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J. Exp. Med.,
Volume 187, Number 10, May 18, 1998 1565-1573
By
§§
From the * Department of Immunology, School of Life Science, Faculty of Medicine, Tottori University,
Yonago 683, Japan; the 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.
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
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