Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations

Manas K. Majumdar, Eric T. Everett, Xiangli Xiao, Ryan Cooper, Keith Langley, Reuben Kapur, Terry Vik, David A. Williams

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3203-3211
Number of pages9
JournalBlood
Volume87
Issue number8
StatePublished - Apr 15 1996
Externally publishedYes

Fingerprint

Stem Cell Factor
Transgenic Mice
Forehead
Cells
Dental Caries
Mutation
Protein Isoforms
Color
Alleles
Membranes
Phenotype
Metrorrhagia
Receptor Protein-Tyrosine Kinases
Stromal Cells
Transgenes
Germ Cells
Anemia
Cell Survival
Membrane Proteins
Animals

ASJC Scopus subject areas

  • Hematology

Cite this

Majumdar, M. K., Everett, E. T., Xiao, X., Cooper, R., Langley, K., Kapur, R., ... Williams, D. A. (1996). Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations. Blood, 87(8), 3203-3211.

Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations. / Majumdar, Manas K.; Everett, Eric T.; Xiao, Xiangli; Cooper, Ryan; Langley, Keith; Kapur, Reuben; Vik, Terry; Williams, David A.

In: Blood, Vol. 87, No. 8, 15.04.1996, p. 3203-3211.

Research output: Contribution to journalArticle

Majumdar, MK, Everett, ET, Xiao, X, Cooper, R, Langley, K, Kapur, R, Vik, T & Williams, DA 1996, 'Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations', Blood, vol. 87, no. 8, pp. 3203-3211.
Majumdar MK, Everett ET, Xiao X, Cooper R, Langley K, Kapur R et al. Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations. Blood. 1996 Apr 15;87(8):3203-3211.
Majumdar, Manas K. ; Everett, Eric T. ; Xiao, Xiangli ; Cooper, Ryan ; Langley, Keith ; Kapur, Reuben ; Vik, Terry ; Williams, David A. / Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations. In: Blood. 1996 ; Vol. 87, No. 8. pp. 3203-3211.
@article{a43ab3f2498049e1abf82f4a6def53b2,
title = "Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations",
abstract = "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.",
author = "Majumdar, {Manas K.} and Everett, {Eric T.} and Xiangli Xiao and Ryan Cooper and Keith Langley and Reuben Kapur and Terry Vik and Williams, {David A.}",
year = "1996",
month = "4",
day = "15",
language = "English (US)",
volume = "87",
pages = "3203--3211",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "8",

}

TY - JOUR

T1 - Xenogeneic expression of human stem cell factor in transgenic mice mimics codominant c-kit mutations

AU - Majumdar, Manas K.

AU - Everett, Eric T.

AU - Xiao, Xiangli

AU - Cooper, Ryan

AU - Langley, Keith

AU - Kapur, Reuben

AU - Vik, Terry

AU - Williams, David A.

PY - 1996/4/15

Y1 - 1996/4/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0029866193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029866193&partnerID=8YFLogxK

M3 - Article

C2 - 8605335

AN - SCOPUS:0029866193

VL - 87

SP - 3203

EP - 3211

JO - Blood

JF - Blood

SN - 0006-4971

IS - 8

ER -