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J. Biol. Chem., Vol. 282, Issue 21, 15912-15920, May 25, 2007

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Keratinocyte-specific Expression of Fatty Acid Transport Protein 4 Rescues the Wrinkle-free Phenotype in Slc27a4/Fatp4 Mutant Mice^*

Casey L. Moulson^¶, Meei-Hua Lin, J. Michael White, Elizabeth P. Newberry^¶, Nicholas O. Davidson^¶||, and Jeffrey H. Miner^**1

From the Renal Division, Department of Internal Medicine and Department of Pathology and Immunology, ^¶Division of Gastroenterology, Department of Internal Medicine, ^||Department of Molecular Biology and Pharmacology, and ^**Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110

FATP4 (fatty acid transport protein 4; also known as SLC27A4) is the most widely expressed member of a family of six long chain fatty acid transporters. FATP4 is highly expressed in enterocytes and has therefore been proposed to be a major importer of dietary fatty acids. Two independent mutations in Fatp4 cause mice to be born with thick, tight, shiny, "wrinkle-free" skin and a defective skin barrier; they die within hours of birth from dehydration and restricted movements. In contrast, induced keratinocyte-specific deficiency of FATP4 in adult mice causes only mild skin abnormalities. Therefore, whether the loss of FATP4 from skin or a systemic gestational metabolic defect causes the severe skin defects and neonatal lethality remain important unanswered questions. To investigate the basis for the phenotype, we first generated wild-type tetraploid/mutant diploid aggregates that should lead to rescue of any abnormalities caused by loss of FATP4 from the placenta. However, the skin phenotype was not ameliorated. We then generated transgenic mice expressing exogenous FATP4 either widely or specifically in suprabasal keratinocytes, and we bred the transgenes onto the Fatp4^-/- background. Both modes of FATP4 expression led to rescue of the neonatally lethal skin defects, and the resulting mice were viable and fertile. Keratinocyte expression of an FATP4 variant with mutations in the acyl-CoA synthetase domain did not provide any degree of rescue. We conclude that expression of FATP4 with an intact acyl-CoA synthetase domain in suprabasal keratinocytes is necessary for normal skin development and that FATP4 functions in establishing the cornified envelope.

Received for publication, February 28, 2007

^* This work was supported by National Institutes of Health Grants R01AR049269 (to J. H. M.), R37HL038180, and R01DK056260 (to N. O. D.), National Institutes of Health Grant K01DK075811, and a Washington University Digestive Diseases Research Core Center Pilot and Feasibility Grant P30DK052574 (to C. L. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Renal Division, Washington University School of Medicine, 660 S. Euclid Ave., Box 8126, St. Louis, MO 63110. Tel.: 314-362-8235; Fax: 314-362-8237; E-mail: minerj{at}wustl.edu.

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