Al Tanoury Ziad, Gaouar Samia, Piskunov Aleksandr, Ye Tao, Urban Sylvia, Jost Bernard, Keime Céline, Davidson Irwin, Dierich Andrée, Rochette-Egly Cécile
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.
J Cell Sci. 2014 May 1;127(Pt 9):2095-105. doi: 10.1242/jcs.145979. Epub 2014 Feb 25.
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.
维甲酸（RA）通过激活核维甲酸受体（RARs）（α、β和γ）在细胞分化和生长停滞中发挥关键作用，这些受体是配体依赖性转录因子。RARs也会因RA而发生磷酸化。在此，我们研究了在小鼠胚胎干细胞（mESCs）的RA诱导神经元分化过程中RARs磷酸化的体内相关性。利用编码每种RAR亚型的基因已被灭活的胚胎干细胞，以及表达在磷酸化位点发生突变的RARs的稳定拯救系，我们表明RA诱导的神经元分化涉及RARγ2且需要RARγ2磷酸化。通过基因表达谱分析，我们发现RARγ2的磷酸化形式通过结合由两个带有七个碱基对间隔区的直接重复序列组成的异常RA反应元件来调节一小部分基因。这些新发现表明RARγ磷酸化在细胞分化过程中具有重要作用，并为胚胎发育过程中的进一步研究铺平了道路。
