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Vol. 12, No. 11, pp. 1610-1620, June 1, 1998
1 Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver, British Columbia V5Z 1L3, Canada;
2 Department
of Pathology and Laboratory Medicine, University of British Columbia,
Vancouver, British Columbia V6T 2B5, Canada;
3 Center for
Molecular Medicine and Therapeutics, University of British Columbia,
Vancouver, British Columbia V6T 1Z4, Canada;
4 Department of
Medicine, University of British Columbia, Vancouver,
British Columbia V6T 2B5, Canada
SHIP is a 145-kD SH2-containing
inositol-5-phosphatase widely expressed in
hemopoietic cells. It was first identified as a tyrosine phosphoprotein
associated with Shc in response to numerous cytokines. SHIP has been
implicated in Fc
RIIB receptor-mediated negative signaling in B cells
and mast cells and is postulated to down-regulate cytokine signal
transduction in myeloid cells. To define further its role in the
proliferation and differentiation of hemopoietic progenitors, as well
as its function in mature cells, we have generated embryonic stem cells
and mice bearing a targeted disruption of both SHIP alleles.
Here we show that although SHIP null mice are viable and fertile, they
fail to thrive and survival is only 40% by 14 weeks of age. Mortality
is associated with extensive consolidation of the lungs resulting from
infiltration by myeloid cells. Increased numbers of
granulocyte-macrophage progenitors are observed in both the bone
marrow and spleen of SHIP
/
mice, perhaps as a consequence of hyper-responsiveness to stimulation by macrophage-colony stimulating factor, granulocyte-macrophage colony stimulating factor, interleukin-3, or Steel factor as observed in vitro. In contrast, numbers of bone marrow lymphoid and late erythroid progenitors (CFU-E) are reduced. Thus, homozygous disruption of SHIP establishes the crucial role of this molecule in
modulating cytokine signaling within the hemopoietic system and
provides a powerful model for further delineating its function.
[Key Words: SHIP; hemopoiesis; embryonic stem cells; knockout; signal transduction]
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