XENOGENEIC EXPRESSION OF HUMAN STEM-CELL FACTOR IN TRANSGENIC MICE MIMICS CODOMINANT C-KIT MUTATIONS

Mutations of c-kit, which encodes a transmembrane receptor tyrosine ki nase, have been identified in mice by abnormal coat color, anemia, and germ cell defects. Mice heterozygous for mutations of c-kit have a wh ite 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 (hSCF( 220), the ligand for c-kit) is inefficiently processed in murine strom al cell transfectants. Thus, in murine cell lines analyzed in vitro, h SCF(220) transfectants present SCF as a membrane restricted protein in contrast to the murine SCF220 cDNA protein product, which is slowly c leaved and secreted. We show here that transgenic mice expressing the human SCF220 isoform in vivo display a phenotype indistinguishable fro m some alleles of W. Specifically, hSCF(220)-expressing transgenic mic e display a prominent forehead blaze and a white ventral spot. Generat ions of doubly heterozygous animals that carry both a mutated c-kit al lele and the hSCF(220) transgene display a more severe coat color abno rmality. This phenotype appears to be due to occupancy of murine c-kit by human SCF and diminished cell surface expression of endogenous mur ine SCF. Normal signaling events that lead to cell survival or prolife ration appear to be disrupted in vivo in these transgenic mice. (C) 19 96 by The American Society of Hematology.