title: Phosphorylation of the retinoic acid receptor RARγ2 is crucial for the neuronal differentiation of mouse embryonic stem cells.
abstract: Retinoic acid (RA) plays key roles in cell differentiation and growth arrest by activating nuclear RA receptors (RARs) (α, β and γ), which are ligand-dependent transcription factors. RARs are also phosphorylated in response to RA. Here, we investigated the in vivo relevance of the phosphorylation of RARs during RA-induced neuronal differentiation of mouse embryonic stem cells (mESCs). Using ESCs where the genes encoding each RAR subtype had been inactivated, and stable rescue lines expressing RARs mutated in phospho-acceptor sites, we show that RA-induced neuronal differentiation involves RARγ2 and requires RARγ2 phosphorylation. By gene expression profiling, we found that the phosphorylated form of RARγ2 regulates a small subset of genes through binding an unusual RA response element consisting of two direct repeats with a seven-base-pair spacer. These new findings suggest an important role for RARγ phosphorylation during cell differentiation and pave the way for further investigations during embryonic development.
authors.affiliation: IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), INSERM, U596, CNRS, UMR7104, Université de Strasbourg, 1 rue Laurent Fries, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Ziad
authors.initials: Z
authors.lastname: Al Tanoury
authors.forename: Samia
authors.initials: S
authors.lastname: Gaouar
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Piskunov
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Sylvia
authors.initials: S
authors.lastname: Urban
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.forename: Céline
authors.initials: C
authors.lastname: Keime
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.forename: Andrée
authors.initials: A
authors.lastname: Dierich
authors.forename: Cécile
authors.initials: C
authors.lastname: Rochette-Egly
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma
keywords: Differentiation; Nuclear receptor; Phosphorylation; RA; RAR; Retinoic acid; Transcription