Description

Strain Information

Type Coisogenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Noncarrier x Hemizygote         (Female x Male)   10-MAR-09 Species laboratory mouse Generation N6+F5 (10-MAR-11) Generation Definitions   Donating Investigator X. William Yang,   University of California Los Angeles

Description
Mice hemizygous for the BACHD transgene are viable and fertile. Under the control of endogenous human htt regulatory machinery, BACHD mice have relatively high expression levels of a neuropathogenic, full-length human mutant Huntingtin (fl-mhtt) modified to harbor a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). Prior to Cre recombinase exposure, BACHD mice exhibit progressive motor deficits, neuronal synaptic dysfunction, and selective late-onset neuropathology without somatic polyQ repeat instability in the aged brain. Moreover, BACHD mice reproduce a mhtt aggregation pattern reminiscent of that in adult-onset Huntington's disease (HD). Importantly, a relatively steady-state level of predominantly fl-mhtt and a small amount of mhtt N-terminal fragments present in both the nucleus and cytoplasm, are responsible for the onset and progression of neuropathology. Upon exposure to Cre recombinase, the floxed mhtt-exon1 portion of the transgene is removed and fl-mhtt expression is terminated. These BACHD mice represent a robust in vivo paradigm for studying the HD pathogenesis elicited by fl-mhtt. These mice may be useful in the testing of candidate therapeutics and in studies examining the contribution of mhtt expression in individual neuronal and non-neuronal cell types in the pathogenesis of HD-like phenotypes in vivo.

Development
The 240 kb human bacterial artificial chromosome (BAC) RP11-866L6, containing the entire 170 kb human Huntingtin (htt) genomic locus and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences, was modified by replacing the human htt exon 1 with a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). DNA from a modified BAC clone was used as the source for the BACHD transgene and microinjected into FVB fertilized eggs. Mice from founder line BACHD-I were found to express relatively high levels of full-length human mutant Huntingtin (fl-mhtt) and harbor tandem integrates of approximately 5 copies of the transgene. These BACHD-I transgenic mice were subsequently maintained on the FVB/NJ genetic background for many generations prior to arrival at The Jackson Laboratory. Upon arrival, mice were bred to FVB/NJ inbred mice for at least one generation to establish the colony.

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls

Related Strains

Huntington's Disease Models

007708	B6.129-Gt(ROSA)26Sortm1(HD*103Q)Xwy/J
003454	B6.129-Htttm3Mem/J
003597	B6.129-Htttm4Mem/J
003598	B6.129-Htttm5Mem/J
016094	B6.129P2-Git2Gt(XG510)Byg/WeisJ
016522	B6.129P2-Htttm2Detl/100J
004595	B6.129P2-Htttm2Detl/150J
016521	B6.129P2-Htttm2Detl/50J
002688	B6.129S4-Htttm1Mem/J
006471	B6.Cg-Tg(HDexon1)61Gpb/J
008333	B6;129P2-Dldtm1Ptl/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
016095	C.129P2(B6)-Git2Gt(XG510)Byg/WeisJ
008833	C57BL/6-Tg(Camk2a-UBB)3413-1Fwvl/J
007578	CBy.Cg-Tg(HDexon1)61Gpb/J
013732	FVB-Tg(NPEPPS)1Skar/J
004938	FVB-Tg(YAC128)53Hay/J
012630	FVB/N-Tg(GFAP-HTT*160Q)31Xjl/J
007247	FVB/N-Tg(YAC353G6)W7Hay/J
003640	FVB/NJ-Tg(YAC72)2511Hay/J
007749	STOCK Hap1tm1Xjl/J
003453	STOCK Htttm2Mem/J
003455	STOCK Htttm4Mem/J
003456	STOCK Htttm5Mem/J

View Huntington's Disease Models     (28 strains)

Strains carrying other alleles of HTT

007708	B6.129-Gt(ROSA)26Sortm1(HD*103Q)Xwy/J
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
017485	FVB-Tg(HTT*)1Xwy/J
017487	FVB-Tg(HTT*97Q)LXwy/J
004938	FVB-Tg(YAC128)53Hay/J
012630	FVB/N-Tg(GFAP-HTT*160Q)31Xjl/J
007247	FVB/N-Tg(YAC353G6)W7Hay/J
003640	FVB/NJ-Tg(YAC72)2511Hay/J

View Strains carrying other alleles of HTT     (14 strains)

Additional Web Information

Introduction to Cre-lox technology

Visit the Huntington's Diease Resource site for helpful information on Huntington's Disease and research resources.

