Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage.
Mouse embryonic stem (ES) cells are pluripotent cells that differentiate into multiple cell lineages. The commitment of ES cells into the adipocyte lineage is dependent on an early 3-day treatment with all-trans retinoic acid (RA). To characterize the molecular mechanisms underlying this process, we examined the contribution of the extracellular-signal-regulated kinase (ERK) pathway. Treatment of ES cell-derived embryoid bodies with RA resulted in a prolonged activation of the ERK pathway, but not the c-Jun N-terminal kinase, p38 mitogen-activated protein kinase or phosphoinositide 3-kinase pathways. To investigate the role of ERK activation, co-treatment of RA with PD98059, a specific inhibitor of the ERK signalling pathway, prevented both adipocyte formation and expression of the adipogenic markers, adipocyte lipid-binding protein and peroxisome-proliferator-activated receptor gamma. Furthermore, we show that ERK activation is required only during RA treatment. PD98059 does not interfere with the commitment of ES cells into other lineages, such as neurogenesis, myogenesis and cardiomyogenesis. As opposed to the controversial role of the ERK pathway in terminal differentiation, our results clearly demonstrate that this pathway is specifically required at an early stage of adipogenesis, corresponding to the RA-dependent commitment of ES cells.
Bost
Frédéric
F
INSERM E9911 and IFR50, Faculté de Médecine, Université de Nice Sophia Antipolis, Avenue de Valombrose, Nice 06107, France.
Caron
Leslie
L
Marchetti
Irène
I
Dani
Christian
C
Le Marchand-Brustel
Yannick
Y
Binétruy
Bernard
B
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology; D009474:Neurons / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009570:Nitriles; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C113580:U 0126; D014212:Tretinoin; D012313:RNA; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one