Dominant-negative retinoic acid receptors elicit epidermal defects through a non-canonical pathway.
Previous work has shown that a dominant-negative retinoic acid receptor alpha (dnRARalpha), expressed under the K14 promoter, causes severe epidermal defects. Similar defects are, however, not seen in RARalphagamma double null mutant mice, which lack the entire complement of RARs expressed in the epidermis. To investigate the mechanism of action of these dominant-negative receptors, dnRARalpha or a DNA binding-deficient variant, dnRARalpha(DBD), were targeted to the basal epidermis. Expression of either receptor type led to similar epidermal phenotypes suggesting that both RAR mutants acted through a common mechanism. The epidermal phenotype was reminiscent of defects seen in p63(-/-) mice. Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development. By contrast, expression of p63 in the epidermis of RARalphagamma(-/-) offspring was unaffected, indicating that RARs were not essential for p63 expression. These findings suggest that dnRARs may impact on epidermal development through one or more non-canonical pathways, which are independent of receptor-DNA interaction.
Chen
Chang Feng
CF
Division of Experimental Medicine, Department of Medicine, McGill University, Montreal K1H 8M5, Canada.
Lohnes
David
D
D000818:Animals; D019556:COS Cells; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D005799:Genes, Dominant; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000378:metabolism; D007633:Keratins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D019076:Transgenes
D018076:DNA, Complementary; D010750:Phosphoproteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D007633:Keratins; D004247:DNA