Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway

Blood. 2002 Aug 15;100(4):1274-86.

Abstract

The stem cell factor c-kit signaling pathway (SCF/c-kit) has been previously implicated in normal hematopoiesis, melanogenesis, and gametogenesis through the formation and migration of c-kit(+) cells. These biologic functions are also determinants in epithelial-mesenchymal transitions during embryonic development governed by the Snail family of transcription factors. Here we show that the activation of c-kit by SCF specifically induces the expression of Slug, a Snail family member. Slug mutant mice have a cell-intrinsic defect with pigment deficiency, gonadal defect, and impairment of hematopoiesis. Kit(+) cells derived from Slug mutant mice exhibit migratory defects similar to those of c-kit(+) cells derived from SCF and c-kit mutant mice. Endogenous Slug is expressed in migratory c-kit(+) cells purified from control mice but is not present in c-kit(+) cells derived from SCF mutant mice or in bone marrow cells from W/W(v) mice, though Slug is present in spleen c-kit(+) cells of W/W(v) (mutants expressing c-kit with reduced surface expression and activity). SCF-induced migration was affected in primary c-kit(+) cells purified from Slug-/- mice, providing evidence for a role of Slug in the acquisition of c-kit(+) cells with ability to migrate. Slug may thus be considered a molecular target that contributes to the biologic specificity to the SCF/c-kit signaling pathway, opening up new avenues for stem cell mobilization.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anemia, Macrocytic / genetics
  • Animals
  • Bone Marrow Cells / metabolism
  • Cell Line
  • Cell Movement
  • Female
  • Gene Expression
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Leydig Cells / pathology
  • Lymphocyte Count
  • Male
  • Mice
  • Mutation
  • Ovary / pathology
  • Pigmentation / genetics
  • Pregnancy
  • Proto-Oncogene Proteins c-kit / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Snail Family Transcription Factors
  • Stem Cell Factor / analysis
  • Stem Cell Factor / genetics
  • Stem Cell Factor / physiology*
  • T-Lymphocytes / pathology
  • Testis / pathology
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Tumor Cells, Cultured
  • Zinc Fingers*

Substances

  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Stem Cell Factor
  • Transcription Factors
  • Proto-Oncogene Proteins c-kit