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- Description
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- Genes & alleles
- Genotyping
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- References
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Description
Strain Information
Type Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Mating System Inbred x Hemizygote (Female x Male) Species laboratory mouse Generation N12+6 (01-JAN-08) Donating Investigator Michael Hayden, University of British Columbia Description
These transgenic mice express the human huntingtin protein containing a 128 CAG repeat expansion. Human huntingtin mRNA and protein is detected. Hyperkinesis begins at 3 months of age with progressive motor impairment appearing at 6 months of age. This is followed by progressive neurodegeneration, starting at 9 months of age, and hypokinesis at 12 months. The motor dysfunction, Rotorod deficit, is correlated with neuronal loss. Mutants exhibit decreased brain weight and reduced striatal and cortical volumes. 18% shrinkage of striatal neurons is observed in 12 month old mutants. A significant decrease (15%) in the number of striatal neurons occurs by 12 months of age. Nuclear huntingtin aggregate inclusions of striatal neurons from 18 month old mutant mice are detected at the light microscopy level. This mutant mouse strain represents a model that may be useful in studies of Huntington's disease.Development
A YAC containing a full-length human huntingtin gene was modified with a 128 CAG repeat expansion in exon 1. The resulting construct (YAC128) was injected into FVB/N pronuclei.
Control Information
| Control | ||
|---|---|---|
| Noncarrier | ||
| Considerations for Choosing Controls | ||
Related Strains
Strains carrying other alleles of HTT
006471 B6.Cg-Tg(HDexon1)61Gpb/J 004360 B6;SJL-Tg(HD)63Aron/J 003627 B6C3-Tg(HD82Gln)81Dbo/J 002809 B6CBA-Tg(HDexon1)61Gpb/1J 002810 B6CBA-Tg(HDexon1)62Gpb/1J 006494 B6CBA-Tg(HDexon1)62Gpb/3J 007578 CBy.Cg-Tg(HDexon1)61Gpb/J 008197 FVB/N-Tg(HTT*97Q)IXwy/J 007247 FVB/N-Tg(YAC353G6)W7Hay/J 003640 FVB/NJ-Tg(YAC72)2511Hay/J View Strains carrying other alleles of HTT (10 strains)
Additional Web Information
Genetic Quality Control Annual Report
Phenotype
Phenotype Information
assigned by genotype
Tg(YAC128)53Hay/0
FVB/N-Tg(YAC128)53Hay
- nervous system phenotype
- abnormal basal ganglion morphology (MGI Ref ID J:84453)
- mean area of striatal neurons is decreased by 18% in 12 month old mice
- striatal volume is decreased by 15% by 9 months of age
- abnormal striatum morphology (MGI Ref ID J:111237)
- the levels of both the endogenous excitotoxin quinolinic acid (QUIN) and its bioprecursor, 3-hydroxykynurenine (3-HK) are increased in the striatum beginning at 8 months of age, similarly to that seen in Huntington disease patients
- reduced compared to wild-type controls at 18 months (10.9 mm3 vs 12.3 mm3)
- significant volume loss is detected at 12 months compared to wild-type controls
- neuronal loss is observed at 12 months relative to controls
- diffuse huntingtin (htt) fragments showing nuclear localization in striatum at 3 months, and this increases with age such that at 12 months, most striatal neurons are positive for htt
- abnormal medium spiny neuron morphology (MGI Ref ID J:84453)
- medium spiny neurons (MSN) are decreased 8% by 9 months of age
- loss of basal ganglia neurons (MGI Ref ID J:84453)
- transgenic mice exhibit a 9% decrease in striatal neurons by 9 months, progressing to a 15-18% loss by 12 months
- medium spiny neurons (MSN), the major neuronal cell type of the straitum, are decreased 8% by 9 months of age
- abnormal cerebral cortex morphology (MGI Ref ID J:84453)
- cortex volume decreased by 7% by 12 months of age
- QUIN and 3-HK levels are elevated in the cerebral cortex, similarly to that seen in Huntington disease patients
- decreased brain weight (MGI Ref ID J:84453)
- total brain weight decreases by 5% at 9 months, progressing to a 10% decrease by 1 year
- cerebellum weight is unchanged
- reduced compared to wild-type controls at 18 months (0.35 grams vs 0.38 grams)
- neuronal intranuclear inclusions (MGI Ref ID J:84453)
- neuronal inclusions observed throughout nucleoplasm of all striatal cells by 18 months of age
