JAX Mouse Strain Datasheet - 006416

B6;129S1-Map2k3^tm1Flv/J

Stock No:: 006416 |; Mkk3-

Cryo Recovery

Overview

Also Known As: Mkk3-

These Map2k3 knock-out mice exhibit an impaired type I cytokine immune response.

Donating Investigator

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

Genetic overview

Genetic Background	Generation

Map2k3^tm1Flv

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Map2k3	mitogen-activated protein kinase kinase 3

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Research Applications

Immunology, Inflammation and Autoimmunity Research

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Base Price

Starting at:

$2,595.00 Domestic price Cryo Recovery

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Details

Detailed Description

Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. However, the donating investigator reports that reproductive performance is poor for unknown reasons. No gene product (mRNA or protein) is detected by Northern blot analysis of liver and kidney or Western blot analysis of peritoneal macrophages. Mutant mice exhibit an impaired type I cytokine immune response with reduced induced interferon gamma production. Macrophages from mutant mice have a reduced p39 MAPK activation and IL-12 production when challenged with LPS lipopolysaccharide). Dendritic cells also have reduced IL-12 production response. Mutant mouse embryo fibroblasts (MEF) have a reduced cytokine expression response to tumor necrosis factor (TNF). This mutant mouse strain may be useful in studies of inflammatory response.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exons 8 and 9. The construct was electroporated into 129S1/Sv-p⁺ Tyr⁺ Kitl⁺ derived W9.5 embryonic stem (ES) cells, and correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6N mice for at least 10 generations. Upon arriving at The Jackson Laboratory, the mice were crossed with C57BL/6J at least once to establish the colony.SNP (single nucleotide polymorphism) analysis performed by The Jackson Laboratory revealed that this strain is a mixed genetic background (5 out of 27 markers were segregating for non-C57BL/6 alleles).

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Lu HT; Yang DD; Wysk M; Gatti E; Mellman I; Davis RJ; Flavell RA. 1999. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 18(7):1845-57. PubMed: 10202148 MGI: J:54309
Wysk M; Yang DD; Lu HT; Flavell RA; Davis RJ. 1999. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Proc Natl Acad Sci U S A 96(7):3763-8. PubMed: 10097111 MGI: J:54078

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Genetics

Map2k3^tm1Flv

Allele Symbol: Map2k3^tm1Flv

Allele Name	targeted mutation 1, Richard A Flavell
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	MKK3 KO; Mkk3-
Gene Symbol and Name	Map2k3, mitogen-activated protein kinase kinase 3
Gene Synonym(s)	AW212142; MAP kinase kinase 3; MAPKK3; MEK3; MKK3; Mek3; Mkk3; PRKMK3; Prkmk3; Prkmk3; SAPKK-2; SAPKK2; expressed sequence AW212142; protein kinase, mitogen-activated, kinase 3
Strain of Origin	129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Chromosome	11
General Note	Homozygous mutant mice are viable and appear normal, healthy, and fertile with no defects in lymphocyte development (thymocytes, splenocytes, and bone-marrow derived dendritic cells). Compared to control sibs, however, macrophages and primary embryonic fibroblasts from mutant mice show reduced activation of p38 MAPK. Cytokine IL-12 (encoded for by Il12a and Il12b) is strongly reduced in mutant macrophages and dendritic cells. Mutant fibroblasts have a defective response to Tnf. Mutant mice also have defective T-helper cells with respect to the ability to produce Ifng in response to antigen stimulation of keyhole limpet hemocyanin (KLH) both in vitro and in vivo (J:54078, J:54309).
Molecular Note	A neomycin resistance cassette replaced a 1.5kb region that includes exons 8 and 9, which encode amino acids 217-221 of the protein. This region includes the sequences containing the dual phosphorylation sites (serine and threonine) that are required for activation of the protein. Northern blot and Western blot analyses did not detect expression from this allele in homozygous mutant mice.

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

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

Mammalian Phenotype Terms by Genotype

Genotype: Map2k3^tm1Flv/Map2k3^tm1Flv
B6.129S1-Map2k3^tm1Flv

mortality/aging

increased sensitivity to induced morbidity/mortality
- following infection with S. pneumoniae wild-type lysate and S. pneumoniae pneumolysin (PLY), mice begin to die within hours of infection and all mice are dead by 6 hours
- following infection with live Streptococcus pneumoniae, 80% of mice are dead by day 5 and 100% at day 7 compared to 25% and 66% at the same time points for infected wild-type mice

immune system phenotype

increased susceptibility to bacterial infection
- following infection with S. pneumoniae wild-type lysate and S. pneumoniae pneumolysin (PLY), mice begin to die within hours of infection and all mice are dead by 6 hours
- following infection with S. pneumoniae, mice exhibit more massive alveolar hemorrhage compared to infected wild-type mice
- following infection with live Streptococcus pneumoniae, 80% of mice are dead by day 5 and 100% at day 7 compared to 25% and 66% at the same time points for infected wild-type mice

