title: Retinoic acid activation of the ERK pathway is required for embryonic stem cell commitment into the adipocyte lineage.
abstract: 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.
authors.affiliation: INSERM E9911 and IFR50, Faculté de Médecine, Université de Nice Sophia Antipolis, Avenue de Valombrose, Nice 06107, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bost
authors.forename: Leslie
authors.initials: L
authors.lastname: Caron
authors.forename: Irène
authors.initials: I
authors.lastname: Marchetti
authors.forename: Christian
authors.initials: C
authors.lastname: Dani
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Bernard
authors.initials: B
authors.lastname: Binétruy
mesh_terms: 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
chemical_list: 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