Strain Detail Sheet

Strain Name    :

B6.129S2-Ifnar1tm1Agt/Mmjax

Stock Number :

032045-JAX

Gene Information

Gene Details [Including genotyping protocols]

(provided by MGI)
Allele Symbol: Ifnar1tm1Agt
Name: targeted mutation 1, Michel Aguet
Alteration at locus: Knockout
Gene Symbol: Ifnar1
Name: interferon (alpha and beta) receptor 1
Chromosome: 16
Alteration at locus: Knockout

Genetic Alterations:

Genotype Determination:

ES Cell Line: D3

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

Phenotype

Homozygous phenotype: Mice that are homozygous for the targeted mutation are viable, fertile, and normal in size. No gene product (mRNA) is detected by Northern blot analysis of homozygous primary embryonic fibroblasts. Mice that are homozygous for this targeted allele lack type I IFN receptor function, exhibit enhanced osteoclastogenesis with decreased bone density, and impaired response to protozoan parasite (Leishmania) infection. NK cell mediated tumor regression does not occur in homozygotes in response to B16 melanoma tumor implant model.

Heterozygous phenotype:


Mammalian Phenotype Terms:(provided by MGI)      Extend all MPTs
      assigned by genotype
Ifnar1tm1Agt/Ifnar1tm1Agt
        B6.129S2-Ifnar1<tm1Agt>
  • immune system phenotype
    • abnormal osteoclast morphology (MGI Ref ID J:76097)
      • osteoclastogenesis is enhanced
    • abnormal response to infection (MGI Ref ID J:116703)
      • murine cytomegalovirus replication in macrophages is increased greater than 10,000-fold compared to that in wild-type macrophages
    • decreased interferon-alpha secretion (MGI Ref ID J:125611)
      • following infection with Leishmania
    • decreased interferon-beta secretion (MGI Ref ID J:125611)
      • following infection with Leishmania
    • impaired NK cell cytolysis (MGI Ref ID J:118750)
      • natural killer cells from polyI:C-treated mice do not display cytotoxicity towards B16 melanoma cells
  • tumorigenesis
    • increased tumor growth/size (MGI Ref ID J:118750)
      • in mice treated with polyI:C the reduction in tumor growth of injected B16 melanoma cells is less than in polyI:C treated control mice
  • hematopoietic system phenotype
    • abnormal osteoclast morphology (MGI Ref ID J:76097)
      • osteoclastogenesis is enhanced
  • skeleton phenotype
    • abnormal osteoc last morphology (MGI Ref ID J:76097)
      • osteoclastogenesis is enhanced
    • decreased bone mineral density (MGI Ref ID J:76097)


