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Published 26 April 2004. doi:10.1083/jcb.200311122
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 2, 275-285
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Article

 Mesenchymal–epithelial interactions in the skin : increased expression of dickkopf1 by palmoplantar fibroblasts inhibits melanocyte growth and differentiation



Yuji Yamaguchi1, Satoshi Itami2, Hidenori Watabe1, Ken-ichi Yasumoto1, Zalfa A. Abdel-Malek3, Tateki Kubo2, François Rouzaud1, Atsushi Tanemura2, Kunihiko Yoshikawa2, and Vincent J. Hearing1

1 Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
2 Department of Dermatology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871 Japan
3 Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267

Address correspondence to V.J. Hearing, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bldg. 37, Rm. 1B25, Bethesda, MD 20892-4254. Tel.: (301) 496-1564. Fax: (301) 402-8787. email: hearingv{at}nih.gov

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 ß-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.

Key Words: pigmentation; regulation; dickkopf; ß-catenin; MITF

Abbreviations used in this paper: DCT, dopachrome tautomerase; DKK, dickkopf; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; LEF1/TCF, lymphoid enhancer binding factor 1/T-cell–specific factor; MITF, microphthalmia-associated transcription factor; TYR, tyrosinase.


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