Physiological and retinoid-induced proliferations of epidermis basal keratinocytes are differently controlled.
To investigate the roles of retinoic acid (RA) receptors (RARs) in the physiology of epidermis that does not express RAR beta, conditional spatio-temporally controlled somatic mutagenesis was used to selectively ablate RAR alpha in keratinocytes of RAR gamma-null mice. Keratinocyte proliferation was maintained in adult mouse epidermis lacking both RAR alpha and RAR gamma, as well as in RAR beta-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/RAR gamma heterodimers, in which RXR transcriptional activity was subordinated to that of its RAR gamma partner, were required for retinoid-induced epidermal hyperplasia, whereas RXR homodimers and RXR/RAR alpha heterodimers were not involved. RA-induced keratinocyte proliferation was studied in mutant mice in which RXR alpha, RXR alpha and RAR alpha, RAR gamma, or RXR alpha and RAR gamma genes were specifically disrupted in either basal or suprabasal keratinocytes. We demonstrate that the topical retinoid signal is transduced by RXR alpha/RAR gamma 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.
Chapellier
Benoit
B
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
Mark
Manuel
M
Messaddeq
Nadia
N
Calléja
Cécile
C
Warot
Xavier
X
Brocard
Jacques
J
Gérard
Christelle
C
Li
Mei
M
Metzger
Daniel
D
Ghyselinck
Norbert B
NB
Chambon
Pierre
P
D000483:Alleles; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003433:Crosses, Genetic; D019281:Dimerization; D000078404:Epidermal Cells; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics; D004817:Epidermis / Q000473:pathology; D018390:Gene Targeting; D066257:Heparin-binding EGF-like Growth Factor; D006706:Homeostasis; D006965:Hyperplasia; D036341:Intercellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016296:Mutagenesis; D019899:Paracrine Communication; D055503:Protein Multimerization; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000172:deficiency / Q000187:drug effects / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D000097768:Retinoic Acid Receptor gamma
D004815:Epidermal Growth Factor; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D013629:Tamoxifen; D014157:Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C462945:BMS 649; C587884:Hbegf protein, mouse; C000607072:Rara protein, mouse