Skin abnormalities generated by temporally controlled RXR alpha mutations in mouse epidermis

Nuclear receptors for retinoids (RARs) and vitamin D (VDR), and for some ot her ligands (TRs, PPARs and LXRs), may be critical in the development and h omeostasis of mammalian epidermis(1-8). It is believed that these receptors form heterodimers with retinoid X receptors (RXRs) to act as transcription al regulators(9,10). However, most genetic approaches aimed at establishing their physiological functions in the skin have been inconclusive owing eit her to pleiotropic effects and redundancies between receptor isotypes in ge ne knockouts, or to equivocal interpretation of dominant-negative mutant st udies in transgenic mice(1,13-15). Moreover, knockout of RXR alpha, the mai n skin RXR isotype, is lethal in utero before skin formation(11,12,16,17). Here we have resolved these problems by developing an efficient technique t o create spatiotemporally controlled somatic mutations in the mouse. We use d tamoxifen-inducible Cre-ERT recombinases(18,19) to ablate RXR alpha selec tively in adult mouse keratinocytes. We show that RXR alpha has key roles i n hair cycling, probably through RXR/VDR heterodimers, and in epidermal ker atinocyte proliferation and differentiation.