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Blood, Vol. 94 No. 6 (September 15), 1999:
pp. 1915-1925
The Presence of Novel Amino Acids in the Cytoplasmic Domain of Stem
Cell Factor Results in Hematopoietic Defects in
Steel17H Mice
Reuben Kapur,
Ryan Cooper,
Xingli Xiao,
Mitchell J. Weiss,
Peter Donovan, and
David A. Williams
From The Section of Pediatric Hematology/Oncology, Department of
Pediatrics, Herman B Wells Center for Pediatric Research, James
Whitcomb Riley Hospital for Children, Indiana University School of
Medicine, The Howard Hughes Medical Institute, Indiana University
School of Medicine, Indianapolis, IN; Ontogeny, Inc, Cambridge, MA; and
Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.
Stem cell factor (SCF) is expressed as an integral membrane growth
factor that may be differentially processed to produce predominantly
soluble (S) (SCF248) or membrane-associated (MA)
(SCF220) protein. A critical role for membrane presentation
of SCF in the hematopoietic microenvironment (HM) has been suggested
from the phenotype of the Steel-dickie
(Sld) mice, which lack MA SCF, and by studies
performed in our laboratory (and by others) using long-term bone marrow
cultures and transgenic mice expressing different SCF isoforms.
Steel17H (Sl17H) is an SCF
mutant that demonstrates melanocyte defects and sterility in males but
not in females. The Sl17H allele contains a
intronic mutation resulting in the substitution of 36 amino acids
(aa's) in the SCF cytoplasmic domain with 28 novel aa's. This
mutation, which affects virtually the entire cytoplasmic domain of SCF,
could be expected to alter membrane SCF presentation. To investigate
this possibility, we examined the biochemical and biologic properties
of the Sl17H-encoded protein and its impact in vivo
and in vitro on hematopoiesis and on c-Kit signaling. We demonstrate
that compound heterozygous Sl/Sl17H mice manifest
multiple hematopoietic abnormalities in vivo, including red blood cell
deficiency, bone marrow hypoplasia, and defective thymopoiesis. In
vitro, both S and MA Sl17H isoforms of SCF exhibit
reduced cell surface expression on stromal cells and diminished
biological activity in comparison to wild-type (wt) SCF isoforms. These
alterations in presentation and biological activity are associated with
a significant reduction in the proliferation of an SCF-responsive
erythroid progenitor cell line and in the activation of
phosphatidylinositol 3-Kinase/Akt and mitogen-activated protein-Kinase signaling pathways. In vivo, transgene
expression of the membrane-restricted (MR) (SCFX9/D3) SCF
in Sl/Sl17H mutants results in a significant
improvement in peripheral red blood cell counts in comparison to
Sl/Sl17H mice.
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