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Genetic basis of hypo-responsiveness of A/J mice to interleukin-3
KB Leslie, S Jalbert, P Orban, M Welham, V Duronio and JW Schrader
Biomedical Research Centre, University of British Columbia, Vancouver,
Canada.
Hematopoietic progenitor cells of the A/J strain of mice show a pronounced
defect in the ability to form colonies or proliferate in response to
interleukin-3 (IL-3). Comparison of immunoblots of A/J mast cells and of
mast cells from the C57BL/6 strain that respond normally to IL-3 showed
that, in both strains, a 125-kD band of the expected size was recognized by
an antibody against the beta chain of the IL-3 receptor, the AIC2A
molecule. However, in the C57BL/6 cells, there was an additional 110-kD
species not seen in cells of the A/J strain. Analyses using bone
marrow-derived mast cells from a panel of A/J x C57BL/6 and A/J x C57BL/6
recombinant inbred (RI) mice showed that the hypo-responsiveness to IL-3 is
governed by a single gene. However, the absence of this 110-kD species in
the A/J strain did not co-map with IL- 3 hypo-responsiveness but did indeed
map to the AIC2A genetic locus. These data show that this trait in the A/J
strain was due to a polymorphism of the AIC2A gene unrelated to IL-3
hypo-responsiveness. Typing of the RI strains for the markers D14Mit98,
D14Mitl4, and D14Mit133 mapped the locus determining hypo-responsiveness to
IL-3 to the subtelomeric region of chromosome 14, the region that also
bears the gene encoding the alpha chain of the IL-3 receptor (lL-3Ralpha).
Immunofluorescence analyses indicated that IL-3Ralpha protein was
undetectable on fresh bone marrow cells from A/J mice, although clearly
detectable on cells from the responder C57BL/6 strain. However, IL- 3Ralpha
was readily detectable at normal levels on A/J mast cells generated by
culture of A/J bone marrow cells in a combination of IL-3 and steel factor.
Moreover, IL-3Ralpha on these A/J mast cells appears to be functional in
that IL-3 stimulation of these cells results in tyrosine phosphorylation
events characteristic of IL-3 signaling, including tyrosine phosphorylation
of the beta chain of the IL-3 receptor, Jak-2 kinase, and SHPTP2.
Collectively, these data indicate that the hypo-responsiveness of A/J mice
to IL-3 is due to a defect in the gene encoding IL-3Ralpha and that,
although this defect gives rise to reduced expression of alpha chain on
primary bone marrow cells, this defect is not absolute and that, under
certain circumstances, A/J cells can express functional receptors.
Volume 87,
Issue 8,
pp. 3186-3194,
04/15/1996
Copyright © 1996 by The American Society of Hematology
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