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/Wv mice, though Slug is present in spleen c-kit+ cells of W/Wv (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.Supported by Dirección General Ciencia Y Tecnologia (DGCYT) (1FD97-0360, SAF2000-0148, BIO2000-0453-P4-02), Fundación Científica of the Asociación Española Contra el Cáncer (AECC), Junta de Castilla y León (C.S.I. 3/01, CSI1/02), Fondo Investigación Sanitaria (FIS) (99/0935, 01/0114), and the National Institutes of Health (1 R01 CA79955-01). A.R.-G. is a scholarship holder from Consejo Superior Investigaciones Científicas (CSIC)-GLAXO.Peer reviewe