BOTH RETINOIC ACID RECEPTORS ALPHA (RAR-ALPHA) AND GAMMA(RAR-GAMMA) ARE ABLE TO INITIATE MOUSE UPPER-LIP SKIN GLANDULAR METAPLASIA

Embryonic mouse upper-lip skin explants treated with 16.7 mu M all-tra ns retinoic acid (tRA) give rise to a glandular metaplasia of hair vib rissa follicles; however, at this concentration, tRA can activate not only the three retinoic acid receptors (RAR alpha, beta, and gamma), b ut also the retinoid X receptors (RXR alpha, beta, and gamma) as a con sequence of its isomerization to 9-cis retinoic acid. We therefore stu died the respective roles of the RXR and RAR by treating RAR alpha(-/- ), beta(-/-), and gamma(-/-) skin explants with tRA and wildtype expla nts with synthetic retinoids specific for RXR or for each of the RAR. The null mutation of the RAR alpha, RAR beta, and RAR gamma genes did not prevent tRA-induced hair glandular metaplasia, but RAR gamma inact ivation dramatically reduced its ratio. As demonstrated by treating ex plants with a RAR- or a RXR-specific panagonist (CD367 and Ro25-7386, respectively), RAR are primarily responsible for this metaplasia. The use of two retinoids (Ro40-6055, 8 x 10(-3) mu M, or CD437, 7.7 x 10(- 2) mu M) that are believed to act, respectively, as a RAR alpha- or a RAR gamma-specific agonist showed that both these receptors can initia te a metaplasia, In contrast, BMS453, a RAR beta-specific agonist, was unable to give rise to any metaplasia, Nevertheless, the highest degr ees and ratios of metaplasia were only obtained after treatment with t he CD367 RAR panagonist, or with either Ro40-6055 or CD437 at a concen tration sufficient to allow the activation of the three RAR, suggestin g that RAR beta activation is required for a metaplasia of all vibriss ae.