Strain Name:

B6.129S6(Cg)-Eif2ak3tm1Dron/HotaJ

Stock Number:

009340

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Availability:

Repository- Live

Use Restrictions Apply, see Terms of Use
These mice harbor a knockout mutation of the Eif2ak3 gene and may serve as a mouse model of Wolcott-Rallison syndrome.

Description

Strain Information

Former Names STOCK Eif2ak3tm1Dron/HotaJ    (Changed: 30-JAN-14 )
B6.129S6(Cg)-Eif2ak3tm1Dron/HotaJ    (Changed: 31-JAN-11 )
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 SystemHeterozygote x +/+ sibling         (Female x Male)   26-OCT-10
Mating System+/+ sibling x Heterozygote         (Female x Male)   14-JAN-14
Specieslaboratory mouse
GenerationN8+pN1 (11-OCT-13)
Generation Definitions
 
Donating Investigator David Ron,   NYU School of Medicine

Important Note
Of note, Perk-mutant mice may also be useful along with other Eif2ak-mutant mice from the same investigator, including Eif2ak4-knockout mice (Stock No. 008240) and Eif2ak4-floxed mice (Stock No. 008452).

Description
These mice harbor a targeted mutation of the Eif2ak3 (eukaryotic translation initiation factor 2 alpha kinase 3 [also called Perk]) locus that abolishes endogenous gene expression. To date (Feb 2010), the donating investigator has not been able to generate homozygous mice on a C57BL/6J congenic background. The following phenotype describes mice on a mixed albino Swiss Webster;129/SvEv genetic background. Heterozygous mice are viable and fertile. Homozygous (Perk-/-) mice appear runty within a few days of birth and develop a rapid and progressive decline in endocrine and exocrine pancreatic function. This results in a complex pleiotropic phenotype including hyperglycemia, exocrine pancreatic insufficiency, diabetes, growth retardation, inability to breed, and early mortality. The phenotype of the Perk-/- mice is very similar to that observed in humans with Wolcott-Rallison syndrome; the consistent feature of which is severe diabetes mellitus developing in infancy. Heterozygous mice are viable and fertile with a mild defect in glycemic control (mildly impaired glucose tolerance). Perk-mutant mice may be useful in studying eIF2 (eukaryotic initiation factor 2) phosphorylation in response to environmental or endoplasmic reticulum stresses, exocrine pancreatic dysfunction, stress signals initiated by protein malfolding, and infantile diabetes mellitus.

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. It should be noted that the phenotype could vary from that originally described. We may modify the strain description if necessary as published results become available.

Development
A targeting vector was designed by the laboratory of Dr. David Ron (New York University School of Medicine) to replace a 1.6 kbp region of the targeted gene (encoding the transmembrane domain) with a reverse-oriented PGK-Neo cassette. The construct was electroporated into 129S6/SvEvTac-derived W4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with "black Swiss Webster" females to generate the mutant colony. The Perk-mutant colony was subsequently maintained on a mixed albino Swiss Webster;129/SvEv genetic background for many generations and then sent to Dr. Gokhan S. Hotamisligil (Harvard University School of Public Health). There, Perk-mutant mice were reportedly backcrossed to C57BL6/J mice for at least eight generations (see SNP results below) prior to sending males to The Jackson Laboratory Repository in 2013. Upon arrival, heterozygous mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

In 2013, a 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the first generation rederived living colony at The Jackson Laboratory Repository. While all 27 markers throughout the genome suggested a C57BL/6 genetic background, 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest that the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.

