Strain Name:

B6.129S6-Eif2ak4tm1.2Dron/J

Stock Number:

008240

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Availability:

Repository- Live

Use Restrictions Apply, see Terms of Use
Homozygous knock-out Eif2ak4tm1.2Dron mice (sometimes referred to as GCN2-KO mice) have a deletion of exon XII of the eukaryotic translation initiation factor 2 alpha kinase 4 (Eif2ak4 or GCN2) gene, and may be useful in studying eIF2 (eukaryotic initiation factor 2) phosphorylation in response to environmental stresses such as amino acid starvation, proteasome inhibition and UV irradiation.

Description

Strain Information

Former Names B6.129S6-Eif2ak4tm1Munn/J    (Changed: 04-SEP-08 )
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 SystemHomozygote x Homozygote         (Female x Male)   21-APR-09
Specieslaboratory mouse
GenerationN11+N1F3 (11-DEC-13)
Generation Definitions
 
Donating Investigator David Ron,   NYU School of Medicine

Description
Mice homozygous for the GCN2.KO4 mutant locus (also called GCN2.KO4-, GCN2-, GCN2.KO4ex, or GCN2-KO) are viable, fertile and overtly indistinguishable from wild-type mice, with little if any mRNA expressed from the mutant locus. Homozygous GCN2-deficiency is associated with altered inflammatory responses and altered stress responses, including sensitivity to nutritional deficiencies and aberrant eating behavior. As GCN2 is a protein kinase that phosphorylates eIF2 (eukaryotic initiation factor 2) in response to environmental stresses (amino acid starvation, proteasome inhibition and UV irradiation) to reduce global translation and activate stress-related transcription factors (such as NF-kappaB) to alleviate cellular injury or alternatively induce apoptosis, these GCN2.KO4 mutant mice may be useful for such immunology, inflammatory, immunity cell biology, or neurobiology research.

Of note, mice with a conditional allele (loxP-flanked exon XII) are also available (see Stock No. 008452).

Development
A targeting vector was designed to place a loxP site just upstream of, and a loxP-flanked PGK-Neo resistance cassette just downstream of exon XII of the targeted gene. The construct was electroporated into 129S6/SvEvTac-derived W4 embryonic stem (ES) cells. Correctly targeted ES cells were then transiently transfected with a Cre recombinase expression plasmid. The resulting ES cells with recombination across all three loxP sites (with the 1.1kbp fragment encompassing exon XII deleted) were injected into recipient blastocysts. Chimeric males were bred to C57BL/6 females to generate mice harboring the GCN2.KO4 mutant locus (also called GCN2.KO4-, GCN2-, GCN2.KO4ex, or GCN2-KO). These mutant mice were then backcrossed to C57BL/6 for at least 10 generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred with C57BL/6J for at least one generation to establish the colony.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Eif2ak4
008452   B6;129-Eif2ak4tm1.1Dron/J
View Strains carrying other alleles of Eif2ak4     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Pulmonary Venoocclusive Disease 2, Autosomal Recessive; PVOD2   (EIF2AK4)
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.

Eif2ak4tm1.2Dron/Eif2ak4tm1.2Dron

        involves: 129S6/SvEvTac * C57BL/6 * CBA
  • immune system phenotype
  • abnormal cytokine secretion
    • splenic CD19+ dendritic cells do not secrete IFNalpha upon CTLA4-Ig treatement   (MGI Ref ID J:120813)
  • abnormal dendritic cell physiology
    • splenic CD19+ dendritic cells treated with CTLA4-immunoglobulin do not produce IFNalpha, indicating a defect in response to CD80/86 (B7) ligation; production induced by TLR9 stimulation is equivalent to that in wild-type   (MGI Ref ID J:120813)

Eif2ak4tm1.2Dron/Eif2ak4tm1.2Dron

        129S6/SvEvTac-Eif2ak4tm1.2Dron
  • behavior/neurological phenotype
  • abnormal contextual conditioning behavior
    • homozygotes display impaired contextual fear conditioning but normal auditory fear conditioning   (MGI Ref ID J:100646)
  • abnormal spatial reference memory
    • homozygotes display impaired hippocampus-dependent spatial memory in a Morris water maze with repeated trials (strong conditioning) but improved spatial memory with a single trial (weak conditioning)   (MGI Ref ID J:100646)
  • nervous system phenotype
  • abnormal long term potentiation
    • a single tetanus induces a robust and sustained late LTP unlike in wild-type mice where a single tetanus induces early LTP   (MGI Ref ID J:100646)
    • after repeated tetanic stimulation (4 trains at 100 Hz) the duration of late LTP is reduced, returning to baseline within 3 hours   (MGI Ref ID J:100646)

