TCF/Lef1-Mediated Control of Lipid Metabolism Regulates Skin Barrier Function Dagmar Fehrenschild, Uwe Galli, Bernadette Breiden, Wilhelm Bloch, Peter.

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TCF/Lef1-Mediated Control of Lipid Metabolism Regulates Skin Barrier Function Dagmar Fehrenschild, Uwe Galli, Bernadette Breiden, Wilhelm Bloch, Peter Schettina, Susanne Brodesser, Christian Michels, Christian Günschmann, Konrad Sandhoff, Carien M. Niessen, Catherin Niemann Journal of Investigative Dermatology Volume 132, Issue 2, Pages 337-345 (February 2012) DOI: 10.1038/jid.2011.301 Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Disrupted epidermal barrier function in Lef1 (lymphoid enhancer-binding factor 1) mutant mice. (a) Postnatal lethality in mutant mice. Wild-type (wt) and mutant animals expressed as percentage of living mice at birth (wt-b and Mut-b) and at weaning age (wt-w and Mut-w). (b) Image of mice at 5 days of age displaying reduced body size and scaling of the skin of mutant animals. (c) Transepidermal water loss (TEWL) measured on the back skin of postnatal mice (n=4). (d) Immunostaining for Lef1 (green) detects mutant Lef1 protein in the skin of mutant embryos (arrows, right panels). Endogenous Lef1 production is seen in the bulbs of developing hair follicles at E18.5 (arrowhead). Nuclear counterstaining with propidium iodide is shown in red. Bar=80μm. (e) Toluidine blue dye exclusion assay of wt and Lef1 mutant embryos. Journal of Investigative Dermatology 2012 132, 337-345DOI: (10.1038/jid.2011.301) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Maturation of corneocytes and profilaggrin processing are defective in Lef1 (lymphoid enhancer-binding factor 1) mutant skin. (a, b) Morphological analysis of back skin by transmission electron microscopy of mutant (b) and control littermates (a). SC, stratum corneum; SG, stratum granulosum. (c) Morphology of corneocytes isolated from wild-type (wt) and Lef1 mutant mice. (d) Surface areas of corneocytes of control (n=703, light gray bars) and mutant mice (n=884, dark gray bars) were defined using Analysis computer software. (e) Western blot analysis of keratin 10 (K10), involucrin, and profilaggrin processing in epidermal lysates of 6-day-old wt and Lef1 mutant mice. Bar=700nm (a, b), 100μm (c). Journal of Investigative Dermatology 2012 132, 337-345DOI: (10.1038/jid.2011.301) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Abnormal lipid composition in Lef1 (lymphoid enhancer-binding factor 1) mutant mice. (a) Free stratum corneum (SC) lipids of Lef1 mutant mice and control littermates. Cer, total ceramides; Chol, cholesterol; FA, free fatty acids; wt, wild type. (b) Quantitative analysis of probarrier lipids sphingomyelin (SM), cholesterol sulfate (CSO4), and glucosyl ceramide (GlcCer). (c, d) Free extractable ceramides from stratum corneum. (c) Representative thin layer chromatography (TLC) analysis at 5 months and 3 weeks of age. (d) Individual lipid levels of 3-week-old mice quantified by densitometric analysis. (e) Representative TLC of covalently bound lipids analyzed at 5 months and 3 weeks of age. (f) Decrease in sebum lipids in Lef1 mutant mice demonstrated by TLC. CE, cholesterol ester; DAG, diglyceride; TAG, triglyceride; WE, wax ester. *P<0.05; **P<0.01; **P<0.001; ***P<0.0005. Journal of Investigative Dermatology 2012 132, 337-345DOI: (10.1038/jid.2011.301) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Defective lamellar bodies in Lef1 (lymphoid enhancer-binding factor 1) mutant mice. (a–c) Transmission electron microscopy reveals abnormal lamellar body structures within the granular layer of mutant mice (b, c, arrows). Normal lamellar bodies with typical regular lipid lamellae are seen in skin samples from wild-type mice (a, arrow). SC, stratum corneum; SG, stratum granulosum. Bars=100nm, inset in a=30nm. Journal of Investigative Dermatology 2012 132, 337-345DOI: (10.1038/jid.2011.301) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 SCD1 (stearoyl coenzyme A desaturase 1) is a direct target of mutant Lef1 (lymphoid enhancer-binding factor 1). (a) Increase in ELOVL3 RNA in skin from 20-day-old (20d) and 2-month-old (2m) Lef1 mutant mice. (b) Analysis of SCD1 RNA in Lef1 mutant mice at birth (Pd0) up to Pd9. (c) Western blot for SCD1 of wild-type and Lef1 mutant skin lysates. (d) Mouse SCD1 promoter sequence containing putative TCF (T cell factor)/Lef1-binding sites (dark boxes) and deletion constructs for reporter assays (Prom1, Prom2, and Prom3). (e) Promoter assays detect opposite regulation by mutant Lef1 (ΔNLef1) and full-length Lef1 (Lef1). (f) Chromatin immunoprecipitation (ChIP) experiments demonstrate binding of mutant Lef1 (mut) by applying myc tag antibody to Prom2 and Prom3 fragment of the SCD1 regulatory sequence. Chromatin precipitates were analyzed by PCR. (g) Model of mutant Lef1 function in barrier acquisition. Journal of Investigative Dermatology 2012 132, 337-345DOI: (10.1038/jid.2011.301) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions