Description

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. Mating System Homozygote x Homozygote         (Female x Male)   23-AUG-06 Species laboratory mouse Generation N7+F6 (05-JAN-09) Generation Definitions   Donating Investigator Richard Flavell,   Yale University School of Medicine

Description
Homozygous mice are viable and fertile with normal lymphoid and myeloid cellularity and no intestinal inflammation up to 6 months of age. Homozygotes do not express the targeted gene in spleen or intestinal crypts. Null mice, as well as antigen presenting cells derived from them, lack the protective immunity (IgG1, interleukin-6, and NF-kappaB-related responses) normally afforded by endogenous protein recognition of its ligand, bacterial muramyl dipeptide (MDP). Mice homozygous for the mutation have increased susceptibility to oral (intragastric) bacterial challenge and diminished cryptdins. This mouse may be useful in studies of Crohn's disease and other inflammatory bowel diseases, innate immunity, signal transduction, and bacterial susceptibility.

Development
A targeting vector was designed to replace exon 3 of the endogenous gene (containing the second caspase recruitment domain (CARD) and nucleotide-binding oligomerization domain (NOD)) with a lox-P-flanked neomycin resistance gene. The construct was electroporated into 129S1/Sv-derived W9.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimeric males were bred to C57BL/6 females. The resulting heterozygotes were backcrossed to C57BL/6 mice for 6 generations before arrival at The Jackson Laboratory. Upon arrival, heterozygous males were bred to C57BL/6J for one generation and then maintained by crossing mutant mice.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

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

Nod2^tm1Flv/Nod2^tm1Flv

        involves: 129S1/Sv * C57BL/6

• immune system phenotype
• abnormal macrophage physiology
  • the synergistic effect of bacterial muramyl dipeptide and TLR ligands on the production of IL6 and IL12 is absent in mutant macrophages   (MGI Ref ID J:96035)
  • bone marrow derived macrophages produce less IL-6 and TNF when cultured in the presence of L. monocytogenes   (MGI Ref ID J:132126)
  • in macrophages pre-treated with TLR ligands (i.e. "tolerized"), macrophages produce significantly less inflammatory cytokines upon incubation with L. monocytogenes than controls that were LPS pre-treated   (MGI Ref ID J:132126)
• altered susceptibility to infection
  • homozygotes are more susceptible to Listeria monocytogenes infection via intragastric exposure but not via intraperitoneal or intravenous exposure   (MGI Ref ID J:96035)
  • however, no signs of intestinal inflammation and no difference in susceptibility to dextran sulfate induced colitis are seen   (MGI Ref ID J:96035)
• decreased IgG level
  • decreased antigen specific Ig and IgG1 production are seen following stimulation with bacterial muramyl dipeptide and HSA; however, production is normal when stimulated by HAS plus an artificial TLR7 ligand   (MGI Ref ID J:96035)
• decreased interleukin-6 secretion
  • bone marrow derived macrophages secrete 73% the amount of IL-6 as wild-type controls due in response to culturing with L. monocytogenes   (MGI Ref ID J:132126)
  • a similar relative reduction is observed when macrophages are pre-treated with LPS prior to L. monocytogenes incubation   (MGI Ref ID J:132126)
• decreased susceptibility to endotoxin shock
  • homozygotes are resistant to endotoxin shock produced by LPS following bacterial muramyl dipeptide priming but not to endotoxin shock produced by LPS alone   (MGI Ref ID J:96035)
• decreased tumor necrosis factor secretion
  • bone marrow derived macrophages secrete 77% the amount of TNF as wild-type controls in response to culturing with L. monocytogenes   (MGI Ref ID J:132126)
  • TNF secretion is 57% that of controls when macrophages are pre-treated with LPS prior to L. monocytogenes incubation   (MGI Ref ID J:132126)

View Research Applications

Research Applications

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

Cell Biology Research
Signal Transduction

Hematological Research
Immunological Defects

Immunology and Inflammation Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
      genes regulating susceptibility to infectious disease and endotoxin
Immunodeficiency
      Inflammatory bowel disease
      Tlr deficiency
      defects in humoral immune responses
Inflammation
      Inflammatory bowel disease
      Tlr deficiency
Intracellular Signaling Molecules