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Map2k3^tm1Flv/Map2k3^tm1Flv
involves: 129S1/Sv

immune system phenotype

abnormal CD4-positive, alpha-beta T cell physiology
- CD4+T cells are resistant to activation-induced cell death and cytokine-withdrawal-induced apoptosis

decreased T cell apoptosis
- CD4+T cells are resistant to activation-induced cell death and cytokine-withdrawal-induced apoptosis

cellular phenotype

decreased T cell apoptosis
- CD4+T cells are resistant to activation-induced cell death and cytokine-withdrawal-induced apoptosis

hematopoietic system phenotype

abnormal CD4-positive, alpha-beta T cell physiology
- CD4+T cells are resistant to activation-induced cell death and cytokine-withdrawal-induced apoptosis

decreased T cell apoptosis
- CD4+T cells are resistant to activation-induced cell death and cytokine-withdrawal-induced apoptosis

References

Lu HT; Yang DD; Wysk M; Gatti E; Mellman I; Davis RJ; Flavell RA. 1999. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J 18(7):1845-57. PubMed: 10202148 MGI: J:54309
Wysk M; Yang DD; Lu HT; Flavell RA; Davis RJ. 1999. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Proc Natl Acad Sci U S A 96(7):3763-8. PubMed: 10097111 MGI: J:54078

