Strain Name:

STOCK Atf4tm1Tow/J

Stock Number:

013072

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Availability:

Repository- Live

Use Restrictions Apply, see Terms of Use
In this strain, a neomycin phosphotransferase resistance (neo) cassette replaces the entire coding region of the endogenous mouse activating transcription factor 4 (Atf4) gene, abolishing gene function. These mice may be useful for studying cell proliferation defects associated with blindness, osteoporosis, and stress responses.

Description

Strain Information

Former Names B6;129-Atf4tm1Tow/J    (Changed: 31-MAY-11 )
Type Mutant Stock; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Mating SystemHeterozygote x Wild-type         (Female x Male)   19-DEC-11
Specieslaboratory mouse
GenerationF?+F3 (26-SEP-11)
Generation Definitions
 
Donating InvestigatorDr. Tim Townes,   University of Alabama at Birmingham

Description
In this strain, a neomycin phosphotransferase resistance (neo) cassette replaces the entire coding region of the endogenous mouse activating transcription factor 4 (Atf4) gene, abolishing gene function. Mice homozygous for the Atf4 allele exhibit low viability, with delayed bone formation during embryonic development and low bone mass throughout postnatal life. They exhibit a reduction in oxidative stress-induced gene expression, resistance to oxidative death, and decreased consumption of the antioxidant glutathione. They also have decreased insulin sensitivity, smaller fat pads, and delayed hair growth as compared with control mice. Adults are severely microphthalmic, with no recognizable lens, anterior chamber, iris, or vitreous body. These mice may be useful for studying cell proliferation defects associated with blindness, osteoporosis, and stress responses.

Development
A targeting vector was designed to replace exons 2-3 encoding the activating transcription factor 4 (Atf4) gene with a neomycin phosphotransferase resistance (neo) cassette. The construct was electroporated into either (129X1/SvJ x 129S1/Sv)F1-Kitl+-derived R1 embryonic stem (ES) cells or 129P2/OlaHsd-derived HM1 ES cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric mice were bred to Black Swiss mice. Subsequently, these mice were bred to C57BL/6 mice to generate a colony of Atf4-/- mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Control Information

  Control
   Wild-type from the colony
   101043 B6129SF1/J (approximate)
   101045 B6129SF2/J (approximate)
   000664 C57BL/6J (approximate)
 
  Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Atf4tm1Tow/Atf4tm1Tow

        either: (involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6J * NIH Black Swiss) or (involves: 129P2/OlaHsd * C57BL/6J * NIH Black Swiss)
  • homeostasis/metabolism phenotype
  • abnormal gluconeogenesis
    • reduced after pyruvate challenge   (MGI Ref ID J:152695)
  • decreased circulating glucose level
    • at 2 weeks, 1 month, and 2 months   (MGI Ref ID J:152695)
  • improved glucose tolerance   (MGI Ref ID J:152695)
  • increased circulating insulin level   (MGI Ref ID J:152695)
  • increased insulin secretion   (MGI Ref ID J:152695)
  • increased insulin sensitivity
    • in mice and liver, muscle, and fat cells but not hepatocytes   (MGI Ref ID J:152695)
  • endocrine/exocrine gland phenotype
  • abnormal pancreatic beta cell physiology
    • beta cell proliferation is increased compared to in wild-type mice   (MGI Ref ID J:152695)
    • increased insulin secretion   (MGI Ref ID J:152695)
  • increased pancreatic beta cell mass
    • beta cell area and mass are increased compared to in wild-type mice   (MGI Ref ID J:152695)
  • adipose tissue phenotype
  • decreased total fat pad weight
    • at 8 weeks, mice exhibit decreased fad pad size and weight compared to in wild-type mice   (MGI Ref ID J:152695)

