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J Cell Sci. 2014 May 1;127(Pt 9):2095-105. doi: 10.1242/jcs.145979. Epub 2014 Feb 25.

Phosphorylation of the retinoic acid receptor RARγ2 is crucial for the neuronal differentiation of mouse embryonic stem cells.

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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.


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.


Differentiation; Nuclear receptor; Phosphorylation; RA; RAR; Retinoic acid; Transcription

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