Control Information

  Control
   Wild-type from the colony
   000664 C57BL/6J (approximate)
   005304 C57BL/6NJ (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Eif2ak3
023066   STOCK Eif2ak3tm1.2Drc/J
View Strains carrying other alleles of Eif2ak3     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).
Epiphyseal Dysplasia, Multiple, with Early-Onset Diabetes Mellitus
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

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

Eif2ak3tm1Dron/Eif2ak3+

        either: 129S6/SvEvTac-Eif2ak3tm1Dron or (involves: 129S6/SvEvTac * C57BL/6)
  • homeostasis/metabolism phenotype
  • impaired glucose tolerance
    • reduced ability to clear glucose following an intraperitoneal glucose injection, however weight and longevity were normal   (MGI Ref ID J:70005)

Eif2ak3tm1Dron/Eif2ak3tm1Dron

        involves: 129S6/SvEvTac * Swiss Webster
  • mortality/aging
  • postnatal lethality
    • about half the expected number of homozygous mice were recovered at weaning   (MGI Ref ID J:70005)
  • growth/size/body phenotype
  • decreased body weight   (MGI Ref ID J:70005)
  • postnatal growth retardation   (MGI Ref ID J:70005)
  • homeostasis/metabolism phenotype
  • decreased circulating insulin level   (MGI Ref ID J:70005)
  • hyperglycemia
    • seen after 4 weeks of age, primarily due to the failure of the endocrine pancreas to secrete adequate amounts of insulin   (MGI Ref ID J:70005)
  • digestive/alimentary phenotype
  • abnormal exocrine pancreas morphology
    • increased cell death in the exocrine pancreas   (MGI Ref ID J:70005)
    • the endoplasmic reticulum (ER) in the exocrine pancreas was segmented instead of organized into long, thin, densely packed cisterna and its lumen was distended with material of higher electron density than the contents of wildtype ER   (MGI Ref ID J:70005)
  • exocrine pancreatic insufficiency
    • observed in most homozygotes by 6-8 weeks of age   (MGI Ref ID J:70005)
  • steatorrhea
    • resulted from pancreatic maldigestion   (MGI Ref ID J:70005)
  • endocrine/exocrine gland phenotype
  • abnormal exocrine pancreas morphology
    • increased cell death in the exocrine pancreas   (MGI Ref ID J:70005)
    • the endoplasmic reticulum (ER) in the exocrine pancreas was segmented instead of organized into long, thin, densely packed cisterna and its lumen was distended with material of higher electron density than the contents of wildtype ER   (MGI Ref ID J:70005)
  • abnormal pancreas physiology
    • increased levels of endoplasmic reticulum stress in the pancreas   (MGI Ref ID J:70005)
    • abnormal pancreatic beta cell physiology
      • increased glucose-induced proinsulin biosynthesis in islets of Langerhans, however processing of proinsulin was normal   (MGI Ref ID J:70005)
    • exocrine pancreatic insufficiency
      • observed in most homozygotes by 6-8 weeks of age   (MGI Ref ID J:70005)
  • abnormal pancreatic islet morphology
    • observed occasional cells with striking, abundant, and dilated membrane-bounded cisterna filled with a dense content and these cells generally had fewer secretory granules   (MGI Ref ID J:70005)
    • with time, size of islets decreased   (MGI Ref ID J:70005)
    • decreased pancreatic beta cell number
      • with time, the mass of insulin-producing cells diminished   (MGI Ref ID J:70005)
    • increased pancreatic alpha cell number
      • with time, proportion of glucagon-positive cells increased and they were found to populate the core of the islet as well as its mantle   (MGI Ref ID J:70005)

Eif2ak3tm1Dron/Eif2ak3tm1Dron

        129S6/SvEvTac-Eif2ak3tm1Dron
  • mortality/aging
  • complete postnatal lethality
    • died in the first few days of life   (MGI Ref ID J:70005)

Eif2ak3tm1Dron/Eif2ak3tm1Dron

        involves: 129S6/SvEvTac
  • cellular phenotype
  • abnormal cell physiology
    • expression of unfolded protein response target genes (Hspa5, Ddit3, Edem, Dnajc3a, Wars, Ero1lb and Pdia4) is decreased in mouse embryonic fibroblasts stressed with tunicamycin or thapsigargin results   (MGI Ref ID J:124971)
    • mouse embryonic fibroblast cells are profoundly deficient in their recovery from dithiothreitol realtive to wild-type cells   (MGI Ref ID J:124971)
  • homeostasis/metabolism phenotype
  • increased physiological sensitivity to xenobiotic
    • mouse embryonic fibroblast cells are profoundly deficient in their recovery from dithiothreitol   (MGI Ref ID J:124971)
View Research Applications

