Allele Symbol: Flt3m1Btlr
Name: mutation 1, Bruce Beutler
Alteration at locus: Chemically Induced
G to A transition at position 33572 of the Flt3 genomic sequence (Genbank genomic region NC_000071 for linear genomic sequence of Flt3). The mutation destroys the donor site of intron 9, and results in the usage of an alternative donor site six nucleotides away in exon 9. This causes the in-frame deletion of the last two amino acids (YS) from exon 9.
ES Cell Line: Not applicable
Homozygous phenotype: The warmflash (wmfl) phenotype was identified among ENU-mutagenized G3 mice in a screen for susceptibility to mouse cytomegalovirus (MCMV). 100% of wmfl homozygotes died when infected with 2 x 10^5 pfu of MCMV, a normally sublethal inoculum. Five days after infection with 10^5 pfu of MCMV wmfl homozygotes showed increased viral titers in the spleen and liver comparable to those observed in BALB/c mice. 36 hours post-MCMV infection, exaggerated production of tumor necrosis factor (TNF)-? and IL-6 were noticeable in the serum of wmfl homozygotes, possibly driven by an increased viral load. In contrast, the level of interferon (IFN)-? was significantly reduced, and levels of interleukin (IL)-12 p70 and type I IFN were moderately but not significantly reduced in the serum of wmfl mice relative to those of WT control mice. The wmfl mutation did not impair virus recognition or alter TLR-mediated signaling in macrophages in vitro. Wmfl homozygotes also failed to control lymphocytic choriomeningitis virus (LCMV) (clone 13) infection.
Wmfl homozygotes have reduced numbers of natural killer (NK) cells and dendritic cells (DCs). Wmfl NK cells are intrinsically capable of acquiring full functionality in response to activating stimuli in vitro and in vivo. However, wmfl DCs produce reduced amounts of IL-12p40, type I IFN, and surface IL-15R? relative to WT DCs infected with MCMV or stimulated with TLR7 or TLR9 ligands. Co-culture experiments indicated that wmfl DC-mediated NK cell activation was impaired in response to TLR ligands and MCMV infection. Thus, the principal defect underlying MCMV susceptibility caused by the Flt3^wmfl mutation appears to be an impaired ability of DCs to assist in the activation of NK cells, which exist in diminished numbers in homozygous wmfl mice.
Wmfl DCs display a moderate defect, similar in magnitude to that of DCs from Unc93b1^3d/3d mice, in an in vivo assay for T cell proliferation dependent on cross- presentation by DCs.
The spleens and lymph nodes, but not thymi, of wmfl homozygotes were consistently smaller and showed reduced cellularity compared to those of control mice. Wmfl homozygotes were also slightly smaller than control mice of equivalent age and sex.
Heterozygous phenotype: Wild type.
Founder genetic background: C57BL/6J
Strain genetic background: C57BL/6J
Strain Development: Original mutant was a C57BL/6J G3 ENU- induced mutant; all subsequent crosses to maintain strain were on C57BL/6J background only.
Suggested Control Mice:
Donor: Bruce Beutler, M.D., The Scripps Research Institute
Random intra-strain mating.
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