The following phenotype information may relate to one or more alleles on a genetic background differing from this MMRRC strain.
Ifnar1tm1Agt/Ifnar1tm1Agt
        involves: 129S2/SvPas
  • mortality/aging
    • increased susceptibility to viral infection induced morbidity/mortality (MGI Ref ID J:115139)
      • MCMV-treated mice exhibit a 800-fold lower LD50 compared with similarly treated wild-type mice
  • immune system phenotype
    • abnormal NK cell physiology (MGI Ref IDs J:79552, J:139001)
      • NK cells in vivo make much about a fifth less IFN-gamma in response to injections of the TLR9 agonist CpG (MGI Ref ID J:139001)
      • there is 50% less actively proliferating NK cells in the spleen after MCMV infection compared to controls (MGI Ref ID J:79552)
      • impaired NK cell cytolysis (MGI Ref ID J:79552)
        • NK cells from MCMV-infected mice have 10-fold less cytotoxicity than wild-type NK cells
    • abnormal cytokine secretion (MGI Ref ID J:114555)
      • upon viral infection, interferon alpha induction is normal initially, but in later phases does not reach wild-type levels
    • abnormal dendritic cell physiology (MGI Ref ID J:114555)
      • in mutant dendritic cells, induction of MHC and costimulatory molecules does not occur in response poly(I:C), in contrast to wild-type cells; LPS or CpG-dependent induction of MHC I and costimulatory molecules is also suppressed
      • Ifn beta stimulation of dendritic cells elicits a significantly lower response in mutant cells than in wild-type
      • amplification of dendritic signaling is suppressed in mutant dendritic cells stimulated with poly(I:C); RelA activation is suppressed
      • induction of MHC and costimulatory molecules is abolished in dendritic cells upon infection with Newcastle disease virus (NDC)
      • maturation of dendritic cells is impaired when stimulated by poly(I:C), LPS or NDV, but migration in T cell zone of spleen is not affected
      • stimulatory activity of CD4+ and CD8+ T cells by poly(I:C) is impaired in poly(I:C)-stimulated mutant dendritic cells; stimulatory activity of CD8+ T cells is impaired in the LPS- or CpG-stimulated dendritic cells to a lesser extent than in poly(I:C)-stimulated cells
    • abnormal immunoglobulin level (MGI Ref ID J:101427)
      • levels of IgG1a, IgG2a and IgG2b neutralizing antibodies are reduced relative to controls after secondary infection with Ectromelia virus
    • abnormal inflammatory response (MGI Ref ID J:114555)
      • in mutant dendritic cells, induction of MHC and costimulatory molecules does not occur in response poly(I:C), in contrast to wild-type cells; LPS or CpG-dependent induction of MHC I and costimulatory molecules is also suppressed
      • MHC I induction is severely impaired in response to all three stimuli
    • increased susceptibility to viral infection (MGI Ref IDs J:101427, J:137522, J:81243)
      • mice are 100-fold more susceptible to MCMV viral infection than controls (MGI Ref ID J:81243)
      • increased susceptibility of encephalomyocarditis virus induced lethality (MGI Ref ID J:137522)
      • increased susceptibility to Ectromelia virus (MGI Ref ID J:101427)
      • 100% mortality by day 6-12 after primary infection infection (MGI Ref ID J:101427)
      • elevated virus titers in all organs tested after primary infection but much improved after secondary infections (MGI Ref ID J:101427)
      • survive secondary infections (MGI Ref ID J:101427)
      • increased susceptibility to viral infection induced morbidity/mortality (MGI Ref ID J:115139)
        • MCMV-treated mice exhibit a 800-fold lower LD50 compared with similarly treated wild-type mice
  • vision/eye phenotype
    • corneal vascularization (MGI Ref ID J:114973)
      • corneal injection of a plasmid encoding short hairpin RNA targeting the C terminus of the secreted form of Flt1 (pshRNA-sflt1) induces corneal vascularization within 3 days of injection in wild-type and mutant mice
  • cardiovascular system phenotype
    • corneal vascularization (MGI Ref ID J:114973)
      • corneal injection of a plasmid encoding short hairpin RNA targeting the C terminus of the secreted form of Flt1 (pshRNA-sflt1) induces corneal vascularization within 3 days of injection in wild-type and mutant mice
Ifnar1tm1Agt/Ifnar1tm1Agt
        involves: 129S2/SvPas * 129S6/SvEvTac
  • immune system phenotype
    • abnormal CD8-positive T cell physiology (MGI Ref ID J:54482)
      • the antigen specificity of CD8 T cells to common LCMV-derived peptides differs from controls with a higher percentage being specific for the GP33-41 peptide
    • abnormal interferon-gamma secretion (MGI Ref ID J:54482)
      • splenic leukocyte production of IFN-gamma is increased 3-fold 8 days after infection with LCMV compared to controls
      • two-thirds of this IFN-gamma production is dependent on CD8 T cells
      • these T cells produce less IFN-gamma on a per cell basis
    • increased circulating interleukin-12 level (MGI Ref ID J:54482)
      • 3-4 pg/ml of IL-12 heterodimer are present in the serum 1.5- and 3- days after infection with LCMV while no IL-12 is detected at this timepoint in wild-type mice
    • increased susceptibility to viral infection (MGI Ref ID J:54482)
      • mice have a 2-log higher viral titer in the spleen, and a 4-log higher viral titer in the liver, 4.5 days after infection with LCMV virus
      • mice took much longer to clear virus, around 28 days, compared to 7 days for wild-type mice
  • homeostasis/metabolism phenotype
    • increased circulating interleukin-12 level (MGI Ref ID J:54482)
      • 3-4 pg/ml of IL-12 heterodimer are present in the serum 1.5- and 3- days after infection with LCMV while no IL-12 is detected at this timepoint in wild-type mice
Ifnar1tm1Agt/Ifnar1tm1Agt
        involves: 129S2/SvPas * BALB/c * C57BL/6 * SJL
  • immune system phenotype
    • increased susceptibility to viral infection (MGI Ref ID J:119783)
      • mice infected with Thogoto virus all succumb within 3 days compared to 5 days for littermate controls
Ifnar1tm1Agt/Ifnar1tm1Agt
        involves: 129S2/SvPas * C57BL/6
  • immune system phenotype
    • altered susceptibility to infection (MGI Ref ID J:120938)
      • infection with hvPR8 produces high titers of 5x107
      • infection with lvPR8 produces low titers of 5x104

Strain Development: A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exon 3. The construct was electroporated into 129S2/SvPas derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The mice were backcrossed to C57BL/6 for at least 5 generations, as reported by the donating investigator.

Suggested Control Mice: Wild-type littermates

Research Applications

    Strain Origin

    Donor: Michel Aguet, Ph.D., Swiss Inst. for Experimental Cancer Res.

    Primary Reference:

    Muller U; Steinhoff U; Reis LF; Hemmi S; Pavlovic J; Zinkernagel RM; Aguet M, Functional role of type I and type II interferons in antiviral defense., Science 1994 Jun 24;264(5167):1918-21 (Medline PMID: 8009221)

    Colony and Husbandry Information

    Special Considerations

    When maintaining a live colony, these mice can be bred as homozygotes. SPF conditions are recommended.

    Health Status Report

    Colony's Current Health Status Report

    For more information about this colony's health status contact csmmrrc@jax.org

    Order Request Information

    Availability Level

    Limited quantities of breeder mice (up to 2 males and 2 females or 4 mice) per investigator per month are available from a live colony, usually available to ship in under 12 weeks. Larger quantities may be available, please contact the distributing center directly at csmmrrc@jax.org for more details.

    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.

    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
    032045-JAX-HOM-FHomozygous female
    032045-JAX-HOM-MHomozygous male
    $218.00 / $571.00
    Non-Profit / For-Profit
    Per Mouse The csmmrrc@jax.org may assess additional fees for any special requests (e.g., specific age or weight of mice, etc.).

    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.



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