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 Huda Zoghbi,   Baylor College of Medicine

Description
Mice that are heterozygous for the targeted mutation are viable but have a reduced lifespan (34-40 weeks). The allele consists of a 154 CAG trinucleotide repeat unit placed within exon 8 of the targeted endogenous mouse locus. Modified transcripts and protein can be detected in brain tissue. By 8 weeks of age, mutant mice exhibit noticeable growth retardation. Progressive neurological degeneration initiates by 9 weeks of age, when mutant mice begin to exhibit a clasping phenotype when held by the tail. By 20 weeks of age muscle wasting, ataxia and an abnormal gait are observed. A lack of motor coordination is detected via an accelerating rotarod test by 5 to 7 weeks. Cognitive defects include poor spatial learning performance and reduced Pavlovian conditioned fear response (impaired memory). Hippocampal basal synaptic function is impaired. Immunohistochemical and immunofluorescent analysis of brain tissue reveals neuronal intranuclear inclusions by 6 weeks of age. Older animals exhibit decreased brain weight, reduced dendritic arborization and loss of Purkinje cells. The onset and progression of the phenotype observed in these mutant mice mimics many of the features of spinaocerebellar ataxia type 1 (SCA1) and my be useful in SCA1- and neurodegenerative disease- related studies.

Development
A targeting vector containing sequence of an expanded repeat of 154 CAGs and a floxed (loxP site flanked) neomycin resistance selection cassette was used to disrupt exon 8. The construct was electroporated into 129S7/SvEvBrd-Hprt^b-m2 derived AB2.2 embryonic stem (ES) cells which were transiently transfected with a Cre recombinase vector to remove the selection cassette. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to the same for 10 generations.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

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).

Spinocerebellar Ataxia 1; SCA1

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Atxn1^tm1Hzo/Atxn1⁺

        B6.129S7-Atxn1^tm1Hzo

• mortality/aging
• premature death
  • mice die before 60 weeks of age   (MGI Ref ID J:119643)
  • mice exhibit premature lethality   (MGI Ref ID J:177841)
  • however, exercise improves survival   (MGI Ref ID J:177841)
• nervous system phenotype
• decreased Purkinje cell number   (MGI Ref ID J:119643)
• neuronal intranuclear inclusions   (MGI Ref ID J:177841)
• behavior/neurological phenotype
• abnormal associative learning
  • impaired fear conditioning   (MGI Ref ID J:177841)
• ataxia   (MGI Ref ID J:119643)
• hypoactivity
  • in an open field test   (MGI Ref ID J:177841)
• impaired coordination   (MGI Ref ID J:119643)
  • on a rotarod and dowel test   (MGI Ref ID J:177841)
• growth/size phenotype
• decreased body weight   (MGI Ref ID J:177841)

