Targeting expression of a dominant-negative retinoic acid receptor mutant in the epidermis of transgenic mice results in loss of barrier function

To study the effects of retinoic acid on the skin in vivo, we have subverted the activity of endogenous receptors by targeting expression of a dominant negative mutant of retinoic acid receptor alpha (RAR alpha) to the epidermis of transgenic mice. At birth, mice expressing the mutant RAR alpha transgene exhibited a marked phenotype of a red, shiny skin that was somewhat sticky to touch. Severely affected neonates died within 24 hr. Histological changes in the epidermis were subtle with the phenotypic stratum corneum appearing slightly thinner and more loosely packed than in controls. Electron microscopic studies revealed that lipid multilamellar structures were not present between cells in the stratum corneum of phenotypic mice. When assayed for transepidermal water loss, phenotypic skin lost water at a rate three times faster than controls, suggesting that neonatal lethality resulted from loss of epidermal barrier function. The absence of a functional lipid barrier in transgenic mice first became evident at E17 when lipids were extruded initially into the intercellular space. We have identified a potential pathway linking inhibition of retinoid signaling with disruption of the lipid barrier that involves peroxisome proliferator-activated receptors. This study documents the role of the retinoid signaling pathway in formation and maintenance of a functional epidermis and provides the first evidence that this is mediated in part by modulation of lipid metabolism.