TY - JOUR
T1 - Inhibition of retinoid signaling in transgenic mice alters lipid processing and disrupts epidermal barrier function
AU - Attar, Paul S.
AU - Wertz, Philip W.
AU - McArthur, Mark
AU - Imakado, Sumihisa
AU - Bickenbach, Jackie R.
AU - Roop, Dennis R.
PY - 1997
Y1 - 1997
N2 - To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RARα4O3) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RARα403 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 RARα403 transgene, indicating that the RARα403 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 corneum, 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.
AB - To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RARα4O3) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RARα403 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 RARα403 transgene, indicating that the RARα403 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 corneum, 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.
UR - http://www.scopus.com/inward/record.url?scp=0030925532&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0030925532&partnerID=8YFLogxK
U2 - 10.1210/mend.11.6.0010
DO - 10.1210/mend.11.6.0010
M3 - Article
C2 - 9171242
AN - SCOPUS:0030925532
SN - 0888-8809
VL - 11
SP - 792
EP - 800
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 6
ER -