Description

Strain Information

Type Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Michael Hayden,   University of British Columbia

Description
Mice homozygous for this transgene are viable and fertile. The human huntingtin transgenic protein is expressed widely in many tissues (identical to the endogenous huntingtin protein), but has highest levels of expression in the brain and testes. Electrophysiological abnormalities can be measured by six months. A behavioral phenotype is first detected at seven months when evidence of mild hyperkinetic movement disorder is noticeable. This disorder is characterized by progressive spontaneous hyperactivity during the dark phase of open field-testing. By 12 months of age selective degeneration of medium spiny neurons in the lateral striatum is observed. This degeneration is associated with the translocation of N-terminal huntingtin fragments to the nucleus. This strain represents a Huntington's Disease mouse model where a mutant full-length human huntingtin is expressed under control of its endogenous promoter.

Development
A YAC containing a full-length human huntingtin gene was modified with a 72 CAG repeat expansion in exon 1. The resulting construct (YAC72) was injected into FVB/N pronuclei.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
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
004938	FVB-Tg(YAC128)53Hay/J
008197	FVB/N-Tg(HTT*97Q)IXwy/J
007247	FVB/N-Tg(YAC353G6)W7Hay/J

View Strains carrying other alleles of HTT     (10 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Huntington Disease; HD -

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Tg(YAC72)2511Hay/?

        FVB/N

• nervous system phenotype
• abnormal excitatory postsynaptic potential (MGI Ref ID J:55405)
  • hippocampal slices from 6 month old mice display a hyperexcitability exhibited as a broad EPSP at the distal dendrites
• abnormal long term potentiation (MGI Ref ID J:55405)
  • following tetanization most slices from 6 month old mice exhibit a greater short-term potentiation when compared to controls
• reduced long term potentiation (MGI Ref ID J:55405)
  • by 10 months of age, LTP is not induced in CA1 neurons; high frequency stimulation induces depression instead of potentiation
• abnormal striatum morphology (MGI Ref ID J:55405)
  • nuclear translocation of the N-terminal portion of HD is observed in striatal neurons of 12 month old mice with an immunoreactive antibody (EM48)
• enhanced NMDA-mediated synaptic currents (MGI Ref ID J:55405)
  • fast synaptic response in these mice has a prominent NMDA component
• neuron degeneration (MGI Ref ID J:55405)
  • selective degeneration is observed in the striatum at 12 months of age
  • neurons are shrunken and hyperchromatic
• behavior/neurological phenotype
• hyperactivity (MGI Ref ID J:55405)
  • progressive hyperactivity is observed in the dark phase of open field testing beginning at 7 months of age
• unidirectional circling (MGI Ref ID J:55405)
  • circling was observed in one mouse at 8.5 months of age
• hearing/vestibular/ear phenotype
• unidirectional circling (MGI Ref ID J:55405)
  • circling was observed in one mouse at 8.5 months of age

View Research Applications

Research Applications

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(YAC72)2511Hay
Allele Name		transgene insertion 2511, Michael Hayden
Allele Type		Transgenic (random, expressed)
Common Name(s)		YAC72;
Mutation Made By		J. Hodgson,   University of British Columbia
Strain of Origin		FVB/N
Expressed Gene		HTT, huntingtin, human
Promoter		HTT, huntingtin, human
General Note		Homozygous transgenic mice are viable and fertile. In these mice the human huntingtin transgenic protein is expressed widely in many tissues (identical to the endogenous huntingtin protein), with highest expression levels in the brain and testes. Electrophysiological abnormalities can be measured by 6 months. A behavioral phenotype is first detected at 7 months when evidence of mild hyperkinetic movement disorder is noticeable. This disorder is characterized by progressive spontaneous hyperactivity during the dark phase of open field-testing. By 12 months of age selective degeneration of medium spiny neurons in the lateral striatum is observed. This degeneration is associated with the translocation of N-terminal huntingtin fragments to the nucleus.
Molecular Note		A YAC containing a full-length human huntingtin gene was modified with a 72 CAG repeat expansion in exon 1. The resulting construct (YAC72) was used to generate transgenic mice. The endogenous human HDH promoter directed expression in many tissues with levels in the brain and testes being the highest. [MGI Ref ID J:55405]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(YAC72)2511Hay - (HDexon1), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Hodgson JG; Agopyan N; Gutekunst CA; Leavitt BR; LePiane F; Singaraja R ; Smith DJ ; Bissada N ; McCutcheon K ; Nasir J ; Jamot L ; Li XJ ; Stevens ME ; Rosemond E ; Roder JC ; Phillips AG ; Rubin EM ; Hersch SM ; Hayden MR. 1999. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron 23(1):181-92. [PubMed: 10402204]  [MGI Ref ID J:55405]

