Phosphorylation of the retinoic acid receptor RARgamma2 is crucial for the neuronal differentiation of mouse embryonic stem cells

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Al Tanoury, Ziad | Gaouar, Samia | Piskunov, Aleksandr | Ye, Tao | Urban, Sylvia | Jost, Bernard | Keime, Céline | Davidson, Irwin | Dierich, Andrée | Rochette-Egly, Cécile

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Retinoic acid (RA) plays key roles in cell differentiation and growth arrest by activating nuclear RA receptors (RARs) (alpha, beta and gamma), 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 RARgamma2 and requires RARgamma2 phosphorylation. By gene expression profiling, we found that the phosphorylated form of RARgamma2 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 RARgamma phosphorylation during cell differentiation and pave the way for further investigations during embryonic development.

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