Research Tools
Genetics Research
      Mutagenesis and Transgenesis: transcriptional activation
Immunology and Inflammation Research
      Macrophage Deficiency

Genes & Alleles

Gene & Allele Information

Allele Symbol		Nod2tm1Flv
Allele Name		targeted mutation 1, Richard A Flavell
Allele Type		Targeted (knock-out)
Common Name(s)		Nod2-;
Mutation Made By		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		Nod2, nucleotide-binding oligomerization domain containing 2
Chromosome		8
Gene Common Name(s)		ACUG; BLAU; CARD15; CD; CLR16.3; Card15; F830032C23Rik; IBD1; NLRC2; NOD2B; PSORAS1; RIKEN cDNA F830032C23 gene; caspase recruitment domain family, member 15;
Molecular Note		A loxP-flanked neo replaced exon 3, encoding the CARD domain and P-loop of the NOD domain. Spleens of mutant animals demonstrated a lack of protein by immunoblot analysis. [MGI Ref ID J:96035]

Genotyping

Genotyping Information

Genotyping Protocols

Nod2^tm1Flv, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Kobayashi KS; Chamaillard M; Ogura Y; Henegariu O; Inohara N; Nunez G; Flavell RA. 2005. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307(5710):731-4. [PubMed: 15692051]  [MGI Ref ID J:96035]

Additional References

Nod2^tm1Flv related

Chauhan VS; Sterka DG Jr; Furr SR; Young AB; Marriott I. 2009. NOD2 plays an important role in the inflammatory responses of microglia and astrocytes to bacterial CNS pathogens. Glia 57(4):414-23. [PubMed: 18803303]  [MGI Ref ID J:156220]

Chung SW; Liu X; Macias AA; Baron RM; Perrella MA. 2008. Heme oxygenase-1-derived carbon monoxide enhances the host defense response to microbial sepsis in mice. J Clin Invest 118(1):239-47. [PubMed: 18060048]  [MGI Ref ID J:130827]

Clarke TB; Davis KM; Lysenko ES; Zhou AY; Yu Y; Weiser JN. 2010. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 16(2):228-31. [PubMed: 20081863]  [MGI Ref ID J:157078]

Deshmukh HS; Hamburger JB; Ahn SH; McCafferty DG; Yang SR; Fowler VG Jr. 2009. Critical role of NOD2 in regulating the immune response to Staphylococcus aureus. Infect Immun 77(4):1376-82. [PubMed: 19139201]  [MGI Ref ID J:147177]

Divangahi M; Mostowy S; Coulombe F; Kozak R; Guillot L; Veyrier F; Kobayashi KS; Flavell RA; Gros P; Behr MA. 2008. NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity. J Immunol 181(10):7157-65. [PubMed: 18981137]  [MGI Ref ID J:140937]

Kanneganti TD; Lamkanfi M; Kim YG; Chen G; Park JH; Franchi L; Vandenabeele P; Nunez G. 2007. Pannexin-1-mediated recognition of bacterial molecules activates the cryopyrin inflammasome independent of Toll-like receptor signaling. Immunity 26(4):433-43. [PubMed: 17433728]  [MGI Ref ID J:123579]

Kim YG; Park JH; Shaw MH; Franchi L; Inohara N; Nunez G. 2008. The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity 28(2):246-57. [PubMed: 18261938]  [MGI Ref ID J:132126]

Loving CL; Osorio M; Kim YG; Nunez G; Hughes MA; Merkel TJ. 2009. Nod1/Nod2-mediated recognition plays a critical role in induction of adaptive immunity to anthrax after aerosol exposure. Infect Immun 77(10):4529-37. [PubMed: 19620350]  [MGI Ref ID J:153262]

Marina-Garcia N; Franchi L; Kim YG; Miller D; McDonald C; Boons GJ; Nunez G. 2008. Pannexin-1-Mediated Intracellular Delivery of Muramyl Dipeptide Induces Caspase-1 Activation via Cryopyrin/NLRP3 Independently of Nod2. J Immunol 180(6):4050-7. [PubMed: 18322214]  [MGI Ref ID J:132931]

