INHIBITION OF RETINOID SIGNALING IN TRANSGENIC MICE ALTERS LIPID PROCESSING AND DISRUPTS EPIDERMAL BARRIER FUNCTION

To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mu tant (RAR alpha 403) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RAR alpha 403 transgene show atten uated responsiveness to topical application of all-trans retinoic acid , in agreement with our previous in vitro data. We also show that the vitamin D-3 receptor is unaffected in its ability to transactivate in the presence of the dominant-negative RAR alpha 403 transgene, indicat ing that the RAR alpha 403 is unlikely to be functioning through a glo bal sequestration of retinoid X receptors. Additionally, we show that the disruption of epidermal barrier function results in a dramatic 4 C drop in mean body surface temperature, probably accounting for the ex tremely high incidence of neonatal mortality in severely phenotypic pu ps. Some severely affected pups do survive and show a pronounced hyper keratosis at postpartum day 4, consistent with previously documented e ffects of vitamin A deficiency. Biochemical analysis of the severely p henotypic neonates indicates elevated phospholipids and glycosylcerami des in the stratum corneum, which results from altered lipid processin g. Taken together with previous studies, these data provide strong evi dence linking the retinoid-signaling pathway with modulation of lipid processing required for formation of epidermal barrier function.