Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. 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

Additional Web Information

Congenic Nomenclature
Genetic Quality Control Annual Report

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Spinocerebellar Ataxia 1; SCA1 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Atxn1^tm1Hzo/Atxn1⁺

        involves: 129S7/SvEvBrd * C57BL/6

• life span-post-weaning/aging
• premature death (MGI Ref ID J:77225)
  • premature death first occurs between 35 to 45 weeks of age
  • none of the mice survive past 50 weeks of age
• growth/size phenotype
• cachexia (MGI Ref ID J:77225)
  • mice start losing weight after 20 weeks of age
• postnatal slow weight gain (MGI Ref ID J:77225)
  • growth retardation starts at 8 weeks of age
  • mice weigh 20% less than wild-type littermates by 11 weeks of age
• behavior/neurological phenotype
• abnormal cued conditioning behavior (MGI Ref ID J:77225)
  • 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
• abnormal gait (MGI Ref ID J:77225)
  • evident by 20 weeks of age
• abnormal spatial learning (MGI Ref ID J:77225)
  • 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
  • mice perform as wells as wild-type controls in later trials
  • 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
• ataxia (MGI Ref ID J:77225)
  • evident by 20 weeks of age
• impaired coordination (MGI Ref ID J:77225)
  • retention time in a rotarod test is impaired by about half for both 5 and 7 week old mice
• limb grasping (MGI Ref ID J:77225)
  • mice have a clasping phenotype when lifted by the tail starting at 9 weeks of age
• nervous system phenotype
• abnormal Purkinje cell dendrite morphology (MGI Ref ID J:77225)
  • there is a reduction in dendritic arbor of cerebellar Purkinje neurons from mice 6 to 11 weeks of age
  • this reduction in dendritic arbor leads to a reduction in membrane capacitance
• abnormal brain ventricle morphology (MGI Ref ID J:77225)
  • all ventricles are dilated by 40 weeks of age
• abnormal excitatory postsynaptic potential (MGI Ref ID J:77225)
  • EPSP magnitude is significantly decreased in the hippocampus 90 minutes after high-frequency stimulation
• decreased Purkinje cell number (MGI Ref ID J:77225)
  • significantly fewer Purkinje cells are present in 40-week old mice compared to wild-type littermates
• decreased brain weight (MGI Ref ID J:77225)
  • brain weight is significantly reduced by 16 weeks of age
• neuronal intranuclear inclusions (MGI Ref ID J:77225)
  • ubiquitinated neuronal intranuclear inclusions (NI) are present in CA1 hippocampal neurons by 7 weeks of age
  • NI are also present in cortical neurons and thalamic nuclei by 7 weeks of age
  • NI are present in numerous parts of the brain during the endstage of disease
• reduced long term potentiation (MGI Ref ID J:77225)
  • hippocampus LTP is significantly reduced in 24 week old mice
• muscle phenotype
• muscle degeneration (MGI Ref ID J:77225)
  • muscle wasting is evident by 20 weeks of age
  • atrophy of lower limb muscles occurs by 30 weeks of age
• skeleton phenotype
• kyphosis (MGI Ref ID J:77225)
  • is observed by 30 weeks of age

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

Allele Symbol		Atxn1tm1Hzo
Allele Name		targeted mutation 1, Huda Y Zoghbi
Allele Type		Targeted (knock-in)
Common Name(s)		Sca1154Q/2Q;
Strain of Origin		129S7/SvEvBrd-Hprt1
ES Cell Line Name		AB2.2
ES Cell Line Strain		129S7/SvEvBrd-Hprt1
Gene Symbol and Name		Atxn1, ataxin 1
Chromosome		13
Gene Common Name(s)		ATX1; C85907; D6S504E; SCA1; Sca1; expressed sequence C85907; spinocerebellar ataxia 1 homolog (human);
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, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

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

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]

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]

Health & husbandry

Health & Colony Maintenance Information

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

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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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Ordering and Purchasing Information

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Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

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MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.