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.

Huntington Disease; HD

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Tg(HTT*97Q)IXwy/0

        FVB-Tg(HTT*97Q)IXwy

• nervous system phenotype
• abnormal brain morphology
  • at 6 months of age, brains do not display any obvious pathology, but at 12 months, brains are visibly atrophic compared to wild-type   (MGI Ref ID J:137345)
• • abnormal forebrain morphology
    • mice exhibit decreased forebrain weight loss compared with wild-type mice   (MGI Ref ID J:157723)
  • • abnormal cerebral cortex morphology
      • at 12 months, robust decrease in cerebral cortex volume (32% of wild-type) is observed   (MGI Ref ID J:137345)
    • abnormal striatum morphology
      • at 12 months, robust decrease in striatal volume (28% of wild-type) is observed   (MGI Ref ID J:137345)
  • decreased brain weight
    • at 12 months, forebrain weight (whole brain minus cerebellum and olfactory bulb) is 20% lower than wild-type controls; however cerebellar weight is comparable   (MGI Ref ID J:137345)
• abnormal nervous system electrophysiology
  • medium and large amplitude spontaneous currents in medium spiny neurons (MSNs) are reduced compared to wild-type, while probability of occurrence of small amplitude events is significantly elevated   (MGI Ref ID J:137345)
• abnormal neuron morphology
  • at 12 months, mice exhibit protein aggregates in the cortex and striatum unlike in wild-type mice   (MGI Ref ID J:157723)
• • neuron degeneration
    • striatal neuron degeneration is observed at 12 months, but not in wild-type brains   (MGI Ref ID J:137345)
    • at 12 months, mice exhibit selective neuropathy unlike wild-type mice   (MGI Ref ID J:157723)
  • neuronal intranuclear inclusions
    • at 12 and 18 months, large mutant huntingtin (mhtt) protein inclusions are detected in deep cortical layers with smaller inclusions found in the upper cortical layers with very few small inclusions in striatal neurons   (MGI Ref ID J:137345)
• decreased prepulse inhibition
  • observed at 36 and 52 weeks of age in females and 28 and 52 weeks in males   (MGI Ref ID J:185262)
• neurodegeneration
  • evident at 12 months in transgenic mice, but not in wild-type   (MGI Ref ID J:137345)
• • neuron degeneration
    • striatal neuron degeneration is observed at 12 months, but not in wild-type brains   (MGI Ref ID J:137345)
    • at 12 months, mice exhibit selective neuropathy unlike wild-type mice   (MGI Ref ID J:157723)
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • mice do exhibit a deterioration in grip strength as compared to controls   (MGI Ref ID J:185262)
• • abnormal depression-related behavior
    • at 12 months, mice exhibit depressive-like behavior unlike wild-type mice   (MGI Ref ID J:157723)
  • abnormal gait
    • wider base (separation between legs) at 36 weeks   (MGI Ref ID J:185262)
  • • short stride length
      • shorter splay length (contralateral) at 12 weeks, but longer splay at 36 weeks   (MGI Ref ID J:185262)
  • decreased startle reflex
    • observed at 24 and 36 weeks of age in females and 36 weeks in males   (MGI Ref ID J:185262)
  • decreased vertical activity
    • mice rear less in the center of the open field test than controls in light and dark phases at all ages   (MGI Ref ID J:185262)
    • mice exhibit a decrease in climbing activity with many mice not climbing at all   (MGI Ref ID J:185262)
  • hypoactivity
    • mice cover less total distance in light and dark phases of open field test starting at 28 weeks of age   (MGI Ref ID J:185262)
    • mice cover less distance in center starting at 28weeks in light phase   (MGI Ref ID J:185262)
  • impaired coordination
    • at 2, 6 and 12 months, transgenics display decline in performance in rotating rod tests, compared to wild-type controls; performance declines with increasing age in mutants, but age has no effect in controls   (MGI Ref ID J:137345)
    • starting at 2 months and worsening with age   (MGI Ref ID J:157723)
    • mice exhibit a progressive impairment on the rotarod test beginning at 4 weeks of age   (MGI Ref ID J:185262)
  • increased anxiety-related response   (MGI Ref ID J:157723)
    • increased preference for dark in dark/light choice test starting at 12 weeks of age   (MGI Ref ID J:185262)
    • males prefer dark at 4 weeks   (MGI Ref ID J:185262)
• growth/size phenotype
• increased body weight
  • mice show significant weight gain of 20-30% over control weights in the 2-12 month period of testing   (MGI Ref ID J:137345)
  • body weight is significantly increased in females at 12 weeks and in males at 16 weeks of age   (MGI Ref ID J:185262)

