[Genetic dissection of retinoic acid function in epidermis physiology]

The active metabolite of vitamin A (retinoic acid, RA) acts through the nuclear receptors RARalpha, beta and gamma and RXRalpha, beta and gamma. These receptors form RAR/RXR heterodimers, which bind to genetic regulatory DNA sequences and activate transcription of RA target genes. As RXR form heterodimers with a number of other nuclear receptors, such as the vitamin D3 receptor (VDR) and are involved in several signaling pathways. In the skin, RARgamma and RXRalpha predominate, but RARalpha and RXRbeta are also expressed. To elucidate the role of RA in skin physiology, we produced mutant mouse lines null for RAR or RXR. On the one hand, null mutations for RARa or RXRbeta have no effect on the skin, whereas a RARgamma-null mutation induces alterations in the granular cell layer. On the other, genetic inactivation of RXRa leads to embryonic lethality before epidermal development. Consequently, to determine the role of RXRa in adult mice, studies were performed using conditional somatic mutagenesis (permitting inactivation of a given gene in a specific tissue and in a time-dependent manner). Using this novel genetic approach, mutant mice were obtained in which RXRalpha was not expressed in the skin. These mice developed hair follicle degeneration, then alopecia, similar to that observed in VDR-null mutants, suggesting that hair follicle homeostasis depends on RXRalpha/VDR heterodimers. A similar genetic approach applied to the RARgamma locus demonstrated that topical administration of RA on the skin activates RARgamma/RXR heterodimers in suprabasal cells, and induces expression of a paracrine growth factor (HB-EGF) in these cells which, in turn, stimulates the proliferation of basal cells.