Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N10pN1 Generation Definitions   Donating Investigator Dr. Richard A. Flavell,   Yale University School of Medicine

Description
Homozygous Irak3 (interleukin-1 receptor-associated kinase 3; also called IRAK-M) deficient mice develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Mice also exhibit increased cytokine production upon TLR/IL1 stimulation and bacterial challenge, and show increased inflammatory responses to bacterial infection. Endotoxin tolerance is significantly reduced. Absence of gene expression was confirmed by Western blot using an antibody directed against the C terminus of the gene. Homozygotes are viable and fertile.

Development
The targeting vector was designed to replace a 1.2 kb region of the gene (containing three exons encoding two-thirds of the kinase domain) with a loxP-flanked neomycin resistance cassette. The targeting vector was linearized and electroporated into 129S1/Sv-derived W9.5 embryonic stem (ES) cells. Targeted clones were injected into C57BL/6 blastocysts and resulting chimeric males were bred to C57BL/6 females. Interbreeding of heterozygotes was performed to generate homozygotes. This line has been backcrossed to C57BL/6 eleven times by the donating laboratory.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Osteoporosis

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Asthma-Related Traits, Susceptibility to, 5   (IRAK3)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Irak3^tm1Flv/Irak3^tm1Flv

        involves: 129S1/Sv * C57BL/6

• immune system phenotype
• abnormal immune system morphology   (MGI Ref ID J:78189)
• • abnormal Peyer's patch morphology
    • shows hemorrhaging   (MGI Ref ID J:78189)
  • • enlarged Peyer's patches
      • grossly enlarged after infection with gram negative bacteria   (MGI Ref ID J:78189)
  • increased neutrophil cell number
    • increased numbers of polymorphonuclear cells found in Peyer's patches   (MGI Ref ID J:78189)
  • increased osteoclast cell number
    • increased numbers of osteoclasts per unit area of bone surface   (MGI Ref ID J:98035)
• abnormal inflammatory response   (MGI Ref ID J:78189)
• • increased susceptibility to endotoxin shock
    • decreased tolerance to endotoxin   (MGI Ref ID J:78189)
• abnormal innate immunity
  • enhanced innate immunity   (MGI Ref ID J:78189)
  • bacterial load not greatly increased in spleens of mice with bacterial infections   (MGI Ref ID J:78189)
• • abnormal osteoclast physiology
    • bone marrow macrophage have a reduced proliferation rate but fuse more rapidly   (MGI Ref ID J:98035)
    • osteoclasts are generated more rapidly and have more prolonged life spans   (MGI Ref ID J:98035)
• increased interleukin-12b secretion
  • increased amounts of Il12p40 produced by macrophage when challenged by either gram negative or gram positive bacteria   (MGI Ref ID J:78189)
• increased interleukin-6 secretion
  • increased amounts produced by macrophage when challenged by either gram negative or gram positive bacteria   (MGI Ref ID J:78189)
• increased tumor necrosis factor secretion
  • increased amounts produced by macrophage when challenged by gram negative bacteria   (MGI Ref ID J:78189)
• skeleton phenotype
• abnormal compact bone morphology
  • lower cortical bone content at 4 months of age in the femur   (MGI Ref ID J:98035)
• • decreased compact bone thickness
    • cortical thickness of the femur reduced in males   (MGI Ref ID J:98035)
• abnormal osteoclast physiology
  • bone marrow macrophage have a reduced proliferation rate but fuse more rapidly   (MGI Ref ID J:98035)
  • osteoclasts are generated more rapidly and have more prolonged life spans   (MGI Ref ID J:98035)
• abnormal trabecular bone morphology
  • trabecular bone content at epiphyses reduced   (MGI Ref ID J:98035)
• • decreased trabecular bone volume
    • 60% reduction in trabecular bone volume   (MGI Ref ID J:98035)
• decreased diameter of femur
  • decreased diameter of the femur in both sexes   (MGI Ref ID J:98035)
• increased osteoblast cell number
  • increased numbers of osteoblasts seen in males   (MGI Ref ID J:98035)
• increased osteoclast cell number
  • increased numbers of osteoclasts per unit area of bone surface   (MGI Ref ID J:98035)
• kyphosis
  • develops by 4 months of age   (MGI Ref ID J:98035)
• growth/size phenotype
• decreased body size
  • by 4 months of age   (MGI Ref ID J:98035)
• hematopoietic system phenotype
• increased neutrophil cell number
  • increased numbers of polymorphonuclear cells found in Peyer's patches   (MGI Ref ID J:78189)
• increased osteoclast cell number
  • increased numbers of osteoclasts per unit area of bone surface   (MGI Ref ID J:98035)
• limbs/digits/tail phenotype
• decreased diameter of femur
  • decreased diameter of the femur in both sexes   (MGI Ref ID J:98035)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Immunology, Inflammation and Autoimmunity Research
Growth Factors/Receptors/Cytokines
Inflammation