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

Atxn1^tm1Hzo/Atxn1⁺

        involves: 129S7/SvEvBrd * C57BL/6

• mortality/aging
• premature death
  • premature death first occurs between 35 to 45 weeks of age   (MGI Ref ID J:77225)
  • none of the mice survive past 50 weeks of age   (MGI Ref ID J:77225)
• growth/size phenotype
• cachexia
  • mice start losing weight after 20 weeks of age   (MGI Ref ID J:77225)
• slow postnatal weight gain
  • growth retardation starts at 8 weeks of age   (MGI Ref ID J:77225)
  • mice weigh 20% less than wild-type littermates by 11 weeks of age   (MGI Ref ID J:77225)
• behavior/neurological phenotype
• abnormal cued conditioning behavior
  • in a context fear test, mice display significantly less freezing to the conditioned stimulus 24 hours after the training period but not 1 hour after   (MGI Ref ID J:77225)
• abnormal gait
  • evident by 20 weeks of age   (MGI Ref ID J:77225)
• abnormal spatial learning
  • 7-8 week old mice take more time and swim further to locate a submerged but visible platform in a morris water test during the first 6 trials   (MGI Ref ID J:77225)
  • mice perform as wells as wild-type controls in later trials   (MGI Ref ID J:77225)
  • 7-8 week old mice take more time and swim further to locate a hidden platform in a morris water test regardless of trial number   (MGI Ref ID J:77225)
• ataxia
  • evident by 20 weeks of age   (MGI Ref ID J:77225)
• impaired coordination
  • retention time in a rotarod test is impaired by about half for both 5 and 7 week old mice   (MGI Ref ID J:77225)
• limb grasping
  • mice have a clasping phenotype when lifted by the tail starting at 9 weeks of age   (MGI Ref ID J:77225)
• nervous system phenotype
• abnormal Purkinje cell dendrite morphology
  • there is a reduction in dendritic arbor of cerebellar Purkinje neurons from mice 6 to 11 weeks of age   (MGI Ref ID J:77225)
  • this reduction in dendritic arbor leads to a reduction in membrane capacitance   (MGI Ref ID J:77225)
• abnormal brain ventricle morphology
  • all ventricles are dilated by 40 weeks of age   (MGI Ref ID J:77225)
• abnormal excitatory postsynaptic potential
  • EPSP magnitude is significantly decreased in the hippocampus 90 minutes after high-frequency stimulation   (MGI Ref ID J:77225)
• decreased Purkinje cell number
  • significantly fewer Purkinje cells are present in 40-week old mice compared to wild-type littermates   (MGI Ref ID J:77225)
• decreased brain weight
  • brain weight is significantly reduced by 16 weeks of age   (MGI Ref ID J:77225)
• neuronal intranuclear inclusions
  • ubiquitinated neuronal intranuclear inclusions (NI) are present in CA1 hippocampal neurons by 7 weeks of age   (MGI Ref ID J:77225)
  • NI are also present in cortical neurons and thalamic nuclei by 7 weeks of age   (MGI Ref ID J:77225)
  • NI are present in numerous parts of the brain during the endstage of disease   (MGI Ref ID J:77225)
• reduced long term potentiation
  • hippocampus LTP is significantly reduced in 24 week old mice   (MGI Ref ID J:77225)
• muscle phenotype
• muscle degeneration
  • muscle wasting is evident by 20 weeks of age   (MGI Ref ID J:77225)
  • atrophy of lower limb muscles occurs by 30 weeks of age   (MGI Ref ID J:77225)
• skeleton phenotype
• kyphosis
  • is observed by 30 weeks of age   (MGI Ref ID J:77225)

View Research Applications

Research Applications

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

Developmental Biology Research
Growth Defects

Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Cerebellar Defects
      Purkinje cell defect

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Atxn1tm1Hzo
Allele Name		targeted mutation 1, Huda Y Zoghbi
Allele Type		Targeted (knock-in)
Common Name(s)		Atx1-KI; Sca1154Q/2Q; Sca1154Q;
Strain of Origin		129S7/SvEvBrd-Hprt
ES Cell Line Name		AB2.2
ES Cell Line Strain		129S7/SvEvBrd-Hprt
Promoter		Atxn1, ataxin 1, mouse, laboratory
Molecular Note		An expanded tract of 154 CAG repeats was engineered and knocked into exon 8. Additionally, a floxed neo-TK cassette was inserted into the upstream intron and subsequently deleted in ES cells via cre mediated recombination. While equivalent transcript levels were identified in both mutant and wild-type mice by RT-PCR, reduced levels of mutant protein were observed in brain tissue. The authors attributed this apparent reduction in protein level to an increased difficulty of extraction or solubilization dueto the mutant protein accumulating into nuclear aggregates as mice age. [MGI Ref ID J:77225]

Genotyping

Genotyping Information

Genotyping Protocols

Atxn1^tm1Hzo repeat assay, Standard PCR
Atxn1^tm1Hzo, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Watase K; Weeber EJ; Xu B; Antalffy B; Yuva-Paylor L; Hashimoto K; Kano M; Atkinson R; Sun Y; Armstrong DL; Sweatt JD; Orr HT; Paylor R; Zoghbi HY. 2002. A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34(6):905-19. [PubMed: 12086639]  [MGI Ref ID J:77225]