McWhirter SM; Barbalat R; Monroe KM; Fontana MF; Hyodo M; Joncker NT; Ishii KJ; Akira S; Colonna M; Chen ZJ; Fitzgerald KA; Hayakawa Y; Vance RE. 2009. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J Exp Med 206(9):1899-911. [PubMed: 19652017]  [MGI Ref ID J:152182]

Pan Q; Mathison J; Fearns C; Kravchenko VV; Da Silva Correia J; Hoffman HM; Kobayashi KS; Bertin J; Grant EP; Coyle AJ; Sutterwala FS; Ogura Y; Flavell RA; Ulevitch RJ. 2007. MDP-induced interleukin-1{beta} processing requires Nod2 and CIAS1/NALP3. J Leukoc Biol 82(1):177-83. [PubMed: 17403772]  [MGI Ref ID J:122657]

Park JH; Kim YG; McDonald C; Kanneganti TD; Hasegawa M; Body-Malapel M; Inohara N; Nunez G. 2007. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J Immunol 178(4):2380-6. [PubMed: 17277144]  [MGI Ref ID J:143980]

Penack O; Smith OM; Cunningham-Bussel A; Liu X; Rao U; Yim N; Na IK; Holland AM; Ghosh A; Lu SX; Jenq RR; Liu C; Murphy GF; Brandl K; van den Brink MR. 2009. NOD2 regulates hematopoietic cell function during graft-versus-host disease. J Exp Med 206(10):2101-10. [PubMed: 19737867]  [MGI Ref ID J:153357]

Petnicki-Ocwieja T; Hrncir T; Liu YJ; Biswas A; Hudcovic T; Tlaskalova-Hogenova H; Kobayashi KS. 2009. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc Natl Acad Sci U S A 106(37):15813-8. [PubMed: 19805227]  [MGI Ref ID J:153244]

Rosenzweig HL; Jann MM; Glant TT; Martin TM; Planck SR; van Eden W; van Kooten PJ; Flavell RA; Kobayashi KS; Rosenbaum JT; Davey MP. 2009. Activation of nucleotide oligomerization domain 2 exacerbates a murine model of proteoglycan-induced arthritis. J Leukoc Biol 85(4):711-8. [PubMed: 19129483]  [MGI Ref ID J:146911]

Rosenzweig HL; Kawaguchi T; Martin TM; Planck SR; Davey MP; Rosenbaum JT. 2009. Nucleotide oligomerization domain-2 (NOD2)-induced uveitis: dependence on IFN-gamma. Invest Ophthalmol Vis Sci 50(4):1739-45. [PubMed: 19098321]  [MGI Ref ID J:146921]

Rosenzweig HL; Martin TM; Jann MM; Planck SR; Davey MP; Kobayashi K; Flavell RA; Rosenbaum JT. 2008. NOD2, the gene responsible for familial granulomatous uveitis, in a mouse model of uveitis. Invest Ophthalmol Vis Sci 49(4):1518-24. [PubMed: 18385071]  [MGI Ref ID J:136140]

Rosenzweig HL; Martin TM; Planck SR; Galster K; Jann MM; Davey MP; Kobayashi K; Flavell RA; Rosenbaum JT. 2008. Activation of NOD2 in vivo induces IL-1beta production in the eye via caspase-1 but results in ocular inflammation independently of IL-1 signaling. J Leukoc Biol 84(2):529-36. [PubMed: 18495787]  [MGI Ref ID J:138433]

Sabbah A; Chang TH; Harnack R; Frohlich V; Tominaga K; Dube PH; Xiang Y; Bose S. 2009. Activation of innate immune antiviral responses by Nod2. Nat Immunol 10(10):1073-80. [PubMed: 19701189]  [MGI Ref ID J:152795]

Zeuthen LH; Fink LN; Frokiaer H. 2008. Toll-like receptor 2 and nucleotide-binding oligomerization domain-2 play divergent roles in the recognition of gut-derived lactobacilli and bifidobacteria in dendritic cells. Immunology 124(4):489-502. [PubMed: 18217947]  [MGI Ref ID J:142781]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   23-AUG-06
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Induced Mutant Resource Colony collection.
• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

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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phone:	207-288-6470
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