Both retinoic acid receptors alpha (RARalpha) and gamma (RARgamma) are able to initiate mouse upper-lip skin glandular metaplasia.
Embryonic mouse upper-lip skin explants treated with 16.7 microM all-trans retinoic acid (tRA) give rise to a glandular metaplasia of hair vibrissa follicles; however, at this concentration, tRA can activate not only the three retinoic acid receptors (RARalpha, beta, and gamma), but also the retinoid X receptors (RXRalpha, beta, and gamma) as a consequence of its isomerization to 9-cis retinoic acid. We therefore studied the respective roles of the RXR and RAR by treating RARalpha(-/-), beta(-/-), and gamma(-/-) skin explants with tRA and wild-type explants with synthetic retinoids specific for RXR or for each of the RAR. The null mutation of the RARalpha, RARbeta, and RARgamma genes did not prevent tRA-induced hair glandular metaplasia, but RARgamma inactivation dramatically reduced its ratio. As demonstrated by treating explants 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) microM, or CD437, 7.7 x 10(-2) microM) that are believed to act, respectively, as a RARalpha- or a RARgamma-specific agonist showed that both these receptors can initiate a metaplasia. In contrast, BMS453, a RARbeta-specific agonist, was unable to give rise to any metaplasia. Nevertheless, the highest degrees and ratios of metaplasia were only obtained after treatment with the CD367 RAR panagonist, or with either Ro40-6055 or CD437 at a concentration sufficient to allow the activation of the three RAR, suggesting that RARbeta activation is required for a metaplasia of all vibrissae.
Epithelial Differentiation Biology, LEDAC-UMR/CNRS, Albert Bonniot Institute, La Tronche, France.
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S
Blanchet
B
B
Favier
G
G
Chevalier
P
P
Kastner
J J
JJ
Michaille
P
P
Chambon
D
D
Dhouailly
D000818:Animals; D005260:Female; D008046:Lip / Q000473:pathology*; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D012867:Skin / Q000473:pathology*; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607072:Rara protein, mouse