Mesenchymal-epithelial interactions in the skin: increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation.
We investigated whether or not the topographic regulation of melanocyte differentiation is determined by mesenchymal-epithelial interactions via fibroblast-derived factors. The melanocyte density in palmoplantar human skin (i.e., skin on the palms and the soles) is five times lower than that found in nonpalmoplantar sites. Palmoplantar fibroblasts significantly suppressed the growth and pigmentation of melanocytes compared with nonpalmoplantar fibroblasts. Using cDNA microarray analysis, fibroblasts derived from palmoplantar skin expressed high levels of dickkopf 1 (DKK1; an inhibitor of the canonical Wnt signaling pathway), whereas nonpalmoplantar fibroblasts expressed higher levels of DKK3. Transfection studies revealed that DKK1 decreased melanocyte function, probably through beta-catenin-mediated regulation of microphthalmia-associated transcription factor activity, which in turn modulates the growth and differentiation of melanocytes. Thus, our results provide a basis to explain why skin on the palms and the soles is generally hypopigmented compared with other areas of the body, and might explain why melanocytes stop migrating in the palmoplantar area during human embryogenesis.
Yamaguchi
Yuji
Y
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 1B25, Bethesda, MD 20892-4254, USA.
Itami
Satoshi
S
Watabe
Hidenori
H
Yasumoto
Ken-Ichi
K
Abdel-Malek
Zalfa A
ZA
Kubo
Tateki
T
Rouzaud
François
F
Tanemura
Atsushi
A
Yoshikawa
Kunihiko
K
Hearing
Vincent J
VJ
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000818:Animals; D015415:Biomarkers; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D018925:Chemokines; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D005528:Foot / Q000033:anatomy & histology; D020869:Gene Expression Profiling; D006225:Hand / Q000033:anatomy & histology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D051739:Microphthalmia-Associated Transcription Factor; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D012867:Skin / Q000166:cytology* / Q000378:metabolism; D012880:Skin Pigmentation / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin
D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; C495270:CTNNB1 protein, human; D018925:Chemokines; D003598:Cytoskeletal Proteins; C501126:DKK1 protein, human; C498624:DKK3 protein, human; D004268:DNA-Binding Proteins; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C497234:MITF protein, human; D008543:Melanins; D051739:Microphthalmia-Associated Transcription Factor; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin