title: Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/beta-catenin signaling in keratinocytes.
abstract: The epidermis (containing primarily keratinocytes and melanocytes) overlies the dermis (containing primarily fibroblasts) of human skin. We previously reported that dickkopf 1 (DKK1) secreted by fibroblasts in the dermis elicits the hypopigmented phenotype of palmoplantar skin due to suppression of melanocyte function and growth via the regulation of two important signaling factors, microphthalmia-associated transcription factor (MITF) and beta-catenin. We now report that treatment of keratinocytes with DKK1 increases their proliferation and decreases their uptake of melanin and that treatment of reconstructed skin with DKK1 induces a thicker and less pigmented epidermis. DNA microarray analysis revealed many genes regulated by DKK1, and several with critical expression patterns were validated by reverse transcriptase-polymerase chain reaction and Western blotting. DKK1 induced the expression of keratin 9 and alpha-Kelch-like ECT2 interacting protein (alphaKLEIP) but down-regulated the expression of beta-catenin, glycogen synthase kinase 3beta, protein kinase C, and proteinase-activated receptor-2 (PAR-2), which is consistent with the expression patterns of those proteins in human palmoplantar skin. Treatment of reconstructed skin with DKK1 reproduced the expression patterns of those key proteins observed in palmoplantar skin. These findings further elucidate why human skin is thicker and paler on the palms and soles than on the trunk through topographical and site-specific differences in the secretion of DKK1 by dermal fibroblasts that affects the overlying epidermis.
authors.affiliation: Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. yujin@med.nagoya-cu.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Thierry
authors.initials: T
authors.lastname: Passeron
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hoashi
authors.forename: Hidenori
authors.initials: H
authors.lastname: Watabe
authors.forename: François
authors.initials: F
authors.lastname: Rouzaud
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hara
authors.forename: Chiharu
authors.initials: C
authors.lastname: Tohyama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Toru
authors.initials: T
authors.lastname: Miki
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D053534:Keratin-9 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008543:Melanins / Q000378:metabolism; D008875:Middle Aged; D015398:Signal Transduction; D012880:Skin Pigmentation; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053534:Keratin-9; D008543:Melanins; D051153:Wnt Proteins; D051176:beta Catenin