title: Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes.
abstract: Using genetic and pharmacological approaches, we demonstrate that both RARgamma/RXRalpha heterodimers involved in repression events, as well as PPARbeta(delta)/RXRalpha heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (LG), the organelles instrumental to the formation of the skin permeability barrier. In activating PPARbeta(delta)/RXRalpha heterodimers, RXRalpha is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RARgamma/RXRalpha heterodimers, induction of the transcriptional activity of RXRalpha is subordinated to the addition of an agonistic ligand for RARgamma. Thus, the ligand that possibly binds and activates RXRalpha heterodimerized with PPARbeta(delta) cannot be a retinoic acid, as it would also bind RARgamma and relieve the RARgamma-mediated repression, thereby yielding abnormal LGs. Our data also demonstrate for the first time that subordination of RXR transcriptional activity to that of its RAR partner plays a crucial role in vivo, because it allows RXRs to act concomitantly, within the same cell, as heterodimerization partners for repression, as well as for activation events in which they are transcriptionally active.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), CNRS/INSERM/ULP, Collège de France, 67404 Illkirch Cedex, CU de Strasbourg, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Calléja
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.forename: Benoit
authors.initials: B
authors.lastname: Chapellier
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Yang
authors.forename: Wojciech
authors.initials: W
authors.lastname: Krezel
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Mascrez
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
authors.forename: Manuel
authors.initials: M
authors.lastname: Mark
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
mesh_terms: D000818:Animals; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D051379:Mice; D047488:Retinoid X Receptors / Q000819:agonists*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D008024:Ligands; D047488:Retinoid X Receptors; D014212:Tretinoin