View Research Applications

Research Applications

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

Developmental Biology Research
Neurodevelopmental Defects

Mouse/Human Gene Homologs
Huntington's disease (chorea)

Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Cortical Defects
Cre-lox System
      loxP-flanked Sequences
Huntington's disease
Neurodegeneration
Neurodevelopmental Defects
Neurotransmitter Receptor and Synaptic Vesicle Defects
Tremor Defects

Research Tools
Cre-lox System
      loxP-flanked Sequences

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 provided by MGI

Allele Symbol		Tg(HTT*97Q)IXwy
Allele Name		transgene insertion I, X William Yang
Allele Type		Transgenic (random, expressed)
Common Name(s)		BACHD; BACHD-I;
Mutation Made By		X. William Yang,   University of California Los Angeles
Strain of Origin		FVB
Expressed Gene		HTT, huntingtin, human
Promoter		HTT, huntingtin, human
Molecular Note		The 240 kb human bacterial artificial chromosome BAC(RP11-866L6), containing the entire 170 kb human Huntingtin (htt) genomic locus and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences, was modified by replacing the human htt exon 1 with a loxP-flanked human mutant htt exon 1 sequence (containing 97 mixed CAA-CAG repeats encoding a continuous polyglutamine (polyQ) stretch). DNA from a modified BAC clone was used as the source for the BACHD transgene and microinjected into FVB fertilized eggs. Mice from founder line BACHD-I were found to express relatively high levels of full-length human mutant Huntingtin (fl-mhtt) in the brain by qRT-PCR and the mice harbor tandem integrates of approximately 5 copies of the transgene. Another line, named BACHD-L, was analyzed, showing that the phenotypic aspects of line I were replicated in this strain. [MGI Ref ID J:137345]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(HTT*97Q)IXwy repeat assay, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Gray M; Shirasaki DI; Cepeda C; Andre VM; Wilburn B; Lu XH; Tao J; Yamazaki I; Li SH; Sun YE; Li XJ; Levine MS; Yang XW. 2008. Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28(24):6182-95. [PubMed: 18550760]  [MGI Ref ID J:137345]

Menalled L; El-Khodor BF; Patry M; Suarez-Farinas M; Orenstein SJ; Zahasky B; Leahy C; Wheeler V; Yang XW; MacDonald M; Morton AJ; Bates G; Leeds J; Park L; Howland D; Signer E; Tobin A; Brunner D. 2009. Systematic behavioral evaluation of Huntington's disease transgenic and knock-in mouse models. Neurobiol Dis 35(3):319-36. [PubMed: 19464370]  [MGI Ref ID J:185262]

Additional References

Tg(HTT*97Q)IXwy related

Bouchard J; Truong J; Bouchard K; Dunkelberger D; Desrayaud S; Moussaoui S; Tabrizi SJ; Stella N; Muchowski PJ. 2012. Cannabinoid receptor 2 signaling in peripheral immune cells modulates disease onset and severity in mouse models of Huntington's disease. J Neurosci 32(50):18259-68. [PubMed: 23238740]  [MGI Ref ID J:192012]

