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 mutant (RAR alpha403) 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 alpha403 transgene show attenuated responsiveness to topical application of all-trans retinoic acid, in agreement with our previous in vitro data. We also show that the vitamin D3 receptor is unaffected in its ability to transactivate in the presence of the dominant-negative RAR alpha403 transgene, indicating that the RAR alpha403 is unlikely to be functioning through a global 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 extremely high incidence of neonatal mortality in severely phenotypic pups. Some severely affected pups do survive and show a pronounced hyperkeratosis at postpartum day 4, consistent with previously documented effects of vitamin A deficiency. Biochemical analysis of the severely phenotypic neonates indicates elevated phospholipids and glycosylceramides in the stratum comeum, which results from altered lipid processing. Taken together with previous studies, these data provide strong evidence linking the retinoid-signaling pathway with modulation of lipid processing required for formation of epidermal barrier function.
Attar
P S
PS
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Wertz
P W
PW
McArthur
M
M
Imakado
S
S
Bickenbach
J R
JR
Roop
D R
DR
D000287:Administration, Topical; D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature; D002518:Ceramides / Q000032:analysis; D004817:Epidermis / Q000378:metabolism; D005456:Fluorescent Dyes; D007642:Keratosis; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D010078:Oxazines; D010743:Phospholipids / Q000032:analysis; D018167:Receptors, Calcitriol / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000737:chemistry; D014157:Transcription Factors / Q000378:metabolism; D019076:Transgenes; D014212:Tretinoin / Q000494:pharmacology
D002518:Ceramides; D005456:Fluorescent Dyes; D010078:Oxazines; D010743:Phospholipids; C000607072:Rara protein, mouse; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D014212:Tretinoin; C044808:nile red