Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway.
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.
Pérez-Losada
Jesus
J
Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Servicio de Citometría, Universidad de Salamanca, Spain. jpl@usal.es
Sánchez-Martín
Manuel
M
Rodríguez-García
Arancha
A
Sánchez
Maria Luz
ML
Orfao
Alberto
A
Flores
Teresa
T
Sánchez-García
Isidro
I
D000748:Anemia, Macrocytic / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D005260:Female; D015870:Gene Expression; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000502:physiology; D006801:Humans; D007985:Leydig Cells / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D009154:Mutation; D010053:Ovary / Q000473:pathology; D010858:Pigmentation / Q000235:genetics; D011247:Pregnancy; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D019089:Stem Cell Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D013601:T-Lymphocytes / Q000473:pathology; D013737:Testis / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D019089:Stem Cell Factor; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit