We have isolated a novel autosomal recessive mouse mutation, which we call wrinkle-free (wrfr). wrfr-/- mice are born with taut, shiny skin, an abnormally thickened epidermis, and a defective skin barrier. The mice die during their first day of life because their skin is so tight they are unable to breathe properly. There are joint and facial defects that are secondary to the taut skin. This phenotype is very similar to that seen in a human genetic skin disease called restrictive dermopathy. We have found by positional cloning that Sic27a4, the gene which encodes fatty acid transport protein 4 (FATP4), is mutated in wrfr-/- mice. We hypothesize that fatty acid transport mediated by FATP4 plays a fundamental role in proliferation and/or differentiation of keratinocytes and establishment of the skin barrier. The goals of this proposal are to determine why mutation in FATP4 results in the wrinkle-free skin defect and how FATP4 is involved in normal skin development.
The Specific Aims are to: 1) Test the hypothesis that the origin of the wrfr defect lies in the skin. We will use state-of-the-art transgenic approaches to both rescue the wrinkle-free phenotype and to specifically mutate Slc27a4 in skin. 2) Determine the normal expression pattern of FATP4 and assay the effects of its absence on expression of other proteins involved in fatty acid metabolism. We will determine by immunohistochemistry and in situ hybridization where Slc27a4 is expressed and where the FATP4 protein is localized. Expression and localization of the four other FATPs will also be investigated. 3) Determine the effects of the absence of FATP4 on fatty acid metabolism and PPAR signaling in the skin. Because some substrates of FATP4 are also ligands for PPAR family members, and PPARs are known to play a role in skin development, the wrinkle free phenotype may result from aberrant PPAR activity. 4) Graft wrfr-/- skin onto normal nude mouse skin to examine its postnatal development and capacity to form hair and other appendages. 5) Test the hypothesis that human restrictive dermopathy is caused by mutations in SLC27A4. Because fatty acid transport proteins have no defined role in skin development, the results of these experiments could open up a whole new avenue for investigation into the biology of the skin.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-GMA-1 (01))
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Moshell, Alan N
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Lin, Meei-Hua; Miner, Jeffrey H; Turk, John et al. (2017) Linear ion-trap MSn with high-resolution MS reveals structural diversity of 1-O-acylceramide family in mouse epidermis. J Lipid Res 58:772-782
Lin, Meei-Hua; Miner, Jeffrey H (2015) Fatty acid transport protein 1 can compensate for fatty acid transport protein 4 in the developing mouse epidermis. J Invest Dermatol 135:462-470
Lin, Meei-Hua; Khnykin, Denis (2014) Fatty acid transporters in skin development, function and disease. Biochim Biophys Acta 1841:362-8
Lin, Meei-Hua; Hsu, Fong-Fu; Miner, Jeffrey H (2013) Requirement of fatty acid transport protein 4 for development, maturation, and function of sebaceous glands in a mouse model of ichthyosis prematurity syndrome. J Biol Chem 288:3964-76
Li, Songhua; Lee, Jungsoo; Zhou, Yongdong et al. (2013) Fatty acid transport protein 4 (FATP4) prevents light-induced degeneration of cone and rod photoreceptors by inhibiting RPE65 isomerase. J Neurosci 33:3178-89
Poreba, M A; Dong, C X; Li, S K et al. (2012) Role of fatty acid transport protein 4 in oleic acid-induced glucagon-like peptide-1 secretion from murine intestinal L cells. Am J Physiol Endocrinol Metab 303:E899-907
Khnykin, Denis; Miner, Jeffrey H; Jahnsen, Frode (2011) Role of fatty acid transporters in epidermis: Implications for health and disease. Dermatoendocrinol 3:53-61
Mishima, Takuya; Miner, Jeffrey H; Morizane, Mayumi et al. (2011) The expression and function of fatty acid transport protein-2 and -4 in the murine placenta. PLoS One 6:e25865
Lin, Meei-Hua; Chang, Kuo-Wei; Lin, Shu-Chun et al. (2010) Epidermal hyperproliferation in mice lacking fatty acid transport protein 4 (FATP4) involves ectopic EGF receptor and STAT3 signaling. Dev Biol 344:707-19
Miner, Jeffrey H (2010) Restrictive dermopathy and ZMPSTE24 mutations in Mennonites: Evidence for allelic heterogeneity. Am J Med Genet A 152A:2140-1; author reply 2142

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