Xenogeneic Expression of Human Stem Cell Factor in Transgenic Mice Mimics Codominant c-kit Mutations

• Published in: Blood Vol. 87; no. 8; pp. 3203 - 3211
• Main Authors: Majumdar, Manas K., Everett, Eric T., Xiao, Xiangli, Cooper, Ryan, Langley, Keith, Kapur, Reuben, Vik, Terry, Williams, David A.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.04.1996; The Americain Society of Hematology
• Subjects: Alleles; Analytical, structural and metabolic biochemistry; Anemia - genetics; Animals; Base Sequence; Biological and medical sciences; Epistasis, Genetic; Female; Fundamental and applied biological sciences. Psychology; Genes, Dominant; Humans; Infertility - genetics; Male; Mice; Mice, Transgenic; Molecular Sequence Data; Phenotype; Pigmentation Disorders - genetics; Protein hormones. Growth factors. Cytokines; Proteins; Proto-Oncogene Proteins c-kit - genetics; Recombinant Fusion Proteins - biosynthesis; Stem Cell Factor - biosynthesis; Stem Cell Factor - genetics; Transfection; Human origin; Molecular form; Cytokine; Rodentia; Transgenic animal; Stem cell factor; Vertebrata; Phenotype; Mammalia; Mouse; C-Onc gene; Mutation; Protooncogene; Growth factor
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V87.8.3203.bloodjournal8783203

Mutations of c-kit, which encodes a transmembrane receptor tyrosine kinase, have been identified in mice by abnormal coat color, anemia, and germ cell defects. Mice heterozygous for mutations of c-kit have a white forehead blaze and a white ventral spot, leading these mutants to be termed dominant White spotting (W). We have previously demonstrated that the membrane-associated isoform of human stem cell factor (hSCF220, the ligand for c-kit) is inefficiently processed in murine stromal cell transfectants. Thus, in murine cell lines analyzed in vitro, hSCF220 transfectants present SCF as a membrane restricted protein in contrast to the murine SCF220 cDNA protein product, which is slowly cleaved and secreted. We show here that transgenic mice expressing the human SCF220 isoform in vivo display a phenotype indistinguishable from some alleles of W. Specifically, hSCF220-ex-pressing transgenic mice display a prominent forehead blaze and a white ventral spot. Generations of doubly heterozygous animals that carry both a mutated c-kit allele and the hSCF220 transgene display a more severe coat color abnormality. This phenotype appears to be due to occupancy of murine c-kit by human SCF and diminished cell surface expression of endogenous murine SCF. Normal signaling events that lead to cell survival or proliferation appear to be disrupted in vivo in these transgenic mice.