Eif2ak4tm1.2Dron/Eif2ak4tm1.2Dron

        involves: 129S6/SvEvTac
  • behavior/neurological phenotype
  • abnormal food preference
    • mice have much less of an aversion to diets lacking an essential amino acid   (MGI Ref ID J:129841)
    • mice consume 7.7% less leucine-deficient chow after 1 hour compared to wild-type mice that consume 28.8% less   (MGI Ref ID J:129841)
    • mice consume 9.4% less leucine-deficient chow after 4 hours compared to wild-type mice that consume 34.1% less   (MGI Ref ID J:129841)
    • similar responses are observed in threonine-deficient diet   (MGI Ref ID J:129841)
View Research Applications

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

Apoptosis Research
Endogenous Regulators

Cancer Research
Growth Factors/Receptors/Cytokines

Cell Biology Research
DNA Damage Response
Protein Processing
Signal Transduction
Transcriptional Regulation

Immunology, Inflammation and Autoimmunity Research
Growth Factors/Receptors/Cytokines
Inflammation
Intracellular Signaling Molecules

Neurobiology Research
Behavioral and Learning Defects
      genes regulating preferences to alcohol and stress

Research Tools
Apoptosis Research
Genetics Research
      Mutagenesis and Transgenesis
      Mutagenesis and Transgenesis: transcriptional activation

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Eif2ak4tm1.2Dron
Allele Name targeted mutation 1.2, David Ron
Allele Type Targeted (knock-out)
Common Name(s) Eif2ak4tm1Munn; Eif2ak4tm1Nso; GCN2-KO; GCN2.KO4; GCN2.KO4ex; GNC2-;
Mutation Made By David Ron,   NYU School of Medicine
Strain of Origin129S6/SvEvTac
ES Cell Line NameW4
ES Cell Line Strain129S6/SvEvTac
Gene Symbol and Name Eif2ak4, eukaryotic translation initiation factor 2 alpha kinase 4
Chromosome 2
Gene Common Name(s) GCN2; PVOD2;
Molecular Note Exon 12 was deleted via Cre-mediated excision, removing sequence encoding the essential lysine 618, required for kinase activity. [MGI Ref ID J:99090]

Genotyping

Genotyping Information

Genotyping Protocols

Eif2ak4tm1.2Dron, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Munn DH; Sharma MD; Baban B; Harding HP; Zhang Y; Ron D; Mellor AL. 2005. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22(5):633-42. [PubMed: 15894280]  [MGI Ref ID J:99090]

Additional References

Eif2ak4tm1.2Dron related

Baban B; Chandler PR; Sharma MD; Pihkala J; Koni PA; Munn DH; Mellor AL. 2009. IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183(4):2475-83. [PubMed: 19635913]  [MGI Ref ID J:151475]

Cobbold SP; Adams E; Farquhar CA; Nolan KF; Howie D; Lui KO; Fairchild PJ; Mellor AL; Ron D; Waldmann H. 2009. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A 106(29):12055-60. [PubMed: 19567830]  [MGI Ref ID J:150809]

Costa-Mattioli M; Gobert D; Harding H; Herdy B; Azzi M; Bruno M; Bidinosti M; Ben Mamou C; Marcinkiewicz E; Yoshida M; Imataka H; Cuello AC; Seidah N; Sossin W; Lacaille JC; Ron D; Nader K; Sonenberg N. 2005. Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436(7054):1166-73. [PubMed: 16121183]  [MGI Ref ID J:100646]

Harding HP; Novoa I; Zhang Y; Zeng H; Wek R; Schapira M; Ron D. 2000. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099-108. [PubMed: 11106749]  [MGI Ref ID J:99455]

Harding HP; Zhang Y; Zeng H; Novoa I; Lu PD; Calfon M; Sadri N; Yun C; Popko B; Paules R; Stojdl DF; Bell JC; Hettmann T; Leiden JM; Ron D. 2003. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11(3):619-33. [PubMed: 12667446]  [MGI Ref ID J:137331]

Highfill SL; Rodriguez PC; Zhou Q; Goetz CA; Koehn BH; Veenstra R; Taylor PA; Panoskaltsis-Mortari A; Serody JS; Munn DH; Tolar J; Ochoa AC; Blazar BR. 2010. Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 116(25):5738-47. [PubMed: 20807889]  [MGI Ref ID J:167423]

Iken K; Liu K; Liu H; Bizargity P; Wang L; Hancock WW; Visner GA. 2012. Indoleamine 2,3-dioxygenase and metabolites protect murine lung allografts and impair the calcium mobilization of T cells. Am J Respir Cell Mol Biol 47(4):405-16. [PubMed: 22517796]  [MGI Ref ID J:201245]

