Xenogeneic expression of human stem cell factor in transgenic mice mimics
codominant c-kit mutations
MK Majumdar, ET Everett, X Xiao, R Cooper, K Langley, R Kapur, T Vik and DA Williams
Herman B Wells Center for Pediatric Research, Indiana University School of
Medicine, Indianapolis, 46202-5225, USA.
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-
expressing 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.
Volume 87,
Issue 8,
pp. 3203-3211,
04/15/1996
Copyright © 1996 by The American Society of Hematology