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

Apoptosis Research
Endogenous Regulators

Cell Biology Research
Protein Processing
Signal Transduction

Developmental Biology Research
Embryonic Lethality (Homozygous)
Perinatal Lethality
      Homozygous

Diabetes and Obesity Research
Hyperglycemia
      more severe

Endocrine Deficiency Research
Pancreas Defects

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

Metabolism Research
Enzyme Deficiency
      exocrine pancreatic insufficiency

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

Research Tools
Apoptosis Research
Diabetes and Obesity Research

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Eif2ak3tm1Dron
Allele Name targeted mutation 1, David Ron
Allele Type Targeted (knock-out)
Common Name(s) perk -;
Mutation Made By David Ron,   NYU School of Medicine
Strain of Origin129S6/SvEvTac
Gene Symbol and Name Eif2ak3, eukaryotic translation initiation factor 2 alpha kinase 3
Chromosome 6
Gene Common Name(s) AI427929; PEK; PERK; WRS; expressed sequence AI427929;
Molecular Note A neomycin selection cassette replaced 1.6 kb of DNA containing the transmembrane domain. Northern blot analysis demonstrated that at least 10-fold less transcript was produced from this allele that the wild-type. However, western blot analysis on cells derived from homozygous mice confirmed that no detectable protein was expressed from this allele. [MGI Ref ID J:62257]

Genotyping

Genotyping Information

Genotyping Protocols

Eif2ak3tm1Dronalternate1, Separated PCR
Generic Neo Quantitative PCR-QPCR- 1.2, QPCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Harding HP; Zeng H; Zhang Y; Jungries R; Chung P; Plesken H; Sabatini DD; Ron D. 2001. Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7(6):1153-63. [PubMed: 11430819]  [MGI Ref ID J:70005]

Harding HP; Zhang Y; Bertolotti A; Zeng H; Ron D. 2000. Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5(5):897-904. [PubMed: 10882126]  [MGI Ref ID J:62257]

Additional References

Eif2ak3tm1Dron related

Baltzis D; Qu LK; Papadopoulou S; Blais JD; Bell JC; Sonenberg N; Koromilas AE. 2004. Resistance to vesicular stomatitis virus infection requires a functional cross talk between the eukaryotic translation initiation factor 2alpha kinases PERK and PKR. J Virol 78(23):12747-61. [PubMed: 15542627]  [MGI Ref ID J:94221]

Blais JD; Filipenko V; Bi M; Harding HP; Ron D; Koumenis C; Wouters BG; Bell JC. 2004. Activating transcription factor 4 is translationally regulated by hypoxic stress. Mol Cell Biol 24(17):7469-82. [PubMed: 15314157]  [MGI Ref ID J:92781]

Gass JN; Jiang HY; Wek RC; Brewer JW. 2008. The unfolded protein response of B-lymphocytes: PERK-independent development of antibody-secreting cells. Mol Immunol 45(4):1035-43. [PubMed: 17822768]  [MGI Ref ID J:126349]

Ghosh R; Lipson KL; Sargent KE; Mercurio AM; Hunt JS; Ron D; Urano F. 2010. Transcriptional regulation of VEGF-A by the unfolded protein response pathway. PLoS One 5(3):e9575. [PubMed: 20221394]  [MGI Ref ID J:158673]

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]

Huang G; Yao J; Zeng W; Mizuno Y; Kamm KE; Stull JT; Harding HP; Ron D; Muallem S. 2006. ER stress disrupts Ca2+-signaling complexes and Ca2+ regulation in secretory and muscle cells from PERK-knockout mice. J Cell Sci 119(Pt 1):153-61. [PubMed: 16352659]  [MGI Ref ID J:105342]