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

Atf4tm1Tow/Atf4tm1Tow

        involves: 129S1/Sv * 129X1/SvJ * NIH Black Swiss
  • mortality/aging
  • partial perinatal lethality
    • most mice died within an hour of birth, although some mice persisted   (MGI Ref ID J:74479)
  • partial postnatal lethality
    • some mice that survived the perinatal period died within the first 3 weeks of life   (MGI Ref ID J:74479)
  • cellular phenotype
  • decreased cell proliferation   (MGI Ref ID J:74479)
  • growth/size phenotype
  • decreased body length   (MGI Ref ID J:74479)
  • decreased body weight   (MGI Ref ID J:74479)
  • postnatal growth retardation   (MGI Ref ID J:74479)
  • hematopoietic system phenotype
  • absent common myeloid progenitor cells
    • due to a cell-autonomous proliferation defect   (MGI Ref ID J:74479)
  • anemia
    • severe fetal anemia   (MGI Ref ID J:74479)
    • mice that survived the perinatal period had mild anemia   (MGI Ref ID J:74479)
  • decreased hematocrit   (MGI Ref ID J:74479)
  • impaired hematopoiesis
    • impaired fetal liver definitive hematopoiesis   (MGI Ref ID J:74479)
  • liver/biliary system phenotype
  • decreased hepatocyte number
    • fetal liver hypoplasia   (MGI Ref ID J:74479)
  • pale liver
    • the fetal liver was pale   (MGI Ref ID J:74479)
  • reproductive system phenotype
  • female infertility
    • inspite of having grossly normal ovaries   (MGI Ref ID J:74479)
  • male infertility
    • most males that survived the perinatal period were infertile   (MGI Ref ID J:74479)
  • reduced male fertility
    • mice that surivived the perinatal period and that were not completely sterile jad a reduced period of fertility and impregnated females at a reduced rate   (MGI Ref ID J:74479)
  • vision/eye phenotype
  • microphthalmia
    • severe microphthalmia with no recognizable lens, anterior chamber, iris, or vitreous body   (MGI Ref ID J:74479)
    • eye development was impaired after E14.5, when the lens normally undergoes rapid cellular proliferation   (MGI Ref ID J:74479)
  • integument phenotype
  • delayed hair appearance
    • by 1 week of age, surviving mice had only a sparse coat   (MGI Ref ID J:74479)
    • the delay resolved itself by adulthood   (MGI Ref ID J:74479)
  • ruffled hair   (MGI Ref ID J:74479)

Atf4tm1Tow/Atf4tm1Tow

        either: (involves: 129P2/OlaHsd * NIH Black Swiss) or (involves: 129S1/Sv * 129X1/SvJ * NIH Black Swiss)
  • craniofacial phenotype
  • abnormal neurocranium morphology
    • skull trabeculae were short and thin, putatively compromising the protection of the brain during delivery   (MGI Ref ID J:89403)
    • abnormal fontanelle morphology
      • widened at birth   (MGI Ref ID J:89403)
    • abnormal frontal bone morphology
      • decreased mineralization   (MGI Ref ID J:89403)
    • abnormal parietal bone morphology
      • decreased mineralization   (MGI Ref ID J:89403)
  • digestive/alimentary phenotype
  • abnormal pancreatic acinus morphology
    • number of acini is greatly reduced   (MGI Ref ID J:129974)
    • pancreatic acini are dispersed and are not in close proximity to neighboring acini resulting in an expanded extracellular space   (MGI Ref ID J:129974)
    • the centroacinar duct is greatly expanded in adults   (MGI Ref ID J:129974)
    • abnormal pancreatic acinar cell morphology
      • acinar cell size is greatly reduced   (MGI Ref ID J:129974)
      • abnormal pancreatic acinar cell zymogen granule morphology
        • acinar cells appear smaller with less zymogen granule content   (MGI Ref ID J:129974)
  • exocrine pancreas hypoplasia
    • exocrine pancreas of P4 mutants is severely underdeveloped   (MGI Ref ID J:89403)
  • endocrine/exocrine gland phenotype
  • abnormal pancreas morphology
    • adult pancreas contains numerous adipoctyes   (MGI Ref ID J:129974)
    • abnormal pancreatic acinus morphology
      • number of acini is greatly reduced   (MGI Ref ID J:129974)
      • pancreatic acini are dispersed and are not in close proximity to neighboring acini resulting in an expanded extracellular space   (MGI Ref ID J:129974)
      • the centroacinar duct is greatly expanded in adults   (MGI Ref ID J:129974)
      • abnormal pancreatic acinar cell morphology
        • acinar cell size is greatly reduced   (MGI Ref ID J:129974)
        • abnormal pancreatic acinar cell zymogen granule morphology
          • acinar cells appear smaller with less zymogen granule content   (MGI Ref ID J:129974)
    • exocrine pancreas hypoplasia
      • exocrine pancreas of P4 mutants is severely underdeveloped   (MGI Ref ID J:89403)
  • skeleton phenotype
  • abnormal bone ossification
    • normal skeletogenesis prior to E13, however defects were observed between E14 and E16   (MGI Ref ID J:89403)
    • abnormal bone mineralization
      • observed in both frontal and parietal bones, clavicles, and long bones   (MGI Ref ID J:89403)
  • abnormal bone trabecula morphology
    • abnormal trabeculae   (MGI Ref ID J:89403)
  • abnormal clavicle morphology
    • decreased mineralization   (MGI Ref ID J:89403)
  • abnormal neurocranium morphology
    • skull trabeculae were short and thin, putatively compromising the protection of the brain during delivery   (MGI Ref ID J:89403)
    • abnormal fontanelle morphology
      • widened at birth   (MGI Ref ID J:89403)
    • abnormal frontal bone morphology
      • decreased mineralization   (MGI Ref ID J:89403)
    • abnormal parietal bone morphology
      • decreased mineralization   (MGI Ref ID J:89403)
  • decreased bone mineral density   (MGI Ref ID J:89403)
  • decreased osteoblast cell number
    • delay in differentiation   (MGI Ref ID J:129974)
View Research Applications

