ABSTRACT
Selenoproteins are essential molecules for the mammalian antioxidant network. We previously demonstrated that targeted loss of all selenoproteins in mouse epidermis disrupted skin and hair development, and caused premature death. In the current study, we targeted specific selenoproteins for epidermal deletion to determine whether similar phenotypes developed. Keratinocyte-specific knockout mice lacking either the glutathione peroxidase 4 (GPx4) or thioredoxin reductase 1 (TR1) gene were generated by cre-lox technology using K14-cre. TR1 knockout mice had a normal phenotype in resting skin, whereas GPx4 loss in the epidermis caused epidermal hyperplasia, dermal inflammatory infiltrate, dysmorphic hair follicles, and alopecia in perinatal mice. Unlike epidermal ablation of all selenoproteins, mice ablated for GPx4 recovered after 5 weeks and had a normal life span. GPx1 and TR1 were upregulated in the skin and keratinocytes of GPx4-knockout mice. GPx4 deletion reduces keratinocyte adhesion in culture and increases lipid peroxidation and cyclooxygenase-2 (COX-2) levels in cultured keratinocytes and whole skin. Feeding a COX-2 inhibitor to nursing mothers partially prevents development of the abnormal skin phenotype in knockout pups. These data link the activity of cutaneous GPx4 to the regulation of COX-2 and hair follicle morphogenesis, and provide insight into the function of individual selenoprotein activity in maintaining cutaneous homeostasis.
Subject(s)
Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/drug effects , Epithelial Cells/metabolism , Glutathione Peroxidase/deficiency , Hair Follicle/growth & development , Morphogenesis/physiology , Skin/metabolism , Animals , Animals, Newborn , Cell Adhesion/physiology , Cell Differentiation/physiology , Cell Proliferation , Cells, Cultured , Cyclooxygenase 2/metabolism , Epithelial Cells/cytology , Female , Glutathione Peroxidase/genetics , Glutathione Peroxidase/metabolism , Keratinocytes/cytology , Keratinocytes/metabolism , Lipid Peroxidation/physiology , Male , Mice , Mice, Knockout , Mice, Transgenic , Phenotype , Phospholipid Hydroperoxide Glutathione Peroxidase , Skin/cytology , Thioredoxin Reductase 1/deficiency , Thioredoxin Reductase 1/genetics , Thioredoxin Reductase 1/metabolismABSTRACT
Dietary selenium is known to protect skin against UV-induced damage and cancer and its topical application improves skin surface parameters in humans, while selenium deficiency compromises protective antioxidant enzymes in skin. Furthermore, skin and hair abnormalities in humans and rodents may be caused by selenium deficiency, which are overcome by dietary selenium supplementation. Most important biological functions of selenium are attributed to selenoproteins, proteins containing selenium in the form of the amino acid, selenocysteine (Sec). Sec insertion into proteins depends on Sec tRNA; thus, knocking out the Sec tRNA gene (Trsp) ablates selenoprotein expression. We generated mice with targeted removal of selenoproteins in keratin 14 (K14) expressing cells and their differentiated descendents. The knockout progeny had a runt phenotype, developed skin abnormalities and experienced premature death. Lack of selenoproteins in epidermal cells led to the development of hyperplastic epidermis and aberrant hair follicle morphogenesis, accompanied by progressive alopecia after birth. Further analyses revealed that selenoproteins are essential antioxidants in skin and unveiled their role in keratinocyte growth and viability. This study links severe selenoprotein deficiency to abnormalities in skin and hair and provides genetic evidence for the role of these proteins in keratinocyte function and cutaneous development.
