Yap Controls Stem/Progenitor Cell Proliferation in the Mouse Postnatal Epidermis Annemiek Beverdam, Christina Claxton, Xiaomeng Zhang, Gregory James,

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Yap Controls Stem/Progenitor Cell Proliferation in the Mouse Postnatal Epidermis Annemiek Beverdam, Christina Claxton, Xiaomeng Zhang, Gregory James, Kieran F. Harvey, Brian Key Journal of Investigative Dermatology Volume 133, Issue 6, Pages 1497-1505 (June 2013) DOI: 10.1038/jid.2012.430 Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 YAP is expressed in the proliferative zones of the epidermis. (a–i) Immunofluoresence staining in sections through the dorsal skin of P89 wild-type mice detecting pan-YAP (a–c), phospho-Serine127 YAP (P-YAP) (d–f), and basal cell marker Keratin 14 (g–i). Arrows point at YAP expression in basal cells in b and in bulge cells in c. Asterisks mark hair shafts. Basement membranes are demarcated by dashed lines. DAPI, 4′,6-diamidino-2-phenylindole; IFE, interfollicular epidermis; YAP, yes-associated protein. Scale bars=100μm. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Progressive dorsal alopecia in YAP2-5SA-ΔC transgenic mice. 1x wild-type (left) and 3x YAP2-5SA-ΔC transgenic (right) P106 littermates. Note that transgenic animals display alopecia and loss of whiskers. Affected regions of dorsal skin of each transgenic mouse are magnified and displayed at bottom of the figure. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Ontology of the epidermal phenotype in YAP2-5SA-ΔC transgenic mice. H&E (a, b, e–p) and Keratin 14 immunostaining assays (c, d) of wild-type (a, c, e, g, i, k, m, o) and YAP2-5SA-ΔC transgenic (b, d, f, h, j, l, n, p) skin of P0 (a–d), P10 (e, f, k, l), P49 (g, h, m, n), and P85 (i, j, o, p) littermates. Single white arrows in d point at irregularities in the basal layer of P0 YAP2-5SA-ΔC transgenic epidermis. Opposing arrows in e–j highlight thickness of the interfollicular epidermis. Opposing arrowheads in g, h highlight the thickness of the hair follicle shaft. Single arrows in j point at expanded cell masses in hair follicles of P85 YAP2-5SA-ΔC transgenic skin. Asterisks in j mark enlarged sebaceous glands. Basement membranes are demarcated by dashed lines. DAPI, 4′,6-diamidino-2-phenylindole; DP, dermal papilla; H&E, hematoxylin and eosin staining; Mx, matrix; PCX, precortex. Scale bars=100μm. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Expansion of basal stem/progenitor cells and suprabasal layers in the interfollicular epidermis of YAP2-5SA-ΔC transgenic mice. Immunostaining assays on sections of wild-type (a, c, e, g, i, k) and YAP2-5SA-ΔC transgenic (b, d, f, h, j, l) skin of P85 littermates showing the expression of basal marker K14 (a, b), spinous cell marker K10 (c, d), granular cell marker involucrin (e, f), cornified layer marker loricrin (g, h), proliferation marker PHH3 (i, j), and basal stem/progenitor cell marker P63 (k, l). Double arrows in b, d, f, h highlight thickness of the relevant epidermal layers. Arrows in i, j indicate proliferating cells. Arrows in k, l indicate P63-expressing nuclei. Basement membranes are demarcated by dashed lines. DAPI, 4′,6-diamidino-2-phenylindole; PHH3, phospho-histone H3. Scale bars=100μm. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Expansion of hair follicle bulge stem/progenitor cell population in YAP2-5SA-ΔC transgenic mice. Immunostaining (a–p), quantitative real-time reverse transcriptase–PCR (q), and alkaline phosphatase staining assays (r–w) on the epidermis of wild-type and YAP2-5SA-ΔC transgenic littermates showing the expression of outer root sheath marker Keratin 14 (a, b), companion layer marker K6 (c, d), proliferation marker PHH3 (e, f), bulge stem/progenitor cell markers K15 (g, h), SOX9 (i, j), LHX2 (k, l), and CD34 (m, n), P-Cadherin and CD34 (o, p), and the location of the dermal papilla (r–w). (q) Quantitative real-time reverse transcriptase–PCR assays show the expression levels of hair matrix markers Lef1 and Msx2, inner root sheath marker AE13, and hair shaft marker AE15 in the epidermis of wild-type and YAP2-5SA-ΔC transgenic littermates. Arrows in e, f indicate dividing cells. Double arrows in g–b highlight size of the hair follicle bulge region. Arrow in o indicates the hair germ. (q) y Axis displays relative fold expression levels with the expression levels in wild-type set to 1. Error bars represent mean±SEM (N=3). Asterisks indicate statistically significant differences in gene expression levels (P<0.05). Arrows in r–w indicate location of the dermal papilla. Asterisk mark hair shafts. Basement membranes are demarcated by dashed lines. AP, alkaline phosphatase; DAPI, 4′,6-diamidino-2-phenylindole; mRNA, messenger RNA; NFR, nuclear fast red; PCAD, P-Cadherin; PHH3, phospho-histone H3; tg, transgenic; wt, wild-type. Scale bars=100μm. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 YAP lacking it C-terminus can still interact with TEAD transcription factors and activate transcription of target genes, Gli2 and inhibin beta-A. (a) Immunoprecipitations with mouse anti-Flag agarose beads and rabbit anti-HA were used to detect HA-TEAD2, whereas mouse anti-Flag was used to detect YAP and YAP-ΔC. Top panel: equivalent amounts of TEAD2 were immunoprecipitated by YAP and YAP-ΔC. (b, c) y Axis displays relative fold expression levels with the expression levels in wild-type set to 1. Error bars represent SEM (N=3). Asterisks indicate statistically significant differences in gene expression levels (P<0.05). (d, e) GLI2 protein is expressed in hyperproliferative cells of YAP2-5SA-ΔC skin. Asterisks in d marks hair shaft. Double arrows in e highlight increased thickness of the interfollicular epidermis. Single arrows indicate location of the hair follicle bulge. Basement membranes are demarcated by dashed lines. CON, control; DAPI, 4′,6-diamidino-2-phenylindole; GLI2, glioma-associated oncogene family zinc finger 2; IB, immunoblot; Inhba, inhibin beta-A; IP, immunoprecipitation; SG, sebaceous gland; YAP, yes-associated protein. Scale bars=100μm. Journal of Investigative Dermatology 2013 133, 1497-1505DOI: (10.1038/jid.2012.430) Copyright © 2013 The Society for Investigative Dermatology, Inc Terms and Conditions