Endothelin 3 Induces Skin Pigmentation in a Keratin-Driven Inducible Mouse Model Roman J. Garcia, Avner Ittah, Sheyla Mirabal, Jessica Figueroa, Lidice.

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Endothelin 3 Induces Skin Pigmentation in a Keratin-Driven Inducible Mouse Model Roman J. Garcia, Avner Ittah, Sheyla Mirabal, Jessica Figueroa, Lidice Lopez, Adam B. Glick, Lidia Kos Journal of Investigative Dermatology Volume 128, Issue 1, Pages 131-142 (January 2008) DOI: 10.1038/sj.jid.5700948 Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Transgenic mice exhibit a hyperpigmentation phenotype. K5-tTA;TRE-Edn3-lacZ(369) mice (arrowheads). (a) Dorsal skin of 0, 2, 10, and 20 days controls (wild-type) and K5-tTA;TRE-Edn3-lacZ(369) mice (not all 0 day transgenics were born with pigmentation). Hyperpigmented muzzle of (b) E16.5 and (c) 30 days mice. Adult (d) foot pads and (e) tail. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Embryonic and postnatal cells expressing the tetracycline system establish melanocytes in the dermis. (a) At E9.5, β-galactosidase activity is absent along the trunk neural tube (arrows) in K5-tTA;TRE-Edn3-lacZ(369) embryos. By E10.5, β-galactosidase activity begins along the neural tube and persists during early development (E11.5). By E15.5, β-galactosidase activity is found over most areas of the developing skin. (b) E12.5 cryosections reveal β-galactosidase activity on the surface ectoderm (arrowhead indicates lateral ridge) and roof plate of the neural tube (NT; bar=50μm). (c) TRE-Edn3-lacZ(369) expressing cells in E10.5 and E12.5 embryos. (d and e) lacZ staining in K5-tTA;TRE-Edn3-lacZ(369) skin at (d) 0 day and (e) 2 days localizes to the epidermis, hair follicles, and underlying connective tissue. An ectopic population of dermal melanocytes can be observed in these mice (arrows). (f) TRE-Edn3-lacZ(369) expression in the epidermis of 2 days pups (arrow). (g) 2 days lacZ-stained skin from the K5-tTA;TRE-Edn3-lacZ(476) line reveals sparse to no β-galactosidase activity. Bar=100μm. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Transgenic embryos have large numbers of Dct+ cells. Dct+ cells in Dct-lacZ control mice (C) and K5-tTA;TRE-Edn3-lacZ(476)/Dct-lacZ (Tg) mice. (a) E13.5 and E16.5 Dct+ cells in Tg and C (TRE-Edn3-lacZ(476)/Dct-lacZ) embryos. Sections reveal Dct+ cells scored to the dermis (horizontal arrows), epidermis (vertical arrows), and E16.5 hair follicles (HF). (b) Number of Dct+ cells in representative areas of the dermis and epidermis of E13.5 and E16.5 embryos. E16.5 embryos were also assayed for Dct+ cells in individual hair follicles. Significant increases (asterisks; P<0.001) are seen in dermal, epidermal, and hair follicle Dct+ cell populations. (c) Dct+ cells (arrows) localize to pigmented regions in 1-day Tg mice. Bar=25μm. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Transgene expression is required at all times for maintenance of the hyperpigmentation phenotype. (a) Embryos that receive dox at E10.5 lose β-galactosidase activity over 2 days. (b) K5-tTA;TRE-Edn3-lacZ(369) embryos administered dox at E12.5 never manifest hyperpigmented skin; a 4-day-old litter determined to have two K5-tTA;TRE-Edn3-lacZ(369) pups after PCR analysis is shown. (c) K5-tTA;TRE-Edn3-lacZ(369) mice (arrowheads) repressed with dox at 0 day begin to lose their hyperpigmented skin. (d) Ammoniacal silver nitrate staining indicates melanocyte lineage cells (arrows) in the dark skin of a 20 days K5-tTA;TRE-Edn3-lacZ(369) mouse, and on the pink skin of a 20 days K5-tTA;TRE-Edn3-lacZ(369) littermate treated with dox at 0 day. Bar=25μm. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Activation of transgene expression at E10.5 is required for the generation of the hyperpigmentation phenotype. (a) After dox induction at E7.5, β-galactosidase activity first appears 3 days later (E10.5) and increases by E12.5. (b) Two-day-old K5-rTA;TRE-Edn3-lacZ(369) skin induced at E7.5 shows a decreased lacZ staining pattern in the epidermis and little to no muscular staining relative to the skin of 2 days K5-tTA;TRE-Edn3-lacZ(369) mice. (c) A litter of K5-rTA;TRE-Edn3-lacZ(369) mice treated with dox at E8.5. Three pups from this litter were identified as K5-rTA;TRE-Edn3-lacZ(369); they never developed hyperpigmented skin. (d) K5-rTA;TRE-Edn3-lacZ(369) mice (arrowheads) induced with dox at E7.5. Bar=100μm. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Transgene-mediated Edn3 expression alters the phenotypes of Edn3ls/ls, KitWv/Wv, and Ay mice. (a–c) K5-tTA;TRE-Edn3-lacZ(476)/Edn3ls/ls mice (arrowheads) are shown with Edn3ls/ls littermates. (a and b) White dorsal patches in the coats (a) of 10 days K5-tTA;TRE-Edn3-lacZ(476)/Edn3ls/ls mice correlate to (b) depigmented regions of the skin underlying these same areas in the coat. A partial correction to the spotting phenotype is seen in the rostral areas of transgenic mice (arrows) (a and b). (c) The ventral belly spot of Edn3ls/ls mice is not rescued in 30 days K5-tTA;TRE-Edn3-lacZ(476)/Edn3ls/ls transgenics. (d) The coat of 20 days K5-rTA;TRE-Edn3-lacZ(476)/Edn3ls/ls mice (arrowhead) induced with dox at E13.5 resembles its Edn3ls/ls littermate. (e) Rescued ventral coat phenotype of K5-tTA;TRE-Edn3-lacZ(476)/KitWv/+ mice (arrowhead) shown with a hypopigmented KitWv/+ littermate. (f and g) K5-tTA;TRE-Edn3-lacZ(476)/KitWv/Wv mice (arrowheads) manifest rostral and caudal areas of dark skin (arrows) at (f) 7 days; however, by (g) 15 days, these areas give rise to unpigmented white hair follicles (arrows). (h) The dorsal agouti coat of K5-tTA;TRE-Edn3-lacZ mice (arrowhead) is darkened relative to littermate controls. Magnified individual hair shafts are shown for each coat. (i) K5-tTA;TRE-Edn3-lacZ(476)/Ay mice (arrowhead) display a darkened coat color relative to Ay littermates. (j) The depilated skin of K5-tTA;TRE-Edn3-lacZ(476)/Ay mice (arrowhead) develop pigmented skin in contrast to their Ay littermates. Bar=15μm. Journal of Investigative Dermatology 2008 128, 131-142DOI: (10.1038/sj.jid.5700948) Copyright © 2008 The Society for Investigative Dermatology, Inc Terms and Conditions