 mitogen activated kinase (p38MAPK) pathway controls the commitment of ES cells toward either cardiomyogenesis (p38 on) or neurogenesis (p38 off ). In this study, we show that p38α knock-out ES cells do not differentiate into cardiac, endothelial, smooth muscle, and skeletal muscle lineages. Reexpression of p38MAPK in these cells partially rescues their mesodermal differentiation defects and corrects the high level of spontaneous neurogenesis of knock-out cells. Wild-type ES cells were treated with a p38MAPK-specific inhibitor during the differentiation process. These experiments allowed us to identify 2 early independent successive p38MAPK functions in the formation of mesodermal lineages. Further, the first one correlates with the regulation of the expression of Brachyury, an essential mesodermal-specific transcription factor, by p38MAPK. In conclusion, by genetic and biochemical approaches, we demonstrate that p38MAPK activity is essential for the commitment of ES cell into cardiac, endothelial, smooth muscle, and skeletal muscle mesodermal lineages.
Inserm U626, Université de la Méditerranée, Faculté de Médecine, Marseille, France.
Emilie
E
Barruet
Ola
O
Hadadeh
Franck
F
Peiretti
Valérie M
VM
Renault
Yasmine
Y
Hadjal
Denis
D
Bernot
Roselyne
R
Tournaire
Didier
D
Negre
Irène
I
Juhan-Vague
Marie-Christine
MC
Alessi
Bernard
B
Binétruy
D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D007093:Imidazoles / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D024510:Muscle Development; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D000098908:Brachyury Protein
D005326:Fetal Proteins; D007093:Imidazoles; D048308:Mitogen-Activated Protein Kinase 14; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole