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   Donating Investigator Dr. Richard A. Flavell,   Yale University School of Medicine

Description
Homozygotes are viable and fertile and do not display any gross physical or behavioral abnormalities. Cytokine production in macrophages is reduced upon stimulation with lipopolysaccharide, peptidoglycan and double-stranded RNA, but not with bacterial DNA. Deficient cells are also hyporesponsive to signalling through IL1 and IL18 interleukin receptors, and deficient for signalling through NOD (nucleotide-binding oligomerization domain) proteins. T cells show severely reduced NFKB (nuclear factor of kappa light chain gene enhancer in B-cells) activation, IL2 production and proliferation on T cell receptor (TCR) engagement, and impaired differentiation to T-helper subtype 1 (T_H1)cells. Western blot analysis of thymocytes demonstrates the absence of protein in homozygous mutant mice.

Development
A targeting vector was designed to replace a 4.0 kb genomic fragment (containing the second and third exons encoding the active site aspartate residue) with a loxP-flanked neomycin resistance cassette placed in the opposite orientation. The vector was linearized and injected into 129S1/Sv-derived W9.5 embryonic stem (ES) cells. Targeted clones were injected into C57BL/6 blastocysts. Resultant chimeric mice were backcrossed ten times by the donating laboratory.

Phenotype

Phenotype Information

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.

Ripk2^tm1Flv/Ripk2^tm1Flv

        involves: 129S1/Sv

• immune system phenotype
• abnormal T-helper 1 physiology
  • IFN-gamma production by T helper 1 cells reduced   (MGI Ref ID J:75400)
  • IFN-gamma production severely reduced after stimulation with either Il-18 or Il-12   (MGI Ref ID J:75400)
• abnormal cytokine secretion   (MGI Ref ID J:75400)
• • decreased interleukin-6 secretion
    • production by macrophages severely reduced after stimulation by ligands for some but not all Toll-like receptors   (MGI Ref ID J:75400)
    • production by thymocytes also reduced when stimulated by Il-1beta   (MGI Ref ID J:75400)
  • decreased tumor necrosis factor secretion
    • production by macrophages severely reduced after stimulation by ligands for some but not all Toll-like receptors   (MGI Ref ID J:75400)
• decreased T cell proliferation
  • reduced proliferation of thymocytes after Il-1beta stimulation   (MGI Ref ID J:75400)
• hematopoietic system phenotype
• decreased T cell proliferation
  • reduced proliferation of thymocytes after Il-1beta stimulation   (MGI Ref ID J:75400)
• cellular phenotype
• decreased T cell proliferation
  • reduced proliferation of thymocytes after Il-1beta stimulation   (MGI Ref ID J:75400)

Ripk2^tm1Flv/Ripk2^tm1Flv

        involves: 129S1/Sv * C57BL/6

• immune system phenotype
• abnormal macrophage physiology
  • 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)
• decreased interleukin-6 secretion
  • bone marrow derived macrophages secrete half the amount of IL-6 as wild-type controls in response to culturing with L. monocytogenes   (MGI Ref ID J:132126)
  • IL-6 secretion is 22% that of controls when macrophages are pre-treated with LPS prior to L. monocytogenes incubation   (MGI Ref ID J:132126)
  • bone marrow derived macrophages fail to produce IL-6 when pre-treated with LPS prior to NOD2 stimulation   (MGI Ref ID J:132126)
• decreased tumor necrosis factor secretion
  • bone marrow derived macrophages secrete 61% TNF as wild-type controls in response to culturing with L. monocytogenes   (MGI Ref ID J:132126)
  • IL-6 secretion is about 20% that of controls when macrophages are pre-treated with LPS or LTA prior to L. monocytogenes incubation   (MGI Ref ID J:132126)
  • bone marrow derived macrophages fail to produce TNF when pre-treated with LPS prior to NOD2 stimulation   (MGI Ref ID J:132126)

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
Intracellular Signaling Molecules

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ripk2tm1Flv
Allele Name		targeted mutation 1, Richard A Flavell
Allele Type		Targeted (knock-out)
Common Name(s)		RICK-; Rip2-;
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		Ripk2, receptor (TNFRSF)-interacting serine-threonine kinase 2
Chromosome		4
Gene Common Name(s)		2210420D18Rik; CARD3; CARDIAK; CCK; D4Bwg0615e; DNA segment, Chr 4, Brigham & Women's Genetics 0615 expressed; GIG30; RICK; RIKEN cDNA 2210420D18 gene; RIP2;
Molecular Note		The gene was disrupted by replacement of exons 2 and 3 with a neomycin resistance gene by homologous recombination. Absence of gene expression in homozygous mutant animals was confirmed by Western blot analysis of thymocyte extracts. [MGI Ref ID J:136572] [MGI Ref ID J:75400]

Genotyping

Genotyping Information

Genotyping Protocols

Ripk2^tm1Flv, Melt Curve Analysis
Ripk2^tm1Flv, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Kobayashi K; Inohara N; Hernandez LD; Galan JE; Nunez G; Janeway CA; Medzhitov R; Flavell RA. 2002. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416(6877):194-9. [PubMed: 11894098]  [MGI Ref ID J:75400]

Additional References

Ripk2^tm1Flv related

Anand PK; Tait SW; Lamkanfi M; Amer AO; Nunez G; Pages G; Pouyssegur J; McGargill MA; Green DR; Kanneganti TD. 2011. TLR2 and RIP2 Pathways Mediate Autophagy of Listeria monocytogenes via Extracellular Signal-regulated Kinase (ERK) Activation. J Biol Chem 286(50):42981-91. [PubMed: 22033934]  [MGI Ref ID J:178691]

Archer KA; Ader F; Kobayashi KS; Flavell RA; Roy CR. 2010. Cooperation between multiple microbial pattern recognition systems is important for host protection against the intracellular pathogen Legionella pneumophila. Infect Immun 78(6):2477-87. [PubMed: 20351139]  [MGI Ref ID J:159981]

Balamayooran T; Batra S; Balamayooran G; Cai S; Kobayashi KS; Flavell RA; Jeyaseelan S. 2011. Receptor-interacting protein 2 controls pulmonary host defense to Escherichia coli infection via the regulation of interleukin-17A. Infect Immun 79(11):4588-99. [PubMed: 21844230]  [MGI Ref ID J:177781]

Bertrand MJ; Doiron K; Labbe K; Korneluk RG; Barker PA; Saleh M. 2009. Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30(6):789-801. [PubMed: 19464198]  [MGI Ref ID J:149992]

Brandl K; Plitas G; Schnabl B; DeMatteo RP; Pamer EG. 2007. MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection. J Exp Med 204(8):1891-900. [PubMed: 17635956]  [MGI Ref ID J:125955]

Damgaard RB; Nachbur U; Yabal M; Wong WW; Fiil BK; Kastirr M; Rieser E; Rickard JA; Bankovacki A; Peschel C; Ruland J; Bekker-Jensen S; Mailand N; Kaufmann T; Strasser A; Walczak H; Silke J; Jost PJ; Gyrd-Hansen M. 2012. The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell 46(6):746-58. [PubMed: 22607974]  [MGI Ref ID J:188020]

Geddes K; Rubino S; Streutker C; Cho JH; Magalhaes JG; Le Bourhis L; Selvanantham T; Girardin SE; Philpott DJ. 2010. Nod1 and nod2 regulation of inflammation in the salmonella colitis model. Infect Immun 78(12):5107-15. [PubMed: 20921147]  [MGI Ref ID J:166072]

Hall HT; Wilhelm MT; Saibil SD; Mak TW; Flavell RA; Ohashi PS. 2008. RIP2 contributes to Nod signaling but is not essential for T cell proliferation, T helper differentiation or TLR responses. Eur J Immunol 38(1):64-72. [PubMed: 18085666]  [MGI Ref ID J:130818]

Hasegawa M; Fujimoto Y; Lucas PC; Nakano H; Fukase K; Nunez G; Inohara N. 2008. A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB activation. EMBO J 27(2):373-83. [PubMed: 18079694]  [MGI Ref ID J:130530]

Ippagunta SK; Malireddi RK; Shaw PJ; Neale GA; Walle LV; Fukui Y; Green DR; Lamkanfi M; Kanneganti TD. 2012. Addendum: defective Dock2 expression in a subset of ASC-deficient mouse lines. Nat Immunol 13(7):701-2. [PubMed: 22905357]  [MGI Ref ID J:187712]

Jacquet S; Nishino Y; Kumphune S; Sicard P; Clark JE; Kobayashi KS; Flavell RA; Eickhoff J; Cotten M; Marber MS. 2008. The role of RIP2 in p38 MAPK activation in the stressed heart. J Biol Chem 283(18):11964-71. [PubMed: 18310079]  [MGI Ref ID J:136572]

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]

Koch M; Mollenkopf HJ; Klemm U; Meyer TF. 2012. Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis. Proc Natl Acad Sci U S A 109(19):E1153-62. [PubMed: 22509021]  [MGI Ref ID J:184687]

Koh YS; Koo JE; Biswas A; Kobayashi KS. 2010. MyD88-dependent signaling contributes to host defense against ehrlichial infection. PLoS One 5(7):e11758. [PubMed: 20668698]  [MGI Ref ID J:163082]

Magalhaes JG; Lee J; Geddes K; Rubino S; Philpott DJ; Girardin SE. 2011. Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur J Immunol 41(5):1445-55. [PubMed: 21469090]  [MGI Ref ID J:175412]

Nachbur U; Vince JE; O'Reilly LA; Strasser A; Silke J. 2012. Is BID required for NOD signalling? Nature 488(7412):E4-6; discussion E6-8. [PubMed: 22914170]  [MGI Ref ID J:187146]

Nanda SK; Venigalla RK; Ordureau A; Patterson-Kane JC; Powell DW; Toth R; Arthur JS; Cohen P. 2011. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med 208(6):1215-28. [PubMed: 21606507]  [MGI Ref ID J:176826]

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]

Park JH; Kim YG; Nunez G. 2009. RICK promotes inflammation and lethality after gram-negative bacterial infection in mice stimulated with lipopolysaccharide. Infect Immun 77(4):1569-78. [PubMed: 19188356]  [MGI Ref ID J:147162]

Park JH; Kim YG; Shaw M; Kanneganti TD; Fujimoto Y; Fukase K; Inohara N; Nunez G. 2007. Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. J Immunol 179(1):514-21. [PubMed: 17579072]  [MGI Ref ID J:149411]

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]

Shaw PJ; Barr MJ; Lukens JR; McGargill MA; Chi H; Mak TW; Kanneganti TD. 2011. Signaling via the RIP2 Adaptor Protein in Central Nervous System-Infiltrating Dendritic Cells Promotes Inflammation and Autoimmunity. Immunity 34(1):75-84. [PubMed: 21236705]  [MGI Ref ID J:168072]

Stetson DB; Medzhitov R. 2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24(1):93-103. [PubMed: 16413926]  [MGI Ref ID J:113316]

Theivanthiran B; Batra S; Balamayooran G; Cai S; Kobayashi K; Flavell RA; Jeyaseelan S. 2012. NOD2 signaling contributes to host defense in the lungs against Escherichia coli infection. Infect Immun 80(7):2558-69. [PubMed: 22547547]  [MGI Ref ID J:186675]

Vieira SM; Cunha TM; Franca RF; Pinto LG; Talbot J; Turato WM; Lemos HP; Lima JB; Verri WA Jr; Almeida SC; Ferreira SH; Louzada-Junior P; Zamboni DS; Cunha FQ. 2012. Joint NOD2/RIPK2 signaling regulates IL-17 axis and contributes to the development of experimental arthritis. J Immunol 188(10):5116-22. [PubMed: 22491249]  [MGI Ref ID J:188682]

Wang XA; Deng S; Jiang D; Zhang R; Zhang S; Zhong J; Yang L; Wang T; Hong S; Guo S; She Z; Zhang XD; Li H. 2013. CARD3 deficiency exacerbates diet-induced obesity, hepatosteatosis, and insulin resistance in male mice. Endocrinology 154(2):685-97. [PubMed: 23321697]  [MGI Ref ID J:195886]

Yeretssian G; Correa RG; Doiron K; Fitzgerald P; Dillon CP; Green DR; Reed JC; Saleh M. 2011. Non-apoptotic role of BID in inflammation and innate immunity. Nature 474(7349):96-9. [PubMed: 21552281]  [MGI Ref ID J:172656]

Health & husbandry

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Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

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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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