Strain Detail Sheet

Strain Name    :

C57BL/6J-Flt3m1Btlr/Mmmh

Stock Number :

032824-MU

Gene Information

Gene Details [Including genotyping protocols]

(provided by MGI)
Allele Symbol: Flt3m1Btlr
Name: mutation 1, Bruce Beutler
Alteration at locus: Chemically Induced
Gene Symbol: Flt3
Name: FMS-like tyrosine kinase 3
Chromosome: 5
Alteration at locus: Chemically Induced

Genetic Alterations:
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.

Genotype Determination:

ES Cell Line: Not Applicable

Strain Description [Including phenotype, strain background, strain development and suggested control mice]

Phenotype

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.


Mammalian Phenotype Terms:(provided by MGI)      Extend all MPTs
      assigned by genotype
Flt3m1Btlr/Flt3m1Btlr
        C57BL/6-Flt3<m1Btlr>
  • mortality/aging
    • increased susceptibility to viral infection induced morbidity/mortality (MGI Ref ID J:159599)
      • 100% die due to mouse cytomegalovirus exposure
  • immune system phenotype
    • abnormal NK cell physiology (MGI Ref ID J:159599)
      • failure of CD69 upregulation 6 hours after mouse cytomegalovirus infection
    • abnormal dendritic cell physiology (MGI Ref ID J:159599)
      • abnormal cytokine responses of splenic DC populations in response to MCMV infection or stimulation by TLR7 or TLR9 ligands
      • abnormal dendritic cell antigen presentation (MGI Ref ID J:159599)
        • DCs show a moderate defect in an in vivo assay for T cell proliferation dependent on antigen cross presentation by DCs
    • abnormal macrophage physiology (MGI Ref ID J:105543)
      • the susceptibility of activated mutant macrophages to ex vivo vesicular stomatitis virus (VSV) infection was reversed by the addition of type I interferon
    • decreased NK cell number (MGI Ref ID J:159599)
      • splenic NK cells are reduced in percentage and number, bone marrow NK cells are only moderately reduced
    • decreased circulating interferon-alpha level (MGI Ref ID J:159599)
      • is moderately not significantly reduced in the serum
    • decreased circulating interferon-gamma level (MGI Ref ID J:159599)
    • decreased circulating interleukin-12 level (MGI Ref ID J:159599)
      • is moderately but not significantly reduced in the serum
    • decreased dendritic cell number (MGI Ref ID J:159599)
      • conventional DCs are reduced in bone marrow and spleen
      • decreased plasmacytoid dendritic cell number (MGI Ref ID J:159599)
        • both the number and percentage of pDCs are reduced in bone marrow and spleen
    • decreased interferon-alpha secretion (MGI Ref ID J:159599)
      • by splenic DC populations in response to MCMV infection or stimulation by TLR7 or TLR9 ligands
    • decreased interferon-gamma secretion (MGI Ref ID J:159599)
      • a reduced percentage of NK cells produced IFN-gamma 24 hours after mouse cytomegalovirus infection
    • decreased interleukin-12 secretion (MGI Ref ID J:159599)
      • by splenic DC populations in response to MCMV infection or stimulation by TLR7 or TLR9 ligands
    • decreased splenocyte number (MGI Ref ID J:159599)
      • spleens and lymph nodes are consistently smaller and show reduced cellularity
    • increased circulating interleukin-6 level (MGI Ref ID J:159599)
      • 36 hours after mouse cytomegalovirus infection
    • increased circulating tumor necrosis factor level (MGI Ref ID J:159599)
      • 36 hours after mouse cytomegalovirus infection
    • increased susceptibility to viral infection (MGI Ref ID J:105543)
      • mice are susceptible to infection by mouse cytomegalovirus (MCMV)
      • mice are severely ill and have high viral loads in the spleen five days following infection with MCMV
      • activated macrophages from these mice are susceptible to ex vivo VSV infection
      • increased susceptibility to viral infection induced morbidity/mortality (MGI Ref ID J:159599)
        • 100% die due to mouse cytomegalovirus exposure
    • small lymph nodes (MGI Ref ID J:159599)
  • hematopoietic system phenotype
    • decreased NK cell number (MGI Ref ID J:159599)
      • splenic NK cells are reduced in percentage and number, bone marrow NK cells are only moderately reduced
    • decreased dendritic cell number (MGI Ref ID J:159599)
      • conventional DCs are reduced in bone marrow and spleen
      • decreased plasmacytoid dendritic cell number (MGI Ref ID J:159599)
        • both the number and percentage of pDCs are reduced in bone marrow and spleen
    • decreased splenocyte number (MGI Ref ID J:159599)
      • spleens and lymph nodes are consistently smaller and show reduced cellularity
  • growth/size phenotype
    • decreased body weight (MGI Ref ID J:159599)
      • slightly smaller than wild-type
  • homeostasis/metabolism phenotype
    • decreased circulating interferon-alpha level (MGI Ref ID J:159599)
      • is moderately not significantly reduced in the serum
    • decreased circulating interferon-gamma level (MGI Ref ID J:159599)
    • decreased circulating interleukin-12 level (MGI Ref ID J:159599)
      • is moderately but not significantly reduced in the serum
    • increased circulating interleukin-6 level (MGI Ref ID J:159599)
      • 36 hours after mouse cytomegalovirus infection
    • increased circulating tumor necrosis factor level (MGI Ref ID J:159599)
      • 36 hours after mouse cytomegalovirus infection

Strain of Origin: 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:

  • Wildtype littermates

Research Applications

  • Immunology and Inflammation
  • Research Tools
  • Virology

Strain Origin

Donor: Bruce Beutler, M.D., The Scripps Research Institute

Primary Reference:

  • Eidenschenk, C., Crozat, K., Krebs, P., Arens, R., Popkin, D., Arnold, C. N., Blasius, A. L., Benedict, C. A., Moresco, E. M. Y., Xia, Y., and Beutler, B. (2010) Flt3 Permits Survival during Infection by Rendering Dendritic Cells Competent to Activate NK Cells. Proc Natl Acad Sci U S A. 2010 May 25;107(21):9759-64. (Medline PMID: 20457904)
  • For additional information see: Mutagenetix, a catalog of mutations identified in the Beutler Laboratory at The Scripps Research Institute.

Colony and Husbandry Information

Special Considerations

Random intra-strain mating.

Health Status Report

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@missouri.edu.

Order Request Information

Availability Level

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Conditions of Distribution [Including applicable technology transfer agreements]

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

The donor or their institution limits the distribution to non-profit institutions only.

Fees

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # - Description Distribution
Fee/unit (US $)
Units Notes
032824-MU-RESUSLitter recovered from cryo-archive
$2,022.00
Non-Profit
Litter Recovered litter1; additional fees for any special requests.

1 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

3 An aliquot contains a sufficient number of embryos (in one or more vials and based on the transfer success rate of the MMRRC facility) to transfer to at least two recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section above). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



The MMRRC is a collaborative effort, funded by grants from DPCPSI of the NIH.

This site requires JavaScript. Tested for Firefox 3.5+, Microsoft Internet Explorer 7+, Google Chrome.

Generated: 04/24/2014