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

Developmental Biology Research
Eye Defects
Internal/Organ Defects
      brain
      liver
Skeletal Defects
      osteopetrosis

Research Tools
Apoptosis Research

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Atf4tm1Tow
Allele Name targeted mutation 1, Timothy Townes
Allele Type Targeted (knock-out)
Common Name(s) Atf4 KO; Atf4-; Atf4tm1Tmt;
Mutation Made ByDr. Tim Townes,   University of Alabama at Birmingham
Strain of Origin129
Gene Symbol and Name Atf4, activating transcription factor 4
Chromosome 15
Gene Common Name(s) Atf-4; C/ATF; CREB-2; CREB2; TAXREB67; TXREB;
General Note ES cell line = HM1 (129P2/OlaHsd-Hprtb-m3) or R1 ((129X1/SvJ x 129S1/Sv)F1-Kitl+).

The data presented in J:74479 were obtained using R1 ES cells, though the authors report that they also generated mice with targeted alleles using HM1 ES cells.

Molecular Note Exons 2 and 3, comprising the entire coding region, were replaced with a targeting construct containing a neomycin resistance gene. Expression analysis confirmed the absence of transcript in homozygous mutant mice. [MGI Ref ID J:74479]

Genotyping

Genotyping Information

Genotyping Protocols

Atf4tm1Towalternate1, Separated PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Masuoka HC; Townes TM. 2002. Targeted disruption of the activating transcription factor 4 gene results in severe fetal anemia in mice. Blood 99(3):736-45. [PubMed: 11806972]  [MGI Ref ID J:74479]

Additional References

Atf4tm1Tow related

Bouman L; Schlierf A; Lutz AK; Shan J; Deinlein A; Kast J; Galehdar Z; Palmisano V; Patenge N; Berg D; Gasser T; Augustin R; Trumbach D; Irrcher I; Park DS; Wurst W; Kilberg MS; Tatzelt J; Winklhofer KF. 2011. Parkin is transcriptionally regulated by ATF4: evidence for an interconnection between mitochondrial stress and ER stress. Cell Death Differ 18(5):769-82. [PubMed: 21113145]  [MGI Ref ID J:186974]

Cao H; Yu S; Yao Z; Galson DL; Jiang Y; Zhang X; Fan J; Lu B; Guan Y; Luo M; Lai Y; Zhu Y; Kurihara N; Patrene K; Roodman GD; Xiao G. 2010. Activating transcription factor 4 regulates osteoclast differentiation in mice. J Clin Invest 120(8):2755-66. [PubMed: 20628199]  [MGI Ref ID J:163772]

Chen Y; Wang JJ; Li J; Hosoya KI; Ratan R; Townes T; Zhang SX. 2012. Activating transcription factor 4 mediates hyperglycaemia-induced endothelial inflammation and retinal vascular leakage through activation of STAT3 in a mouse model of type 1 diabetes. Diabetologia 55(9):2533-45. [PubMed: 22660795]  [MGI Ref ID J:189108]

Costa-Mattioli M; Gobert D; Stern E; Gamache K; Colina R; Cuello C; Sossin W; Kaufman R; Pelletier J; Rosenblum K; Krnjevic K; Lacaille JC; Nader K; Sonenberg N. 2007. eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129(1):195-206. [PubMed: 17418795]  [MGI Ref ID J:141584]

Dobreva G; Chahrour M; Dautzenberg M; Chirivella L; Kanzler B; Farinas I; Karsenty G; Grosschedl R. 2006. SATB2 is a multifunctional determinant of craniofacial patterning and osteoblast differentiation. Cell 125(5):971-86. [PubMed: 16751105]  [MGI Ref ID J:115876]

Elefteriou F; Benson MD; Sowa H; Starbuck M; Liu X; Ron D; Parada LF; Karsenty G. 2006. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab 4(6):441-51. [PubMed: 17141628]  [MGI Ref ID J:129752]

Iida K; Li Y; McGrath BC; Frank A; Cavener DR. 2007. PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice. BMC Cell Biol 8:38. [PubMed: 17727724]  [MGI Ref ID J:129974]