Additional References

Fan MM; Fernandes HB; Zhang LY; Hayden MR; Raymond LA. 2007. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J Neurosci 27(14):3768-79. [PubMed: 17409241]  [MGI Ref ID J:119402]

Tg(YAC72)2511Hay related

Benn 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]

Desplats PA; Lambert JR; Thomas EA. 2008. Functional roles for the striatal-enriched transcription factor, Bcl11b, in the control of striatal gene expression and transcriptional dysregulation in Huntington's disease. Neurobiol Dis 31(3):298-308. [PubMed: 18595722]  [MGI Ref ID J:138707]

Fan MM; Fernandes HB; Zhang LY; Hayden MR; Raymond LA. 2007. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J Neurosci 27(14):3768-79. [PubMed: 17409241]  [MGI Ref ID J:119402]

Hodgson JG; Smith DJ; McCutcheon K; Koide HB; Nishiyama K; Dinulos MB; Stevens ME; Bissada N; Nasir J; Kanazawa I; Disteche CM; Rubin EM; Hayden MR. 1996. Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. Hum Mol Genet 5(12):1875-85. [PubMed: 8968738]  [MGI Ref ID J:37964]

Jenkins BG; Andreassen OA; Dedeoglu A; Leavitt B; Hayden M; Borchelt D; Ross CA; Ferrante RJ; Beal MF. 2005. Effects of CAG repeat length, HTT protein length and protein context on cerebral metabolism measured using magnetic resonance spectroscopy in transgenic mouse models of Huntington's disease. J Neurochem 95(2):553-62. [PubMed: 16135087]  [MGI Ref ID J:129784]

Li L; Fan M; Icton CD; Chen N; Leavitt BR; Hayden MR; Murphy TH; Raymond LA. 2003. Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease. Neurobiol Aging 24(8):1113-21. [PubMed: 14643383]  [MGI Ref ID J:127986]

Li L; Murphy TH; Hayden MR; Raymond LA. 2004. Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J Neurophysiol 92(5):2738-46. [PubMed: 15240759]  [MGI Ref ID J:134753]

Seo H; Kim W; Isacson O. 2008. Compensatory changes in the ubiquitin-proteasome system, brain-derived neurotrophic factor and mitochondrial complex II/III in YAC72 and R6/2 transgenic mice partially model Huntington's disease patients. Hum Mol Genet 17(20):3144-53. [PubMed: 18640989]  [MGI Ref ID J:139795]

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]

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]

Weydt P; Pineda VV; Torrence AE; Libby RT; Satterfield TF; Lazarowski ER; Gilbert ML; Morton GJ; Bammler TK; Strand AD; Cui L; Beyer RP; Easley CN; Smith AC; Krainc D; Luquet S; Sweet IR; Schwartz MW; La Spada AR. 2006. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab 4(5):349-62. [PubMed: 17055784]  [MGI Ref ID J:129751]

Zeron MM; Fernandes HB; Krebs C; Shehadeh J; Wellington CL; Leavitt BR; Baimbridge KG; Hayden MR; Raymond LA. 2004. Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease. Mol Cell Neurosci 25(3):469-79. [PubMed: 15033175]  [MGI Ref ID J:89338]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

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

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

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
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.

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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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