This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Attar, P. S. Articles by Roop, D. R. Search for Related Content PubMed PubMed Citation Articles by Attar, P. S. Articles by Roop, D. R.

Inhibition of Retinoid Signaling in Transgenic Mice Alters Lipid Processing and Disrupts Epidermal Barrier Function

Departments of Cell Biology (P.S.T., S.I., J.R.B., D.R.R.), Dermatology (J.R.B., D.R.R.) and Center for Comparative Medicine (M.M.), Baylor College of Medicine, Houston, Texas 77030,
The Dows Institute (P.W.W.), College of Dentistry, University of Iowa, Iowa City, Iowa 52242

To explore the role of retinoids in epidermal development, we recently targeted expression of a dominant-negative, retinoic acid receptor mutant (RAR403) in the epidermis of transgenic mice and observed an unexpected loss of barrier function. In this paper, we demonstrate that transgenic mice expressing the RAR403 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 RAR403 transgene, indicating that the RAR403 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.

This article has been cited by other articles:

				R. Thadhani Is Calcitriol Life-Protective for Patients with Chronic Kidney Disease? J. Am. Soc. Nephrol., November 1, 2009; 20(11): 2285 - 2290. [Full Text] [PDF]

				M. Terao, M. Kurosaki, M. M. Barzago, M. Fratelli, R. Bagnati, A. Bastone, C. Giudice, E. Scanziani, A. Mancuso, C. Tiveron, et al. Role of the Molybdoflavoenzyme Aldehyde Oxidase Homolog 2 in the Biosynthesis of Retinoic Acid: Generation and Characterization of a Knockout Mouse Mol. Cell. Biol., January 15, 2009; 29(2): 357 - 377. [Abstract] [Full Text] [PDF]

				C. Calleja, N. Messaddeq, B. Chapellier, H. Yang, W. Krezel, M. Li, D. Metzger, B. Mascrez, K. Ohta, H. Kagechika, et al. Genetic and pharmacological evidence that a retinoic acid cannot be the RXR-activating ligand in mouse epidermis keratinocytes Genes & Dev., June 1, 2006; 20(11): 1525 - 1538. [Abstract] [Full Text] [PDF]

				L. Michalik, J. N. Feige, L. Gelman, T. Pedrazzini, H. Keller, B. Desvergne, and W. Wahli Selective Expression of a Dominant-Negative Form of Peroxisome Proliferator-Activated Receptor in Keratinocytes Leads to Impaired Epidermal Healing Mol. Endocrinol., September 1, 2005; 19(9): 2335 - 2348. [Abstract] [Full Text] [PDF]

				C. F. Chen and D. Lohnes Dominant-negative Retinoic Acid Receptors Elicit Epidermal Defects through a Non-canonical Pathway J. Biol. Chem., January 28, 2005; 280(4): 3012 - 3021. [Abstract] [Full Text] [PDF]

				X.-C. Xu, W. Y. L. Wong, L. Goldberg, S. C. Baer, J. E. Wolf, W. M. Ramsdell, D. S. Alberts, S. M. Lippman, and R. Lotan Progressive Decreases in Nuclear Retinoid Receptors during Skin Squamous Carcinogenesis Cancer Res., June 1, 2001; 61(11): 4306 - 4310. [Abstract] [Full Text] [PDF]

				M. A. Rogers, H. Winter, C. Wolf, M. Heck, and J. Schweizer Characterization of a 190-Kilobase Pair Domain of Human Type I Hair Keratin Genes J. Biol. Chem., October 9, 1998; 273(41): 26683 - 26691. [Abstract] [Full Text] [PDF]