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Blood, 15 August 2002, Vol. 100, No. 4, pp. 1274-1286
HEMATOPOIESIS
Zinc-finger transcription factor Slug contributes to the function
of the stem cell factor c-kit signaling pathway
Jesus Pérez-Losada,
Manuel Sánchez-Martín,
Arancha Rodríguez-García,
Maria Luz Sánchez,
Alberto Orfao,
Teresa Flores, and
Isidro Sánchez-García
From the Instituto de Biología Molecular y
Celular del Cáncer, Centro de Investigación del
Cáncer, Servicio de Citometría, and Servicio de
Anatomía Patológica, Universidad de Salamanca, Spain.
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.
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