Additional - Map2k3^tm1Flv related

Brancho D; Tanaka N; Jaeschke A; Ventura JJ; Kelkar N; Tanaka Y; Kyuuma M; Takeshita T; Flavell RA; Davis RJ. 2003. Mechanism of p38 MAP kinase activation in vivo. Genes Dev 17(16):1969-78. PubMed: 12893778 MGI: J:84877
Bulat N; Waeber G; Widmann C. 2009. LDLs stimulate p38 MAPKs and wound healing through SR-BI independently of Ras and PI3 kinase. J Lipid Res 50(1):81-9. PubMed: 18757346 MGI: J:146100
Cecil DL; Appleton CT; Polewski MD; Mort JS; Schmidt AM; Bendele A; Beier F; Terkeltaub R. 2009. The pattern recognition receptor CD36 is a chondrocyte hypertrophy marker associated with suppression of catabolic responses and promotion of repair responses to inflammatory stimuli. J Immunol 182(8):5024-31. PubMed: 19342682 MGI: J:147493
Clark JE; Flavell RA; Faircloth ME; Davis RJ; Heads RJ; Marber MS. 2007. Post-infarction remodeling is independent of mitogen-activated protein kinase kinase 3 (MKK3). Cardiovasc Res 74(3):466-70. PubMed: 17399693 MGI: J:162733
Dolinay T; Wu W; Kaminski N; Ifedigbo E; Kaynar AM; Szilasi M; Watkins SC; Ryter SW; Hoetzel A; Choi AM. 2008. Mitogen-activated protein kinases regulate susceptibility to ventilator-induced lung injury. PLoS One 3(2):e1601. PubMed: 18270588 MGI: J:132187
Escolano A; Martinez-Martinez S; Alfranca A; Urso K; Izquierdo HM; Delgado M; Martin F; Sabio G; Sancho D; Gomez-del Arco P; Redondo JM. 2014. Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38. EMBO J 33(10):1117-33. PubMed: 24596247 MGI: J:210829
Fukuda K; Tesch GH; Yap FY; Forbes JM; Flavell RA; Davis RJ; Nikolic-Paterson DJ. 2008. MKK3 signalling plays an essential role in leukocyte-mediated pancreatic injury in the multiple low-dose streptozotocin model. Lab Invest 88(4):398-407. PubMed: 18283273 MGI: J:133320
Gao Y; Tao J; Li MO; Zhang D; Chi H; Henegariu O; Kaech SM; Davis RJ; Flavell RA; Yin Z. 2005. JNK1 is essential for CD8+ T cell-mediated tumor immune surveillance. J Immunol 175(9):5783-9. PubMed: 16237070 MGI: J:119340
Gonzalez-Teran B; Cortes JR; Manieri E; Matesanz N; Verdugo A; Rodriguez ME; Gonzalez-Rodriguez A; Valverde A; Martin P; Davis RJ; Sabio G. 2013. Eukaryotic elongation factor 2 controls TNF-alpha translation in LPS-induced hepatitis. J Clin Invest 123(1):164-78. PubMed: 23202732 MGI: J:194180
Greenblatt MB; Kim JM; Oh H; Park KH; Choo MK; Sano Y; Tye CE; Skobe Z; Davis RJ; Park JM; Bei M; Glimcher LH; Shim JH. 2015. p38alpha MAPK is required for tooth morphogenesis and enamel secretion. J Biol Chem 290(1):284-95. PubMed: 25406311 MGI: J:218387
Hegazi RA; Rao KN; Mayle A; Sepulveda AR; Otterbein LE; Plevy SE. 2005. Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1-dependent pathway. J Exp Med 202(12):1703-13. PubMed: 16365149 MGI: J:118826
Inoue T; Boyle DL; Corr M; Hammaker D; Davis RJ; Flavell RA; Firestein GS. 2006. Mitogen-activated protein kinase kinase 3 is a pivotal pathway regulating p38 activation in inflammatory arthritis. Proc Natl Acad Sci U S A 103(14):5484-9. PubMed: 16567640 MGI: J:108294
Kang Y; Wang F; Lu Z; Ying H; Zhang H; Ding W; Wang C; Shi L. 2013. MAPK kinase 3 potentiates Chlamydia HSP60-induced inflammatory response through distinct activation of NF-kappaB. J Immunol 191(1):386-94. PubMed: 23729445 MGI: J:205361
Kim L; Del Rio L; Butcher BA; Mogensen TH; Paludan SR; Flavell RA; Denkers EY. 2005. p38 MAPK autophosphorylation drives macrophage IL-12 production during intracellular infection. J Immunol 174(7):4178-84. PubMed: 15778378 MGI: J:97936
Kim SI; Na HJ; Ding Y; Wang Z; Lee SJ; Choi ME. 2012. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J Biol Chem 287(15):11677-88. PubMed: 22351764 MGI: J:184288
Kontoyiannis D; Kotlyarov A; Carballo E; Alexopoulou L; Blackshear PJ; Gaestel M; Davis R; Flavell R; Kollias G. 2001. Interleukin-10 targets p38 MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal pathology. EMBO J 20(14):3760-70. PubMed: 11447117 MGI: J:108402
Lim AK; Nikolic-Paterson DJ; Ma FY; Ozols E; Thomas MC; Flavell RA; Davis RJ; Tesch GH. 2009. Role of MKK3-p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice. Diabetologia 52(2):347-58. PubMed: 19066844 MGI: J:144365
Lim JH; Stirling B; Derry J; Koga T; Jono H; Woo CH; Xu H; Bourne P; Ha UH; Ishinaga H; Xu H; Andalibi A; Feng XH; Zhu H; Huang Y; Zhang W; Weng X; Yan C; Yin Z; Briles DE; Davis RJ; Flavell RA; Li JD. 2007. Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections. Immunity 27(2):349-60. PubMed: 17723219 MGI: J:124327
Ma FY; Tesch GH; Flavell RA; Davis RJ; Nikolic-Paterson DJ. 2007. MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney. Am J Physiol Renal Physiol 293(5):F1556-63. PubMed: 17686961 MGI: J:145121
MacNeil AJ; Junkins RD; Wu Z; Lin TJ. 2014. Stem cell factor induces AP-1-dependent mast cell IL-6 production via MAPK kinase 3 activity. J Leukoc Biol 95(6):903-15. PubMed: 24453276 MGI: J:211932
MacNeil AJ; Yang YJ; Lin TJ. 2011. MAPK kinase 3 specifically regulates Fc epsilonRI-mediated IL-4 production by mast cells. J Immunol 187(6):3374-82. PubMed: 21841136 MGI: J:179249