- behavior/neurological phenotype
- bradykinesia (MGI Ref ID J:120991)
- starting at 4 months of age, a hypokinetic phenotype is displayed compared to wild-type controls in open field test
- hyperactivity (MGI Ref ID J:84453)
- hyperkinetic phenotype observed at 3 months in open field apparatus
- hypoactivity (MGI Ref ID J:84453)
- hypokinetic phenotype observed beginning at 6 months of age and becoming significant by 12 months of age in open field apparatus
- impaired coordination (MGI Ref ID J:84453)
- progressive decrease in fixed speed rotarod performance beginning at 6 months of age
- significant deficit in rotarod tests at 2 months of age
- growth/size phenotype
- increased body weight (MGI Ref ID J:84453)
This mouse can be used to support research in many areas including:HTT related
Developmental Biology Research
Neurodevelopmental Defects
Mouse/Human Gene Homologs
Huntington's disease (chorea)
Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Cortical Defects
Huntington's disease
Neurodegeneration
Neurodevelopmental Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects
Tremor Defects
Genes & Alleles
Gene & Allele Information
| Allele Symbol | Tg(YAC128)53Hay | ||
|---|---|---|---|
| Allele Name | transgene insertion 53, Michael Hayden | ||
| Allele Type | Transgenic (random, expressed) | ||
| Common Name(s) | HD53; YAC128; | ||
| Mutation Made By | Elizabeth Slow, University of British Columbia | ||
| Strain of Origin | FVB/N | ||
| Expressed Gene | HTT, huntingtin, human | ||
| Promoter | HTT, huntingtin, human | ||
| Molecular Note | A YAC containing a full-length human huntingtin gene under the control of the endogenous human HDH promoter was modified with a 128 CAG repeat expansion. The resulting construct (YAC128) was used to generate transgenic mice. Founder line 53 integrated the most copies of the transgene and had the highest levels of protein expression (75% of endogenous levels) as determined by densitometric analysis. [MGI Ref ID J:84453] | ||
Genotyping
Genotyping Information
Genotyping Protocols
TG(HDexon1), TG(YAC), STD PCR, vers. 1
Helpful Links
Optimizing PCR Protocols
References
References
Selected Reference(s)
Slow EJ; van Raamsdonk J; Rogers D; Coleman SH; Graham RK; Deng Y; Oh R; Bissada N; Hossain SM; Yang YZ; Li XJ; Simpson EM; Gutekunst CA; Leavitt BR; Hayden MR. 2003. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12(13):1555-67. [PubMed: 12812983] [MGI Ref ID J:84453]
Additional References
Tg(YAC128)53Hay relatedBenn CL; Slow EJ; Farrell LA; Graham R; Deng Y; Hayden MR; Cha JH. 2007. Glutamate receptor abnormalities in the YAC128 transgenic mouse model of Huntington's disease. Neuroscience 147(2):354-72. [PubMed: 17544587] [MGI Ref ID J:124041]
Bjorkqvist M; Wild EJ; Thiele J; Silvestroni A; Andre R; Lahiri N; Raibon E; Lee RV; Benn CL; Soulet D; Magnusson A; Woodman B; Landles C; Pouladi MA; Hayden MR; Khalili-Shirazi A; Lowdell MW; Brundin P; Bates GP; Leavitt BR; Moller T; Tabrizi SJ. 2008. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J Exp Med 205(8):1869-77. [PubMed: 18625748] [MGI Ref ID J:138558]
Difiglia M; Sena-Esteves M; Chase K; Sapp E; Pfister E; Sass M; Yoder J; Reeves P; Pandey RK; Rajeev KG; Manoharan M; Sah DW; Zamore PD; Aronin N. 2007. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A 104(43):17204-9. [PubMed: 17940007] [MGI Ref ID J:125948]
Graham RK; Deng Y; Slow EJ; Haigh B; Bissada N; Lu G; Pearson J; Shehadeh J; Bertram L; Murphy Z; Warby SC; Doty CN; Roy S; Wellington CL; Leavitt BR; Raymond LA; Nicholson DW; Hayden MR. 2006. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 125(6):1179-91. [PubMed: 16777606] [MGI Ref ID J:120991]
Graham RK; Slow EJ; Deng Y; Bissada N; Lu G; Pearson J; Shehadeh J; Leavitt BR; Raymond LA; Hayden MR. 2006. Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models. Neurobiol Dis 21(2):444-55. [PubMed: 16230019] [MGI Ref ID J:105723]
Guidetti P; Bates GP; Graham RK; Hayden MR; Leavitt BR; MacDonald ME; Slow EJ; Wheeler VC; Woodman B; Schwarcz R. 2006. Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol Dis 23(1):190-7. [PubMed: 16697652] [MGI Ref ID J:111237]