Additional References

Atxn1^tm1Hzo related

Bowman AB; Lam YC; Jafar-Nejad P; Chen HK; Richman R; Samaco RC; Fryer JD; Kahle JJ; Orr HT; Zoghbi HY. 2007. Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes. Nat Genet 39(3):373-379. [PubMed: 17322884]  [MGI Ref ID J:119643]

Chen KA; Cruz PE; Lanuto DJ; Flotte TR; Borchelt DR; Srivastava A; Zhang J; Steindler DA; Zheng T. 2011. Cellular fusion for gene delivery to SCA1 affected Purkinje neurons. Mol Cell Neurosci 47(1):61-70. [PubMed: 21420496]  [MGI Ref ID J:177962]

Crespo-Barreto J; Fryer JD; Shaw CA; Orr HT; Zoghbi HY. 2010. Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genet 6(7):e1001021. [PubMed: 20628574]  [MGI Ref ID J:162235]

Cvetanovic M; Patel JM; Marti HH; Kini AR; Opal P. 2011. Vascular endothelial growth factor ameliorates the ataxic phenotype in a mouse model of spinocerebellar ataxia type 1. Nat Med 17(11):1445-7. [PubMed: 22001907]  [MGI Ref ID J:178113]

Dion V; Lin Y; Hubert L Jr; Waterland RA; Wilson JH. 2008. Dnmt1 deficiency promotes CAG repeat expansion in the mouse germline. Hum Mol Genet 17(9):1306-17. [PubMed: 18252747]  [MGI Ref ID J:133928]

Fryer JD; Yu P; Kang H; Mandel-Brehm C; Carter AN; Crespo-Barreto J; Gao Y; Flora A; Shaw C; Orr HT; Zoghbi HY. 2011. Exercise and genetic rescue of SCA1 via the transcriptional repressor Capicua. Science 334(6056):690-3. [PubMed: 22053053]  [MGI Ref ID J:177841]

Gatchel JR; Watase K; Thaller C; Carson JP; Jafar-Nejad P; Shaw C; Zu T; Orr HT; Zoghbi HY. 2008. The insulin-like growth factor pathway is altered in spinocerebellar ataxia type 1 and type 7. Proc Natl Acad Sci U S A 105(4):1291-6. [PubMed: 18216249]  [MGI Ref ID J:131821]

Hubert L Jr; Lin Y; Dion V; Wilson JH. 2011. Xpa deficiency reduces CAG trinucleotide repeat instability in neuronal tissues in a mouse model of SCA1. Hum Mol Genet :. [PubMed: 21926083]  [MGI Ref ID J:177762]

Jafar-Nejad P; Ward CS; Richman R; Orr HT; Zoghbi HY. 2011. Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. Proc Natl Acad Sci U S A 108(5):2142-7. [PubMed: 21245341]  [MGI Ref ID J:169114]

Jorgensen ND; Andresen JM; Lagalwar S; Armstrong B; Stevens S; Byam CE; Duvick LA; Lai S; Jafar-Nejad P; Zoghbi HY; Clark HB; Orr HT. 2009. Phosphorylation of ATXN1 at Ser776 in the cerebellum. J Neurochem 110(2):675-86. [PubMed: 19500214]  [MGI Ref ID J:150968]

Lee Y; Fryer JD; Kang H; Crespo-Barreto J; Bowman AB; Gao Y; Kahle JJ; Hong JS; Kheradmand F; Orr HT; Finegold MJ; Zoghbi HY. 2011. ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization. Dev Cell 21(4):746-57. [PubMed: 22014525]  [MGI Ref ID J:178303]

Shiwaku H; Yoshimura N; Tamura T; Sone M; Ogishima S; Watase K; Tagawa K; Okazawa H. 2010. Suppression of the novel ER protein Maxer by mutant ataxin-1 in Bergman glia contributes to non-cell-autonomous toxicity. EMBO J 29(14):2446-60. [PubMed: 20531390]  [MGI Ref ID J:162095]

Health & husbandry

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.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as heterozygotes. The Donating Investigator indicates that it is best to use male carrier mice in breeding strategies because the allele appears less stable in female mutants. Additionally, the phenotype of homozygous mice is too severe for successful breeding.
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

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

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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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