Overexpression of human stem cell factor impairs melanocyte, mast cell, and thymocyte development: A role for receptor tyrosine kinase-mediated mitogen activated protein kinase activation in cell differentiation

Reuben Kapur, Eric T. Everett, Josh Uffman, Monica McAndrews-Hill, Ryan Cooper, John Ryder, Terry Vik, David A. Williams

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Stem cell factor (SCF) is synthesized as both soluble (S) and membrane- associated (MA) proteins. Indirect insight into the function of MA and S isoforms of SCF has come from studies performed in Steel (Sl) mutant mice. However, the physiologic role(s) of these two isoforms remain unknown. In an attempt to better understand the in vivo role of c-kit/SCF interactions on various cell lineages, transgenic mice were generated that overexpress MA isoform of human SCF (hSCF). In murine cells, hSCF behaves as an antagonist to normal SCF function, due to interference with the interaction between endogenous murine SCF and its receptor; c-kit, encoded by the dominant white spotting (W) gene. Mice expressing the hSCF transgene display a variety of phenotypic abnormalities, which are accentuated when combined with W alleles. Here we show that mice homozygous for the hSCF transgene demonstrate a coat color deficiency seen in some mice homozygous for mild W alleles. Specifically, homozygous hSCF transgenic mice (hSCF220) display a pronounced forehead blaze, with additional white spots over the cervical region, as well as a very large belly spot. Doubly heterozygous animals that carry both a mutated W allele and the hSCF transgene also display an unusual pigment defect and a dramatic reduction in the number of dermal mast cells. Furthermore, overexpression of MA hSCF in the thymus results in abnormal thymocyte differentiation and proliferation, which is associated with reduced mitogen activated protein (MAP) kinase activation. Thus, MAP kinase activation by a receptor tyrosine kinase, such as c-kit, may be critical for the differentiation of thymocytes in vivo.

Original languageEnglish (US)
Pages (from-to)3018-3026
Number of pages9
JournalBlood
Volume90
Issue number8
StatePublished - Oct 15 1997
Externally publishedYes

Fingerprint

Stem Cell Factor
Melanocytes
Receptor Protein-Tyrosine Kinases
Thymocytes
Mitogen-Activated Protein Kinases
Mast Cells
Cell Differentiation
Chemical activation
Protein Isoforms
Transgenes
Membranes
Alleles
Proto-Oncogene Proteins c-kit
Transgenic Mice
Thymus
Steel
Pigments
Metrorrhagia
Forehead
Membrane Proteins

ASJC Scopus subject areas

  • Hematology

Cite this

Overexpression of human stem cell factor impairs melanocyte, mast cell, and thymocyte development : A role for receptor tyrosine kinase-mediated mitogen activated protein kinase activation in cell differentiation. / Kapur, Reuben; Everett, Eric T.; Uffman, Josh; McAndrews-Hill, Monica; Cooper, Ryan; Ryder, John; Vik, Terry; Williams, David A.

In: Blood, Vol. 90, No. 8, 15.10.1997, p. 3018-3026.

Research output: Contribution to journalArticle

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abstract = "Stem cell factor (SCF) is synthesized as both soluble (S) and membrane- associated (MA) proteins. Indirect insight into the function of MA and S isoforms of SCF has come from studies performed in Steel (Sl) mutant mice. However, the physiologic role(s) of these two isoforms remain unknown. In an attempt to better understand the in vivo role of c-kit/SCF interactions on various cell lineages, transgenic mice were generated that overexpress MA isoform of human SCF (hSCF). In murine cells, hSCF behaves as an antagonist to normal SCF function, due to interference with the interaction between endogenous murine SCF and its receptor; c-kit, encoded by the dominant white spotting (W) gene. Mice expressing the hSCF transgene display a variety of phenotypic abnormalities, which are accentuated when combined with W alleles. Here we show that mice homozygous for the hSCF transgene demonstrate a coat color deficiency seen in some mice homozygous for mild W alleles. Specifically, homozygous hSCF transgenic mice (hSCF220) display a pronounced forehead blaze, with additional white spots over the cervical region, as well as a very large belly spot. Doubly heterozygous animals that carry both a mutated W allele and the hSCF transgene also display an unusual pigment defect and a dramatic reduction in the number of dermal mast cells. Furthermore, overexpression of MA hSCF in the thymus results in abnormal thymocyte differentiation and proliferation, which is associated with reduced mitogen activated protein (MAP) kinase activation. Thus, MAP kinase activation by a receptor tyrosine kinase, such as c-kit, may be critical for the differentiation of thymocytes in vivo.",
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