Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled

Abstract

To investigate the roles of retinoic acid (RA) receptors (RARs) in the physiology of epidermis that does not express RARβ, conditional spatio-temporally controlled somatic mutagenesis was used to selectively ablate RARα in keratinocytes of RARγ-null mice. Keratinocyte proliferation was maintained in adult mouse epidermis lacking both RARα and RARγ, as well as in RARβ-null mice. All RAR-mediated signalling pathways are therefore dispensable in epidermis for homeostatic keratinocyte renewal. However, topical treatment of mouse skin with selective retinoids indicated that RXR/RARγ heterodimers, in which RXR transcriptional activity was subordinated to that of its RARγ partner, were required for retinoid-induced epidermal hyperplasia, whereas RXR homodimers and RXR/RARα heterodimers were not involved. RA-induced keratinocyte proliferation was studied in mutant mice in which RXRα, RXRα and RARα, RARγ, or RARα and RARγ genes were specifically disrupted in either basal or suprabasal keratinocytes. We demonstrate that the topical retinoid signal is transduced by RXRα/RARγ heterodimers in suprabasal keratinocytes, which, in turn, stimulate proliferation of basal keratinocytes via a paracrine signal that may be heparin-binding EGF-like growth factor.