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Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes

¹ 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; ² Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Komatsushima, Aoba-ku, Sendai 981-8558, Japan; ³ School of Biomedical Science, Tokyo Medical and Dental University, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan

Using genetic and pharmacological approaches, we demonstrate that both RAR/RXR heterodimers involved in repression events, as well as PPAR()/RXR 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 PPAR()/RXR heterodimers, RXR is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RAR/RXR heterodimers, induction of the transcriptional activity of RXR is subordinated to the addition of an agonistic ligand for RAR. Thus, the ligand that possibly binds and activates RXR heterodimerized with PPAR() cannot be a retinoic acid, as it would also bind RAR and relieve the RAR-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.

[Keywords: Conditional somatic mutagenesis; RAR; PPAR (); skin permeability barrier; transcriptional subordination; ichthyosis]

Received October 4, 2005; revised version accepted March 13, 2006.

⁵ Corresponding author.

E-MAIL chambon{at}igbmc.u-strasbg.fr; FAX 33-388-653-203.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.368706

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