Inhibition of skin development by targeted expression of a dominant-negative retinoic acid receptor

ALTHOUGH pharmacological doses of retinoic acid (RA) have a wide variety of actions in vivo 1 , experimental difficulties have prevented a definitive assignment of its physiological functions. We recently made a dominant-negative retinoic acid receptor (RAR>) by a single amino-acid substitution 2 which creates a dominant-negative thyroid hormone receptor 3 . The mutated RAR efficiently inhibited the endogenous activities of RARs (a, β, y) 2 . Thus, targeted expression of the mutated receptor should reveal RA functions during organogenesis by blocking RA signalling in the tissues concerned. To address this possibility, we expressed the dominant-negative RAR in the epidermis, a potential target organ of RA 4 . We report here that the resultant transgenic mice exhibited dramatic suppression of epidermal maturation, demonstrating the requirement of RA in normal skin development.