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

Using genetic and pharmacological approaches, we demonstrate that both RAR gamma/RXR alpha heterodimers involved in repression events, as well as PPAR beta(delta)/RXR alpha heterodimers involved in activation events, are cell-autonomously required in suprabasal keratinocytes for the generation of lamellar granules (1,G), the organelles instrumental to the formation of the skin permeability barrier. In activating PPAR beta(delta)/RXR alpha heterodimers, RXR alpha is transcriptionally active as its AF-2 activation function is required and can be inhibited by an RXR-selective antagonist. Within repressing RAR gamma/RXR alpha heterodimers, induct, ion of the transcriptional activity of RXR alpha is subordinated to the addition of an agonistic ligand for RAR gamma. Thus, the ligand that possibly binds and activates RXR alpha heterodimerized with PPAR beta(delta) cannot be a retinoic acid, as it would also bind RAR gamma and relieve the RAR gamma-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.