Skin abnormalities generated by temporally controlled RXRα mutations in mouse epidermis

Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some other ligands (TRs, PPARs and LXRs), may be critical in the development and homeostasis of mammalian epidermis1,2,3,4,5,6,7,8. It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcriptional regulators9,10. However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing either to pleiotropic effects and redundancies between receptor isotypes in gene knockouts, or to equivocal interpretation of dominant-negative mutant studies in transgenic mice1,13,14,15. Moreover, knockout of RXRα, the main skin RXR isotype, is lethal in utero before skin formation11,12,16,17. Here we have resolved these problems by developing an efficient technique to create spatio-temporally controlled somatic mutations in the mouse. We used tamoxifen-inducible Cre–ERT recombinases18,19 to ablate RXRα selectively in adult mouse keratinocytes. We show that RXRα has key roles in hair cycling, probably through RXR/VDR heterodimers, and in epidermal keratinocyte proliferation and differentiation.