Murine Cutaneous Mastocytosis and Epidermal Melanocytosis Induced by Keratinocyte Expression of Transgenic Stem Cell Factor

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.

[1]  S. Nishikawa,et al.  Neural and skin cell‐specific expression pattern conferred by steel factor regulatory sequence in transgenic mice , 1996, Developmental dynamics : an official publication of the American Association of Anatomists.

[2]  G. Demetri,et al.  Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo , 1996, The Journal of experimental medicine.

[3]  S. Nishikawa,et al.  Distinct stages of melanocyte differentiation revealed by anlaysis of nonuniform pigmentation patterns. , 1996, Development.

[4]  Laura H. Tang,et al.  Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm , 1996, Nature Genetics.

[5]  S. Nishikawa,et al.  Characterization and isolation of melanocyte progenitors from mouse embryos , 1996, Development, growth & differentiation.

[6]  Y. Suzuki,et al.  Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Grichnik,et al.  Human recombinant stem-cell factor induces melanocytic hyperplasia in susceptible patients. , 1995, Journal of the American Academy of Dermatology.

[8]  S. Nishikawa,et al.  Effects of monoclonal anti-c-kit antibody (ACK2) on melanocytes in newborn mice. , 1995, The Journal of investigative dermatology.

[9]  B. Czarnetzki,et al.  Expression of stem cell factor in cutaneous mastocytosis , 1995, The British journal of dermatology.

[10]  S. Nishikawa,et al.  Cell cycle control of c-kit+IL-7R+ B precursor cells by two distinct signals derived from IL-7 receptor and c-kit in a fully defined medium , 1995, The Journal of experimental medicine.

[11]  Y. Matsuzawa,et al.  Substitution of an aspartic acid results in constitutive activation of c-kit receptor tyrosine kinase in a rat tumor mast cell line RBL-2H3. , 1995, International archives of allergy and immunology.

[12]  T. Duffy,et al.  The mast cell and mast cell disease. , 1995, Journal of the American Academy of Dermatology.

[13]  B. Wehrle-Haller,et al.  Soluble and cell-bound forms of steel factor activity play distinct roles in melanocyte precursor dispersal and survival on the lateral neural crest migration pathway. , 1995, Development.

[14]  H. Kitayama,et al.  Constitutively activating mutations of c-kit receptor tyrosine kinase confer factor-independent growth and tumorigenicity of factor-dependent hematopoietic cell lines. , 1995, Blood.

[15]  J. Longley.  Is mastocytosis a mast cell neoplasia or a reactive hyperplasia? Clues from the study of mast cell growth factor. , 1994, Annals of medicine.

[16]  D. Williams,et al.  Identification and mutation of primary and secondary proteolytic cleavage sites in murine stem cell factor cDNA yields biologically active, cell-associated protein. , 1994, The Journal of biological chemistry.

[17]  L. Ashman,et al.  Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. , 1993, The Journal of clinical investigation.

[18]  D. Williams,et al.  Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. , 1993, The New England journal of medicine.

[19]  E. Huang,et al.  Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. , 1992, Molecular biology of the cell.

[20]  D. Williams,et al.  c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. , 1992, Molecular biology of the cell.

[21]  S. Nishikawa,et al.  In utero manipulation of coat color formation by a monoclonal anti‐c‐kit antibody: two distinct waves of c‐kit‐dependency during melanocyte development. , 1991, The EMBO journal.

[22]  C. Croce,et al.  Alternate splicing of mRNAs encoding human mast cell growth factor and localization of the gene to chromosome 12q22-q24. , 1991, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[23]  L. Larue,et al.  Clonal coat color variation due to a transforming gene expressed in melanocytes of transgenic mice. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Tsai,et al.  The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype , 1991, The Journal of experimental medicine.

[25]  D. Williams,et al.  Steel-Dickie mutation encodes a c-kit ligand lacking transmembrane and cytoplasmic domains. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Wypych,et al.  Amino acid sequence and post-translational modification of stem cell factor isolated from buffalo rat liver cell-conditioned medium. , 1991, The Journal of biological chemistry.

[27]  P. Leder,et al.  Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the SId mutant , 1991, Cell.

[28]  C. March,et al.  Identification of a ligand for the c-kit proto-oncogene , 1990, Cell.

[29]  C. March,et al.  Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms , 1990, Cell.

[30]  P. Leder,et al.  The kit ligand: A cell surface molecule altered in steel mutant fibroblasts , 1990, Cell.

[31]  David A. Williams,et al.  Stem cell factor is encoded at the SI locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor , 1990, Cell.

[32]  K. Zsebo,et al.  Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver-conditioned medium , 1990, Cell.

[33]  Y. Kitamura,et al.  Suppressive effect of Sl/Sld mouse embryo-derived fibroblast cell lines on diffusible factor-dependent proliferation of mast cells. , 1989, Blood.

[34]  E. Fuchs,et al.  Tissue-specific and differentiation-specific expression of a human K14 keratin gene in transgenic mice. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[35]  D. Housman,et al.  The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene , 1988, Cell.

[36]  F. Ruddle,et al.  Primary structure of c‐kit: relationship with the CSF‐1/PDGF receptor kinase family–oncogenic activation of v‐kit involves deletion of extracellular domain and C terminus. , 1988, The EMBO journal.

[37]  A. Ullrich,et al.  Human proto‐oncogene c‐kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. , 1987, The EMBO journal.

[38]  T. Hirobe,et al.  Histochemical survey of the distribution of the epidermal melanoblasts and melanocytes in the mouse during fetal and postnatal periods , 1984, The Anatomical record.

[39]  J. Scott,et al.  ALCIAN BLUE—A CONSUMERS' GUIDE , 1970, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[40]  T. Mayer.  A comparison of pigment cell development in albino, steel, and dominant-spotting mutant mouse embryos. , 1970, Developmental biology.

[41]  Y. Matsuzawa,et al.  Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain. , 1996, Blood.

[42]  H. Kitayama,et al.  Transforming and differentiation-inducing potential of constitutively activated c-kit mutant genes in the IC-2 murine interleukin-3-dependent mast cell line. , 1996, The American journal of pathology.

[43]  D. Whitaker‐Menezes,et al.  Human dermal endothelial cells express membrane-associated mast cell growth factor. , 1995, The Journal of investigative dermatology.

[44]  E. Russell.  Hereditary anemias of the mouse: a review for geneticists. , 1979, Advances in genetics.