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Takahiro Kunisada^*, Shu-Zhuang Lu, Hisahiro Yoshida, Satomi Nishikawa, Shin-ichi Nishikawa, Masako Mizoguchi^||, Shin-ichi Hayashi^*, Lynda Tyrrell, David A. Williams^¶,**, Xiaomei Wang, and B. Jack Longley^,,

From the ^* Department of Immunology, School of Life Science, Faculty of Medicine, Tottori University, Yonago 683, Japan; the Yale University School of Medicine, Department of Dermatology, New Haven, Connecticut 06510; the Department of Molecular Genetics, Faculty of Medicine, Kyoto University, Kyoto 606-01, Japan; the ^|| Department of Dermatology, St. Marianna University School of Medicine, Kawasaki 216, Japan; the ^¶ Herman B. Wells Center for Pediatric Research and the ^** Howard Hughes Medical Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202; the Yale Skin Disease Research Center, New Haven, Connecticut 06510; and the Departments of Dermatology and Pathology, College of Physicians and Surgeons of Columbia University, New York 10032

The growth and differentiation of mast cells and melanocytes require stem cell factor (SCF), the ligand for the kit receptor tyrosine kinase. SCF may exist as a membrane-bound or soluble molecule. Abnormalities of the SCF-kit signaling pathway, with increased local concentrations of soluble SCF, have been implicated in the pathogenesis of the human disease cutaneous mastocytosis, but have not yet been shown to play a causal role. To investigate both the potential of SCF to cause mastocytosis and its role in epidermal melanocyte homeostasis, we targeted the expression of SCF to epidermal keratinocytes in mice with two different transgenes controlled by the human keratin 14 promoter. The transgenes contained cDNAs that either produced SCF, which can exist in both membrane-bound and soluble forms, or SCF, which remains essentially membrane bound. Murine epidermal keratinocyte expression of membrane-bound/ soluble SCF reproduced the phenotype of human cutaneous mastocytosis, with dermal mast cell infiltrates and epidermal hyperpigmentation, and caused the maintenance of a population of melanocytes in the interadnexal epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine skin. Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis. We conclude, first, that a phenotype matching that of human mastocytosis can be produced in mice by keratinocyte overproduction of soluble SCF, suggesting a potential cause of this disease. Second, we conclude that keratinocyte expression of membrane-bound SCF results in the postnatal maintenance of epidermal melanocytes in mice. Since the resulting animals have skin that more closely approximates human skin than do normal mice, their study may be more relevant to human melanocyte biology than the study of skin of normal mice.

Key Words: mastocytosis • melanocyte development • stem cell factor • c-KIT • mast cell

Abbreviations used: SCF, stem cell factor; TG, transgene.

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