Retinoic acid signaling and mouse embryonic stem cell differentiation: Cross talk between genomic and non-genomic effects of RA.

Retinoic acid (RA), the active derivative of vitamin A, a fat-soluble vitamin, plays key roles in cell growth and differentiation by activating nuclear receptors, RARs (α, β and γ), which are ligand dependent regulators of transcription. The past years highlighted several novelties in the field that increased the complexity of RA effects. Indeed, in addition to its classical genomic effects, RA also has extranuclear and non-transcriptional effects. RA induces the rapid and transient activation of kinase cascades, which are integrated in the nucleus via the phosphorylation of RARs at a conserved serine residue located in the N-terminal domain and their coregulators. In order to investigate the relevance of RARs' phosphorylation in cell differentiation, mouse embryonic stem (mES) cells were used as a model. When treated with RA, these pluripotent cells give rise to neuronal cells. Cells invalidated for each RAR were generated as well as stable rescue lines expressing RARs mutated in phosphor acceptor sites. Such a strategy revealed that RA-induced neuronal differentiation involves the RARγ2 subtype and requires RARγ2 phosphorylation. Moreover, in gene expression profiling experiments, the phosphorylated form of RARγ2 was found to regulate a small subset of genes through binding a novel RA response element consisting of two direct repeats with a 7 base pair spacer. These new findings suggest an important role for RAR phosphorylation during cell differentiation, and pave the way for further investigations with other cell types and during embryonic development. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics.