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Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/ β‐catenin signaling in keratinocytes
Author(s) -
Yamaguchi Yuji,
Passeron Thierry,
Hoashi Toshihiko,
Watabe Hidenori,
Rouzaud Francois,
Yasumoto Kenichi,
Hara Takahiko,
Tohyama Chiharu,
Katayama Ichiro,
Miki Toru,
Hearing Vincent J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-9475com
Subject(s) - dkk1 , microphthalmia associated transcription factor , dermis , epidermis (zoology) , wnt signaling pathway , microbiology and biotechnology , biology , gsk 3 , human skin , gsk3b , papillary dermis , keratin 14 , keratinocyte , signal transduction , transcription factor , transgene , anatomy , gene , genetically modified mouse , cell culture , biochemistry , genetics
The epidermis (containing primarily ker‐atinocytes 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‐associ‐ated transcription factor (MITF) and β‐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‐poly‐merase chain reaction and Western blotting. DKK1 induced the expression of keratin 9 and α‐Kelch‐like ECT2 interacting protein (αKLEIP) but down‐regulated the expression of β‐catenin, glycogen synthase kinase 3β, protein kinase C, and proteinase‐activated recep‐tor‐2 (PAR‐2), which is consistent with the expression patterns of those proteins in human palmoplantar skin. Treatment of reconstructed skin with DKK1 repro‐duced 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. Yamaguchi Y., Passeron, T., Hoashi, T., Watabe, H., Rouzaud, F., Yasumoto, K., Hara, T., Tohyama, C., Katayama, I., Miki, T., Hearing V. J. Dickkopf 1 (DKK1) regulates skin pigmentation and thickness by affecting Wnt/β‐catenin signaling in kera‐tinocytes. FASEB J. 22, 1009–1020 (2008)