Shehadeh J; Fernandes HB; Zeron Mullins MM; Graham RK; Leavitt BR; Hayden MR; Raymond LA. 2006. Striatal neuronal apoptosis is preferentially enhanced by NMDA receptor activation in YAC transgenic mouse model of Huntington disease. Neurobiol Dis 21(2):392-403. [PubMed: 16165367] [MGI Ref ID J:105728]
Slow EJ; Graham RK; Osmand AP; Devon RS; Lu G; Deng Y; Pearson J; Vaid K; Bissada N; Wetzel R; Leavitt BR; Hayden MR. 2005. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci U S A 102(32):11402-7. [PubMed: 16076956] [MGI Ref ID J:100467]
Tang TS; Chen X; Liu J; Bezprozvanny I. 2007. Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J Neurosci 27(30):7899-910. [PubMed: 17652581] [MGI Ref ID J:123250]
Tang TS; Slow E; Lupu V; Stavrovskaya IG; Sugimori M; Llinas R; Kristal BS; Hayden MR; Bezprozvanny I. 2005. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci U S A 102(7):2602-7. [PubMed: 15695335] [MGI Ref ID J:96839]
Van Raamsdonk JM; Gibson WT; Pearson J; Murphy Z; Lu G; Leavitt BR; Hayden MR. 2006. Body weight is modulated by levels of full-length Huntingtin. Hum Mol Genet 15(9):1513-23. [PubMed: 16571604] [MGI Ref ID J:108220]
Van Raamsdonk JM; Metzler M; Slow E; Pearson J; Schwab C; Carroll J; Graham RK; Leavitt BR; Hayden MR. 2007. Phenotypic abnormalities in the YAC128 mouse model of Huntington disease are penetrant on multiple genetic backgrounds and modulated by strain. Neurobiol Dis 26(1):189-200. [PubMed: 17276692] [MGI Ref ID J:119003]
Van Raamsdonk JM; Murphy Z; Selva DM; Hamidizadeh R; Pearson J; Petersen A; Bjorkqvist M; Muir C; Mackenzie IR; Hammond GL; Vogl AW; Hayden MR; Leavitt BR. 2007. Testicular degeneration in Huntington disease. Neurobiol Dis 26(3):512-20. [PubMed: 17433700] [MGI Ref ID J:134844]
Van Raamsdonk JM; Pearson J; Murphy Z; Hayden MR; Leavitt BR. 2006. Wild-type huntingtin ameliorates striatal neuronal atrophy but does not prevent other abnormalities in the YAC128 mouse model of Huntington disease. BMC Neurosci 7:80. [PubMed: 17147801] [MGI Ref ID J:117699]
Van Raamsdonk JM; Pearson J; Slow EJ; Hossain SM; Leavitt BR; Hayden MR. 2005. Cognitive dysfunction precedes neuropathology and motor abnormalities in the YAC128 mouse model of Huntington's disease. J Neurosci 25(16):4169-80. [PubMed: 15843620] [MGI Ref ID J:98736]
Wang CE; Tydlacka S; Orr AL; Yang SH; Graham RK; Hayden MR; Li S; Chan AW; Li XJ. 2008. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum Mol Genet 17(17):2738-51. [PubMed: 18558632] [MGI Ref ID J:138148]
Wang CE; Zhou H; McGuire JR; Cerullo V; Lee B; Li SH; Li XJ. 2008. Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181(5):803-16. [PubMed: 18504298] [MGI Ref ID J:137025]
Health & husbandry
Health & Colony Maintenance Information
Animal Health Reports
Room Number AX12
Colony Maintenance
Breeding & Husbandry This strain originated on an FVB/N background, was backcrossed for 12 generations on the same (October 2003). The strain is maintained as a hemizygote. Mating System Inbred x Hemizygote (Female x Male) Diet Information LabDiet® 5K52/5K67
Purchasing information
Pricing, Supply Level & Notes, Controls, General Terms & Conditions
Pricing
| Pricing for USA, Canada and Mexico shipping destinations |
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Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $236.40 Female or Male Hemizygous for Tg(YAC128)53Hay *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $288.65 Hemizygous for Tg(YAC128)53Hay x Noncarrier $288.65 Noncarrier x Hemizygous for Tg(YAC128)53Hay
Additional Supply Details
| Supply Notes |
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| Pricing for International shipping destinations |
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Weeks of Age Price* Gender Genotypes Provided Individual Mouse Price $307.40 Female or Male Hemizygous for Tg(YAC128)53Hay *Price(s) in US dollars ($)
Pairs /Price* Pair Genotype $375.30 Hemizygous for Tg(YAC128)53Hay x Noncarrier $375.30 Noncarrier x Hemizygous for Tg(YAC128)53Hay
Additional Supply Details
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Supply Details
| Standard Supply | Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement. |
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Control Information
| Control | ||
|---|---|---|
| Noncarrier | ||
| 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
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