INHIBITION OF SKIN DEVELOPMENT BY TARGETED EXPRESSION OF A DOMINANT-NEGATIVE RETINOLE ACID RECEPTOR

ALTHOUGH pharmacological doses of retinoic acid (RA) have a wide varie ty of actions in vivo(1), experimental difficulties have prevented a d efinitive assignment of its physiological functions, We recently made a dominant-negative retinoic acid receptor (RAR) by a single amino-aci d substitution(2) which creates a dominant-negative thyroid hormone re ceptor(3). The mutated RAR efficiently inhibited the endogenous activi ties of RARs (alpha, beta, gamma)(2). Thus, targeted expression of the mutated receptor should reveal RA functions during organogenesis by b locking RA signalling in the tissues concerned. To address this possib ility, we expressed the dominant-negative RAR in the epidermis, a pote ntial target organ of RA(4). We report here that the resultant transge nic mice exhibited dramatic suppression of epidermal maturation, demon strating the requirement of RA in normal skin development.