Mannam P; Shinn AS; Srivastava A; Neamu RF; Walker WE; Bohanon M; Merkel J; Kang MJ; Dela Cruz CS; Ahasic AM; Pisani MA; Trentalange M; West AP; Shadel GS; Elias JA; Lee PJ. 2014. MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. Am J Physiol Lung Cell Mol Physiol 306(7):L604-19. PubMed: 24487387 MGI: J:210185
Mannam P; Zhang X; Shan P; Zhang Y; Shinn AS; Zhang Y; Lee PJ. 2013. Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury. J Immunol 190(3):1264-75. PubMed: 23275604 MGI: J:193033
Mikkelsen SS; Jensen SB; Chiliveru S; Melchjorsen J; Julkunen I; Gaestel M; Arthur JS; Flavell RA; Ghosh S; Paludan SR. 2009. RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1. J Biol Chem 284(16):10774-82. PubMed: 19224920 MGI: J:149257
Nagaleekar VK; Sabio G; Aktan I; Chant A; Howe IW; Thornton TM; Benoit PJ; Davis RJ; Rincon M; Boyson JE. 2011. Translational Control of NKT Cell Cytokine Production by p38 MAPK. J Immunol 186(7):4140-6. PubMed: 21368234 MGI: J:170817
Nagelin MH; Srinivasan S; Nadler JL; Hedrick CC. 2009. Murine 12/15-lipoxygenase regulates ATP-binding cassette transporter G1 protein degradation through p38- and JNK2-dependent pathways. J Biol Chem 284(45):31303-14. PubMed: 19713213 MGI: J:156345
Otterbein LE; Otterbein SL; Ifedigbo E; Liu F; Morse DE; Fearns C; Ulevitch RJ; Knickelbein R; Flavell RA; Choi AM. 2003. MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. Am J Pathol 163(6):2555-63. PubMed: 14633627 MGI: J:86602
Riffo-Vasquez Y; Coates AR; Page CP; Spina D. 2012. Mycobacterium tuberculosis chaperonin 60.1 inhibits leukocyte diapedesis in a murine model of allergic lung inflammation. Am J Respir Cell Mol Biol 47(2):245-52. PubMed: 22447969 MGI: J:199771
Schonhoff CM; Park SW; Webster CR; Anwer MS. 2016. p38 MAPK alpha and beta isoforms differentially regulate plasma membrane localization of MRP2. Am J Physiol Gastrointest Liver Physiol 310(11):G999-G1005. PubMed: 27012769 MGI: J:234863
Seimon TA; Obstfeld A; Moore KJ; Golenbock DT; Tabas I. 2006. Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc Natl Acad Sci U S A 103(52):19794-9. PubMed: 17167049 MGI: J:118240
Sorkin LS; Boyle DL; Hammaker D; Herman DS; Vail E; Firestein GS. 2009. MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice. Neuroscience 162(2):462-71. PubMed: 19427893 MGI: J:152926
Tanaka N; Kamanaka M; Enslen H; Dong C; Wysk M; Davis RJ; Flavell RA. 2002. Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO Rep 3(8):785-91. PubMed: 12151339 MGI: J:85266
Wang XM; Kim HP; Nakahira K; Ryter SW; Choi AM. 2009. The heme oxygenase-1/carbon monoxide pathway suppresses TLR4 signaling by regulating the interaction of TLR4 with caveolin-1. J Immunol 182(6):3809-18. PubMed: 19265160 MGI: J:145914
Wang XM; Kim HP; Song R; Choi AM. 2006. Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. Am J Respir Cell Mol Biol 34(4):434-42. PubMed: 16357362 MGI: J:120188
Warr N; Siggers P; Carre GA; Wells S; Greenfield A. 2016. Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biol Reprod 94(5):103. PubMed: 27009039 MGI: J:236335
Wen HC; Avivar-Valderas A; Sosa MS; Girnius N; Farias EF; Davis RJ; Aguirre-Ghiso JA. 2011. p38alpha Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. Sci Signal 4(174):ra34. PubMed: 21610252 MGI: J:185994
Yang Z; Zhang X; Darrah PA; Mosser DM. 2010. The Regulation of Th1 Responses by the p38 MAPK. J Immunol 185(10):6205-13. PubMed: 20937847 MGI: J:165637
Yoshizawa T; Hammaker D; Boyle DL; Corr M; Flavell R; Davis R; Schett G; Firestein GS. 2009. Role of MAPK kinase 6 in arthritis: distinct mechanism of action in inflammation and cytokine expression. J Immunol 183(2):1360-7. PubMed: 19561096 MGI: J:151663
Zhang X; Shan P; Alam J; Davis RJ; Flavell RA; Lee PJ. 2003. Carbon monoxide modulates Fas/Fas ligand, caspases, and Bcl-2 family proteins via the p38alpha mitogen-activated protein kinase pathway during ischemia-reperfusion lung injury. J Biol Chem 278(24):22061-70. PubMed: 12690100 MGI: J:211469
Zuckerbraun BS; Billiar TR; Otterbein SL; Kim PK; Liu F; Choi AM; Bach FH; Otterbein LE. 2003. Carbon monoxide protects against liver failure through nitric oxide-induced heme oxygenase 1. J Exp Med 198(11):1707-16. PubMed: 14657222 MGI: J:86806

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Also Known As: Mkk3-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Map2k3tm1Flv

Allele Symbol: Map2k3tm1Flv

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Map2k3tm1Flv/Map2k3tm1FlvB6.129S1-Map2k3tm1Flv

mortality/aging

immune system phenotype

Genotype: Map2k3tm1Flv/Map2k3tm1Flvinvolves: 129S1/Sv

immune system phenotype

cellular phenotype

hematopoietic system phenotype

References

Additional - Map2k3tm1Flv related

Genotyping Protocols

Breeding Considerations

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Progeny testing is not required

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Map2k3^tm1Flv

Allele Symbol: Map2k3^tm1Flv

Genotype: Map2k3^tm1Flv/Map2k3^tm1Flv
B6.129S1-Map2k3^tm1Flv

Genotype: Map2k3^tm1Flv/Map2k3^tm1Flv
involves: 129S1/Sv

Additional - Map2k3^tm1Flv related