Internal/Organ Research
Skeleton
      Bone

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Irak3tm1Flv
Allele Name		targeted mutation 1, Richard A Flavell
Allele Type		Targeted (knock-out)
Common Name(s)		IRAK-M-;
Mutation Made By		Dr. Richard Flavell,   Yale University School of Medicine
Strain of Origin		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
ES Cell Line Name		W9.5/W95
ES Cell Line Strain		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Gene Symbol and Name		Irak3, interleukin-1 receptor-associated kinase 3
Chromosome		10
Gene Common Name(s)		4833428C18Rik; AI563835; ASRT5; IRAK-M; IRAKM; RIKEN cDNA 4833428C18 gene; expressed sequence AI563835;
Molecular Note		1.2 kb of sequence were replaced with a floxed neo cassette. The deleted region contained 3 exons encoding two thirds of the kinase domain. While Western blot analysis of LPS-stimulated bone marrow macrophage extracts using a carboxy terminal antibody confirmed the absence of normal protein in homozygous mutant mice, truncated transcript was detected by Northern blot analysis using an amino terminal probe. Sequence analysis of RT-PCR products revealed an in frame stop codon generated by aberrant splicingof the endogenous gene and the neo transgene. [MGI Ref ID J:78189]

Genotyping

Genotyping Information

Genotyping Protocols

Irak3^tm1Flv, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Kobayashi K; Hernandez LD; Galan JE; Janeway CA Jr; Medzhitov R; Flavell RA. 2002. IRAK-M is a negative regulator of Toll-like receptor signaling. Cell 110(2):191-202. [PubMed: 12150927]  [MGI Ref ID J:78189]

Additional References

Irak3^tm1Flv related

Arranz A; Androulidaki A; Zacharioudaki V; Martinez C; Margioris AN; Gomariz RP; Tsatsanis C. 2008. Vasoactive intestinal peptide suppresses toll-like receptor 4 expression in macrophages via Akt1 reducing their responsiveness to lipopolysaccharide. Mol Immunol 45(10):2970-80. [PubMed: 18336909]  [MGI Ref ID J:134468]

Ballinger MN; Newstead MW; Zeng X; Bhan U; Horowitz JC; Moore BB; Pinsky DJ; Flavell RA; Standiford TJ. 2012. TLR signaling prevents hyperoxia-induced lung injury by protecting the alveolar epithelium from oxidant-mediated death. J Immunol 189(1):356-64. [PubMed: 22661086]  [MGI Ref ID J:188940]

Biswas A; Wilmanski J; Forsman H; Hrncir T; Hao L; Tlaskalova-Hogenova H; Kobayashi KS. 2011. Negative regulation of Toll-like receptor signaling plays an essential role in homeostasis of the intestine. Eur J Immunol 41(1):182-94. [PubMed: 21182089]  [MGI Ref ID J:174655]

Deng JC; Cheng G; Newstead MW; Zeng X; Kobayashi K; Flavell RA; Standiford TJ. 2006. Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M. J Clin Invest 116(9):2532-42. [PubMed: 16917541]  [MGI Ref ID J:114453]

Hubbard LL; Ballinger MN; Thomas PE; Wilke CA; Standiford TJ; Kobayashi KS; Flavell RA; Moore BB. 2010. A role for IL-1 Receptor-associated kinase-M in Prostaglandin E(2)-induced immunosuppression post-bone marrow transplantation. J Immunol 184(11):6299-308. [PubMed: 20439918]  [MGI Ref ID J:161218]

Li H; Cuartas E; Cui W; Choi Y; Crawford TD; Ke HZ; Kobayashi KS; Flavell RA; Vignery A. 2005. IL-1 receptor-associated kinase M is a central regulator of osteoclast differentiation and activation. J Exp Med 201(7):1169-77. [PubMed: 15809356]  [MGI Ref ID J:98035]

Lyn-Kew K; Rich E; Zeng X; Wen H; Kunkel SL; Newstead MW; Bhan U; Standiford TJ. 2010. IRAK-M regulates chromatin remodeling in lung macrophages during experimental sepsis. PLoS One 5(6):e11145. [PubMed: 20585389]  [MGI Ref ID J:162015]

Seki M; Kohno S; Newstead MW; Zeng X; Bhan U; Lukacs NW; Kunkel SL; Standiford TJ. 2010. Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia. J Immunol 184(3):1410-8. [PubMed: 20042589]  [MGI Ref ID J:159499]

Su J; Xie Q; Wilson I; Li L. 2007. Differential regulation and role of interleukin-1 receptor associated kinase-M in innate immunity signaling. Cell Signal 19(7):1596-601. [PubMed: 17379480]  [MGI Ref ID J:148060]

Turnis ME; Song XT; Bear A; Foster AE; Gottschalk S; Brenner MK; Chen SY; Rooney CM. 2010. IRAK-M removal counteracts dendritic cell vaccine deficits in migration and longevity. J Immunol 185(7):4223-32. [PubMed: 20817880]  [MGI Ref ID J:164297]

Xie Q; Gan L; Wang J; Wilson I; Li L. 2007. Loss of the innate immunity negative regulator IRAK-M leads to enhanced host immune defense against tumor growth. Mol Immunol 44(14):3453-61. [PubMed: 17477969]  [MGI Ref ID J:123571]

Health & husbandry

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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