Kudo T; Kanemoto S; Hara H; Morimoto N; Morihara T; Kimura R; Tabira T; Imaizumi K; Takeda M. 2008. A molecular chaperone inducer protects neurons from ER stress. Cell Death Differ 15(2):364-75. [PubMed: 18049481]  [MGI Ref ID J:146385]

Kumar R; Azam S; Sullivan JM; Owen C; Cavener DR; Zhang P; Ron D; Harding HP; Chen JJ; Han A; White BC; Krause GS; DeGracia DJ. 2001. Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem 77(5):1418-21. [PubMed: 11389192]  [MGI Ref ID J:69887]

Lin W; Bailey SL; Ho H; Harding HP; Ron D; Miller SD; Popko B. 2007. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest 117(2):448-456. [PubMed: 17273557]  [MGI Ref ID J:118037]

Lin W; Harding HP; Ron D; Popko B. 2005. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol 169(4):603-12. [PubMed: 15911877]  [MGI Ref ID J:99655]

Nanua S; Murakami M; Xia J; Grenda DS; Woloszynek J; Strand M; Link DC. 2011. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood 117(13):3539-47. [PubMed: 21285438]  [MGI Ref ID J:170501]

Oyadomari S; Yun C; Fisher EA; Kreglinger N; Kreibich G; Oyadomari M; Harding HP; Goodman AG; Harant H; Garrison JL; Taunton J; Katze MG; Ron D. 2006. Cotranslocational degradation protects the stressed endoplasmic reticulum from protein overload. Cell 126(4):727-39. [PubMed: 16923392]  [MGI Ref ID J:115988]

Pena J; Harris E. 2011. Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner. J Biol Chem 286(16):14226-36. [PubMed: 21385877]  [MGI Ref ID J:171119]

Shang J; Gao N; Kaufman RJ; Ron D; Harding HP; Lehrman MA. 2007. Translation attenuation by PERK balances ER glycoprotein synthesis with lipid-linked oligosaccharide flux. J Cell Biol 176(5):605-16. [PubMed: 17325203]  [MGI Ref ID J:119826]

Wu J; Rutkowski DT; Dubois M; Swathirajan J; Saunders T; Wang J; Song B; Yau GD; Kaufman RJ. 2007. ATF6alpha Optimizes Long-Term Endoplasmic Reticulum Function to Protect Cells from Chronic Stress. Dev Cell 13(3):351-64. [PubMed: 17765679]  [MGI Ref ID J:124971]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB27

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, heterozygous mice may be bred together or to wildtype siblings. The donating investigator has not been able to generate homozygous mice on a C57BL/6J congenic background to date (February 2010). On a mixed albino Swiss Webster;129/SvEv genetic background, homozygous mice appear runty within days of birth. To increase the viability of homozygous pups prior to weaning, one may remove normal sized pups (likely heterozygous or wildtype siblings) from the litter.
Mating SystemHeterozygote x +/+ sibling         (Female x Male)   26-OCT-10
+/+ sibling x Heterozygote         (Female x Male)   14-JAN-14
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 $232.00Female or MaleHeterozygous for Eif2ak3tm1Dron  
Price per Pair (US dollars $)Pair Genotype
$302.00Heterozygous for Eif2ak3tm1Dron x Wild-type for Eif2ak3tm1Dron  
$302.00Wild-type for Eif2ak3tm1Dron x Heterozygous for Eif2ak3tm1Dron  

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 $301.60Female or MaleHeterozygous for Eif2ak3tm1Dron  
Price per Pair (US dollars $)Pair Genotype
$392.60Heterozygous for Eif2ak3tm1Dron x Wild-type for Eif2ak3tm1Dron  
$392.60Wild-type for Eif2ak3tm1Dron x Heterozygous for Eif2ak3tm1Dron  

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
   Wild-type from the colony
   000664 C57BL/6J (approximate)
   005304 C57BL/6NJ (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

Important Note

Of note, Perk-mutant mice may also be useful along with other Eif2ak-mutant mice from the same investigator, including Eif2ak4-knockout mice (Stock No. 008240) and Eif2ak4-floxed mice (Stock No. 008452).

Payment Terms and Conditions

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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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