Kode A; Mosialou I; Silva BC; Rached MT; Zhou B; Wang J; Townes TM; Hen R; DePinho RA; Guo XE; Kousteni S. 2012. FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin. J Clin Invest 122(10):3490-503. [PubMed: 22945629]  [MGI Ref ID J:191669]

Lange PS; Chavez JC; Pinto JT; Coppola G; Sun CW; Townes TM; Geschwind DH; Ratan RR. 2008. ATF4 is an oxidative stress-inducible, prodeath transcription factor in neurons in vitro and in vivo. J Exp Med 205(5):1227-42. [PubMed: 18458112]  [MGI Ref ID J:136222]

Li H; Meng Q; Xiao F; Chen S; Du Y; Yu J; Wang C; Guo F. 2011. ATF4 deficiency protects mice from high-carbohydrate-diet-induced liver steatosis. Biochem J 438(2):283-9. [PubMed: 21644928]  [MGI Ref ID J:177892]

Vidal RL; Figueroa A; Court FA; Thielen P; Molina C; Wirth C; Caballero B; Kiffin R; Segura-Aguilar J; Cuervo AM; Glimcher LH; Hetz C. 2012. Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 21(10):2245-62. [PubMed: 22337954]  [MGI Ref ID J:183791]

Wang W; Lian N; Li L; Moss HE; Wang W; Perrien DS; Elefteriou F; Yang X. 2009. Atf4 regulates chondrocyte proliferation and differentiation during endochondral ossification by activating Ihh transcription. Development 136(24):4143-53. [PubMed: 19906842]  [MGI Ref ID J:154906]

Wang W; Lian N; Ma Y; Li L; Gallant RC; Elefteriou F; Yang X. 2012. Chondrocytic Atf4 regulates osteoblast differentiation and function via Ihh. Development 139(3):601-11. [PubMed: 22190639]  [MGI Ref ID J:179733]

Yadav VK; Ryu JH; Suda N; Tanaka KF; Gingrich JA; Schutz G; Glorieux FH; Chiang CY; Zajac JD; Insogna KL; Mann JJ; Hen R; Ducy P; Karsenty G. 2008. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135(5):825-37. [PubMed: 19041748]  [MGI Ref ID J:146078]

Yamaguchi S; Ishihara H; Yamada T; Tamura A; Usui M; Tominaga R; Munakata Y; Satake C; Katagiri H; Tashiro F; Aburatani H; Tsukiyama-Kohara K; Miyazaki J; Sonenberg N; Oka Y. 2008. ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Cell Metab 7(3):269-76. [PubMed: 18316032]  [MGI Ref ID J:133217]

Yang X; Matsuda K; Bialek P; Jacquot S; Masuoka HC; Schinke T; Li L; Brancorsini S; Sassone-Corsi P; Townes TM; Hanauer A; Karsenty G. 2004. ATF4 is a substrate of RSK2 and an essential regulator of osteoblast biology; implication for Coffin-Lowry Syndrome. Cell 117(3):387-98. [PubMed: 15109498]  [MGI Ref ID J:89403]

Yoshizawa T; Hinoi E; Jung DY; Kajimura D; Ferron M; Seo J; Graff JM; Kim JK; Karsenty G. 2009. The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts. J Clin Invest 119(9):2807-17. [PubMed: 19726872]  [MGI Ref ID J:152695]

Yu S; Franceschi RT; Luo M; Fan J; Jiang D; Cao H; Kwon TG; Lai Y; Zhang J; Patrene K; Hankenson K; Roodman GD; Xiao G. 2009. Critical role of activating transcription factor 4 in the anabolic actions of parathyroid hormone in bone. PLoS One 4(10):e7583. [PubMed: 19851510]  [MGI Ref ID J:154038]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, heterozygous mice may be bred to wildtype littermates. The Donating Investigator confirms homozygous lethality on a 129 background in addition it has been the experience of the Jackson Laboratory that Atf4 homozygous mutants are not generated from heterozygous matings on this mixed genetic background.
Mating SystemHeterozygote x Wild-type         (Female x Male)   19-DEC-11
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 MaleHeterozygous for Atf4tm1Tow  
Price per Pair (US dollars $)Pair Genotype
$265.00Heterozygous for Atf4tm1Tow x Wild-type for Atf4tm1Tow  
$265.00Wild-type for Atf4tm1Tow x Heterozygous for Atf4tm1Tow  

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 MaleHeterozygous for Atf4tm1Tow  
Price per Pair (US dollars $)Pair Genotype
$344.50Heterozygous for Atf4tm1Tow x Wild-type for Atf4tm1Tow  
$344.50Wild-type for Atf4tm1Tow x Heterozygous for Atf4tm1Tow  

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
   101043 B6129SF1/J (approximate)
   101045 B6129SF2/J (approximate)
   000664 C57BL/6J (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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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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