The skinny on Slug

Abstract

The zinc finger transcription factor Slug (Snai2) serves a wide variety of functions in the epidermis, with roles in skin development, hair growth, wound healing, skin cancer, and sunburn. Slug is expressed in basal keratinocytes and hair follicles where it is important in maintaining epidermal homeostasis. Slug also helps coordinate the skin response to exogenous stimuli. Slug is rapidly induced by a variety of growth factors and injurious agents and Slug controls, directly or indirectly, a variety of keratinocyte responses, including changes in differentiation, adhesion, motility, and production of inflammatory mediators. Slug thus modulates the interactions of the keratinocyte with its environment and with surrounding cells. The function of Slug in the epidermis appears to be distinct from that of the closely related Snail transcription factor.

Figure 1

Structure of the Slug transcription factor. Five zinc fingers are located in the carboxy portion of the Slug protein. The amino half of Slug contains a SNAG domain, a CtBP motif, and a Slug-specific sequence. Repressor activity resides in both amino and carboxy regions of the protein, and multiple nuclear localization signals are distributed within and adjacent to the zinc fingers.

Figure 2

Slug and keratin 14 expression in embryonic skin. Slug and keratin 14 was detected in CD1 mouse embryo sections (Zyagen, San Diego, CA) using previously described techniques [40]. During skin development, Slug expression becomes progressively localized to basal keratinocytes and parallels keratin 14 expression. Note clear nuclear localization of Slug at all time points. Scale bar; 50 µm.

Figure 3

Slug induction by UVR and TPA. UVR: SKH-1 hairless mice were exposed to 2800 J/m2 UVR from a solar simulator; unexposed mice provided control skin. TPA: DBA/2 mice were shaved and treated once with 6.8 nm TPA in acetone; control mice were treated with acetone only. Skin was collected 4, 24, and 48 hours after UVR exposure or TPA application. Immunohistochemistry for Slug was performed as previously described [40]. Both UVR and TPA induced Slug expression in basal keratinocytes; however, Slug induction peaked at different time points: 48 hours after UVR exposure and 24 hours after TPA application. Scale bar; 50 µm.

Figure 4

Slug induction during reepithelialization of cutaneous wounds. Wild type 129 mice were shaved and depilated. Two days later, excisional wounds were introduced using sterile skin biopsy punches. Wounds were harvested at 6, 24, 48, and 72 hours after wounding. Immunohistochemistry for Slug was performed as previously described [40]. At 6 hours post-wounding, occasional basal keratinocytes have nuclei immunopositive for Slug. Increased Slug expression is seen in migrating cells at wound margins at 24 and 48 hours after wounding; Slug expression becomes maximal 72 hours post-wounding. In all panels, the wound edge is indicated with an arrowhead. Scale bar; 100 µm.

Figure 5

Slug expression in UVR-induced epithelial and spindle cell tumors of mouse skin. The typical SCC in the SKH-1 hairless mouse was induced by chronic exposure to one minimal erythemal dose of UVR; the spindle cell tumor in the 129 wild type haired mouse was induced by chronic exposure to two minimal erythemal doses of UVR. Immunohistochemistry for Slug was performed as previously described [40]. Note that many nuclei in both tumor types are immunopositive for Slug. Scale bar; 100 µm

Figure 6

Decreased sunburn response in Slug null mice. Wild type and Slug null littermates on a 129 background were shaved and exposed to three minimal erythemal doses of UVR. Skin was sampled 48 hours later. Note the marked inflammatory infiltrate in the dermis and epidermal hyperplasia in the wild type mouse. These changes are much milder in Slug null skin. Scale bar; 100 µm.