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

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

“…Occurrence of 9cRA in pancreas, along with nondetectable concentrations in serum and a host of other tissues, support the deduction on the basis of genetic evidence that 9cRA does not serve as a universal RXR-activating ligand in vivo (47). Validation of 9cRA as an autacoid in pancreas provides framework for evaluating whether it functions via RARs and/or RXRs and for evaluating potential cross-signaling between atRA and 9cRA.…”

Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis

“…Under homeostatic conditions in vivo, epidermal keratinocytes lack RA (11,25 (27,28). We suggest that similar activation by allergen-derived ligands, of skin macrophage, dendritic cell, or, possibly, keratinocyte TLRs (29-31) may provide 1␣,25-(OH) 2 D 3 to keratinocytes in either a paracrine or autocrine manner.…”

Retinoid X receptors: common heterodimerization partners with distinct functions

“…In contrast, low affinity-binding, lipid-activated nuclear receptors such as peroxisome proliferator-activated receptors (PPARs), the bile acid/farnesoid receptor (FXR) or oxysterol receptors (LXRs) are considered as permissive entities, suggesting that the functional control of RXR partners evolved to couple differentially endocrine and metabolic regulations 80 . The mechanism by which this molecular crosstalk takes place is still poorly defined, and is very certainly specific for each heterodimer: indeed, while the C-terminal activating function 2 (AF2, required for coactivator recruitment) of RXR is dispensable for PPARγ synergistic activation, it is required for PPAR and T3R activation 81,82 . The exact physical basis for this functional synergy is unknown, however, mutagenesis studies and structural studies suggest that one coactivator molecule is recruited per heterodimer, with a single LXXLL motif being anchored to each partner 83 .…”