Crook ZR; Housman D. 2011. Huntington's disease: can mice lead the way to treatment? Neuron 69(3):423-35. [PubMed: 21315254]  [MGI Ref ID J:174750]

Gafni J; Papanikolaou T; Degiacomo F; Holcomb J; Chen S; Menalled L; Kudwa A; Fitzpatrick J; Miller S; Ramboz S; Tuunanen PI; Lehtimaki KK; Yang XW; Park L; Kwak S; Howland D; Park H; Ellerby LM. 2012. Caspase-6 Activity in a BACHD Mouse Modulates Steady-State Levels of Mutant Huntingtin Protein But Is Not Necessary for Production of a 586 Amino Acid Proteolytic Fragment. J Neurosci 32(22):7454-7465. [PubMed: 22649225]  [MGI Ref ID J:184973]

Gu X; Greiner ER; Mishra R; Kodali R; Osmand A; Finkbeiner S; Steffan JS; Thompson LM; Wetzel R; Yang XW. 2009. Serines 13 and 16 are critical determinants of full-length human mutant huntingtin induced disease pathogenesis in HD mice. Neuron 64(6):828-40. [PubMed: 20064390]  [MGI Ref ID J:157723]

Kudo T; Schroeder A; Loh DH; Kuljis D; Jordan MC; Roos KP; Colwell CS. 2011. Dysfunctions in circadian behavior and physiology in mouse models of Huntington's disease. Exp Neurol 228(1):80-90. [PubMed: 21184755]  [MGI Ref ID J:170728]

Pouladi MA; Stanek LM; Xie Y; Franciosi S; Southwell AL; Deng Y; Butland S; Zhang W; Cheng SH; Shihabuddin LS; Hayden MR. 2012. Marked differences in neurochemistry and aggregates despite similar behavioural and neuropathological features of Huntington disease in the full-length BACHD and YAC128 mice. Hum Mol Genet 21(10):2219-32. [PubMed: 22328089]  [MGI Ref ID J:183804]

Pouladi MA; Xie Y; Skotte NH; Ehrnhoefer DE; Graham RK; Kim JE; Bissada N; Yang XW; Paganetti P; Friedlander RM; Leavitt BR; Hayden MR. 2010. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression. Hum Mol Genet 19(8):1528-38. [PubMed: 20097678]  [MGI Ref ID J:158346]

Shirendeb UP; Calkins MJ; Manczak M; Anekonda V; Dufour B; McBride JL; Mao P; Reddy PH. 2012. Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease. Hum Mol Genet 21(2):406-20. [PubMed: 21997870]  [MGI Ref ID J:179024]

Southwell AL; Warby SC; Carroll JB; Doty CN; Skotte NH; Zhang W; Villanueva EB; Kovalik V; Xie Y; Pouladi MA; Collins JA; Yang XW; Franciosi S; Hayden MR. 2013. A fully humanized transgenic mouse model of Huntington disease. Hum Mol Genet 22(1):18-34. [PubMed: 23001568]  [MGI Ref ID J:191147]

Spampanato J; Gu X; Yang XW; Mody I. 2008. Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease. Neuroscience 157(3):606-20. [PubMed: 18854207]  [MGI Ref ID J:144587]

Xiang Z; Valenza M; Cui L; Leoni V; Jeong HK; Brilli E; Zhang J; Peng Q; Duan W; Reeves SA; Cattaneo E; Krainc D. 2011. Peroxisome-Proliferator-Activated Receptor Gamma Coactivator 1 {alpha} Contributes to Dysmyelination in Experimental Models of Huntington's Disease. J Neurosci 31(26):9544-9553. [PubMed: 21715619]  [MGI Ref ID J:174060]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, hemizygous mice may be bred to wildtype siblings or to FVB/NJ inbred mice.
Mating System	Noncarrier x Hemizygote         (Female x Male)   10-MAR-09
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Noncarrier
	001800 FVB/NJ
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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