Jasperson LK; Bucher C; Panoskaltsis-Mortari A; Mellor AL; Munn DH; Blazar BR. 2009. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114(24):5062-70. [PubMed: 19828695]  [MGI Ref ID J:155467]

Manlapat AK; Kahler DJ; Chandler PR; Munn DH; Mellor AL. 2007. Cell-autonomous control of interferon type I expression by indoleamine 2,3-dioxygenase in regulatory CD19+ dendritic cells. Eur J Immunol 37(4):1064-71. [PubMed: 17343295]  [MGI Ref ID J:120813]

Marion V; Sankaranarayanan S; de Theije C; van Dijk P; Lindsey P; Lamers MC; Harding HP; Ron D; Lamers WH; Kohler SE. 2011. Arginine Deficiency Causes Runting in the Suckling Period by Selectively Activating the Stress Kinase GCN2. J Biol Chem 286(11):8866-74. [PubMed: 21239484]  [MGI Ref ID J:170634]

Maurin AC; Jousse C; Averous J; Parry L; Bruhat A; Cherasse Y; Zeng H; Zhang Y; Harding HP; Ron D; Fafournoux P. 2005. The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab 1(4):273-7. [PubMed: 16054071]  [MGI Ref ID J:129841]

Peidis P; Papadakis AI; Muaddi H; Richard S; Koromilas AE. 2011. Doxorubicin bypasses the cytoprotective effects of eIF2alpha phosphorylation and promotes PKR-mediated cell death. Cell Death Differ 18(1):145-54. [PubMed: 20559319]  [MGI Ref ID J:186345]

Ravindran R; Khan N; Nakaya HI; Li S; Loebbermann J; Maddur MS; Park Y; Jones DP; Chappert P; Davoust J; Weiss DS; Virgin HW; Ron D; Pulendran B. 2014. Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation. Science 343(6168):313-7. [PubMed: 24310610]  [MGI Ref ID J:205264]

Sharma MD; Baban B; Chandler P; Hou DY; Singh N; Yagita H; Azuma M; Blazar BR; Mellor AL; Munn DH. 2007. Plasmacytoid dendritic cells from mouse tumor-draining lymph nodes directly activate mature Tregs via indoleamine 2,3-dioxygenase. J Clin Invest 117(9):2570-82. [PubMed: 17710230]  [MGI Ref ID J:127409]

Sharma MD; Hou DY; Baban B; Koni PA; He Y; Chandler PR; Blazar BR; Mellor AL; Munn DH. 2010. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33(6):942-54. [PubMed: 21145762]  [MGI Ref ID J:167291]

Sharma MD; Hou DY; Liu Y; Koni PA; Metz R; Chandler P; Mellor AL; He Y; Munn DH. 2009. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113(24):6102-11. [PubMed: 19366986]  [MGI Ref ID J:149490]

Vinay DS; Kim CH; Choi BK; Kwon BS. 2009. Origins and functional basis of regulatory CD11c+CD8+ T cells. Eur J Immunol 39(6):1552-63. [PubMed: 19499519]  [MGI Ref ID J:149436]

Ye J; Mancuso A; Tong X; Ward PS; Fan J; Rabinowitz JD; Thompson CB. 2012. Pyruvate kinase M2 promotes de novo serine synthesis to sustain mTORC1 activity and cell proliferation. Proc Natl Acad Sci U S A 109(18):6904-9. [PubMed: 22509023]  [MGI Ref ID J:183917]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX10

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, homozygous mice may be bred.
Mating SystemHomozygote x Homozygote         (Female x Male)   21-APR-09
Diet Information LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $195.00Female or MaleHomozygous for Eif2ak4tm1.2Dron  
Price per Pair (US dollars $)Pair Genotype
$390.00Homozygous for Eif2ak4tm1.2Dron x Homozygous for Eif2ak4tm1.2Dron  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $253.50Female or MaleHomozygous for Eif2ak4tm1.2Dron  
Price per Pair (US dollars $)Pair Genotype
$507.00Homozygous for Eif2ak4tm1.2Dron x Homozygous for Eif2ak4tm1.2Dron  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1500 unique mouse models across a vast array of research areas. Breeding colonies provide mice for both large and small orders and fluctuate in size depending on current demand for each strain. If a Repository strain is not immediately available, then within 2 to 3 business days, you will receive an estimated availability timeframe for your inquiry or order along with various delivery options. Repository strains typically are delivered at 4 to 8 weeks of age and will not exceed 12 weeks of age on the day of shipping. We will note and try to accommodate requests for specific ages of Repository strains but cannot guarantee provision of these strains at specific ages. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, please let us know.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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