Stem cell factor rescues tyrosinase expression and pigmentation in discreet anatomic locations in albino mice

Abstract

We previously reported a transgenic animal model of variant pigmentation based on epidermal expression of stem cell factor (SCF) and well-characterized coat color genes bred into the C57Bl/6 background. In this system, constitutive expression of SCF by epidermal keratinocytes results in the maintenance of epidermal melanocytes in the interfollicular basal epidermal layer and subsequent pigmentation of the epidermis itself. In this report, we describe extending this animal model by developing a compound mutant transgenic amelanotic animal defective at both the melanocortin 1 receptor (Mc1r) and tyrosinase (Tyr) loci. We have observed SCF-dependent pigment deposition in specific anatomic regions regardless of tyrosinase (Tyr) or Mc1r genetic status. Thus, in the presence of K14-Scf, tyrosinase-null animals (previously thought incapable of synthesizing melanin) exhibited progressive robust epidermal pigmentation with age in the ears and tails. Furthermore, in the presence of the K14-Scf transgene, Tyr-defective animals demonstrated tyrosinase activity, suggesting that the c2j Tyr promoter defect is leaky and that Tyr expression can be rescued in part by SCF in the ears and tail. Lastly, we found that UV sensitivity of K14-Scf congenic animals differing only at the Mc1r or Tyr loci depended mainly on the amount of eumelanin present in the skin. These findings suggest that c-kit signaling can overcome the c2j Tyr promoter mutation in the ears and tails of aging animals but that UV resistance depends on accumulation of epidermal eumelanin.

RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

“…K14-Scf transgenic animals congenic except for function at the Mc1r or tyrosinase (tyr) loci (Figure 1A) were irradiated with UV to ascertain pigment-independent effects of Mc1r on DNA repair (D’Orazio et al, 2006; Vanover et al, 2009). Clearance of UV-induced cyclobutane pyrimidine dimers (CPD) was impaired in animals expressing inactive Mc1r ( Mc1r e/e ) when compared to those with wild type Mc1r , as measured by time taken to repair 50% of UV damage (repair t 1/2 for CPD removal 42 ± 6.3 h vs. 24 ± 0.7 h respectively; p ≤ 0.05) (Figure 1B).…”

Distinct downstream targets manifest p53-dependent pathologies in mice

“…16,27 The phenotype is reminiscent of similar observations reported in K14-Kitl transgenic mice because of increased c-kit signaling in the epidermis. 23,24 In agreement, we observed increase in Kitl mRNA levels in keratinocytes of Mdm2 PND/PND mice. Kitl is an important down-stream target of p53 activity and acts a chemokinetic factor that accelerates melanoblast migration to the hair follicles in the skin of a developing embryo.…”

“…16,22 Transgenic mice that express Kitl under the K14 promoter exhibit a similar skin hyperpigmentation phenotype. 23 To evaluate whether excessive p53-dependent Kitl expression is associated with hyperpigmentation of Mdm2 PND/PND extremities, we performed RT–qPCR for Kitl in keratinocyte RNA from these mice. Indeed, Kitl expression was significantly higher in Mdm2 PND/PND mice ( P =0.03) compared with wild-type keratinocytes (Figure 6a).…”

Pharmacologic Induction of Epidermal Melanin and Protection Against Sunburn in a Humanized Mouse Model

“…In contrast, genetically matched K14-Scf C57BL/6 animals that harbor a mutant inactive Mc1r have almost no eumelanin in the epidermis. Instead, these "extension" animals (Mc1r e/e ) have a fair skin complexion caused by deposition of pheomelanin pigment ( Figure 1A) and are much more UV-sensitive [48][49] .…”

“…In this article, we demonstrate the preparation and topical application of forskolin in extension (Mc1r e/e ) K14-Scf animals which model the fair-skinned UV-sensitive human. We show that twice daily application of the drug promotes accelerated melanization, that skin darkening is due to epidermal deposition of melanin pigment and that induced epidermal melanin protects against UV-induced sunburn through measurement of "minimal erythematous dose" (MED) 48 .…”