JAX Mouse Strain Datasheet - 025637

STOCK Tor1a^tm2Wtd/J

Stock No:: 025637

Targeted Mutation

Cryo Recovery

Overview

Tor1a^ΔE mice contain a pathogenic glutamic acid residue deletion in the Tor1a gene, making this stain useful for studying DYT1 dystonia.

Donating Investigator

William Dauer, University of Michigan Medical School

Genetic overview

Genetic Background	Generation

Tor1a^tm2Wtd

Allele Type	Gene Symbol	Gene Name
Targeted (Hypomorph)	Tor1a	torsin family 1, member A (torsin A)

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Research Applications

Developmental Biology Research
Neurobiology Research

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Base Price

Starting at:

$2,595.00 Domestic price Cryo Recovery

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Details

Detailed Description

Tor1a^ΔE mice contain a pathogenic glutamic acid residue deletion in exon 5 of the torsin family 1, member A (torsin A) (Tor1a) gene, resulting in the ΔE knockin. TOR1A is an ATPases Associated with diverse Activities (AAA⁺) protein residing in the lumen of the ER/nuclear envelope (ER/NE) space. The in-frame ΔE deletion in TOR1A has been shown to cause the autosomal dominant disorder, DYT1 dystonia, which is characterized by abnormal, involuntary twisting movements and muscle contractions due to selective dysfunction of CNS motor circuits. Mice that are homozygous for this allele die within the first day of life due to failure to feed. Heterozygous Tor1a^ΔE/+ mice are viable and do not display abnormal movements, nor any neuropathological abnormalities when analyzed using standard histopathological methods. Detailed morphometric studies suggest that medium spiny striatal neurons show fewer and thinner dendrites, and electron microscopy indicates a reduction in the ration of ado-spinous to axo-dendritic inputs to striatum.

This line can be used in conjunction with mice carrying a floxed Tor1a allele (Stock No. 025832) and B6.Cg-Tg(Nes-cre)1Kln/J mice (Stock No. 003771) to generate the first viable model of primary dystonia with overt twisting movements similar to those seen in the human disease; these animals also exhibit selective areas of neurodegeneration in discrete sensorimotor structures. To generate such nestin selective knock-in mice ("N-SKI"), Stock Nos. 025832 and 003771 are first intercrossed to generate animals with one floxed Tor1a allele and the nestin-Cre transgene. These animals are subsequently crossed to this line carrying the ΔE allele (Stock No. 25637) to yield N-SKI Tor1aflox/ΔE Cre+ animals.

Development

A targeting construct was made to create a pathogenic glutamic acid residue deletion in exon 5 of the torsin family 1, member A (torsin A) (Tor1a) gene, resulting in the ΔE knockin shown to cause the autosomal dominant disorder, DYT1 dystonia. The targeting vector also contained a loxP-flanked neo cassette upstream of exon 5. The construct was electroporated into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺-derived W9.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and resulting chimeric mice were bred to 129SvEv/Tac mice. Offspring were bred with Hs-cre6 transgenic mice to delete the neo cassette, and progeny were crossed to remove the Cre-expressing transgene. These Tor1a^ΔE mice were maintained on a mixed background. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Goodchild RE; Kim CE; Dauer WT. 2005. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48(6):923-32. PubMed: 16364897 MGI: J:107596

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Genetics

Tor1a^tm2Wtd

Allele Symbol: Tor1a^tm2Wtd

Allele Name	targeted mutation 2, William T Dauer
Allele Type	Targeted (Hypomorph)
Allele Synonym(s)	DYT1 KI; DYT1(deltaE); Tor1a^deltaE; Tor1a^deltagag
Gene Symbol and Name	Tor1a, torsin family 1, member A (torsin A)
Gene Synonym(s)	DQ2; DYT1; Dyt1; Dyt1; dystonia 1; torsin family 1, member A; torsinA
Strain of Origin	129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Chromosome	2
Molecular Note	A targeting vector was designed to create a pathogenic glutamic acid deletion in exon 5. A neomycin resistance gene included in the vector was subsequently removed via cre mediated recombination.

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

Developmental Biology Research
- Postnatal Lethality
  - Homozygous
Neurobiology Research
- Ataxia (Movement) Defects
- Cerebellar Defects
- Channel and Transporter Defects
  - calcium: glutamate receptor
- Receptor Defects
  - dopamine receptor

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Tor1a^tm2Wtd/Tor1a⁺
B6.129S1-Tor1a^tm2Wtd

nervous system phenotype

abnormal Purkinje cell dendrite morphology
- Purkinje cells show subtle abnormalities among the dendritic trees, showing fewer dendrites and shorter total dendritic lengths
- dendritic spines in Purkinje cells appear thinner and less complex, showing a 14% lower spine density in mutants and 5% lower spine density in females compared to males

abnormal brain white matter morphology
- abnormal white matter microstructure, showing a reduction in fractional anisotropy, a magnetic resonance diffusion tensor imaging index of axonal integrity and coherence
- white matter abnormalities are localized to the right superior cerebellar tract, the white matter subjacent to the right primary sensorimotor cortex, and the left caudate/putamen

abnormal cerebellum vermis morphology
- FDG microPET indicates a single brain region with abnormal glucose utilization localized to the superior cerebellar vermis, with increased local metabolic activity

abnormal dorsal striatum morphology
- fractional anisotropy reduction in the caudate/putamen

abnormal nervous system tract morphology
- fewer tracts, with fiber count reductions, in the rostral (-59%) and caudal (-86%) pontocerebellar pathways
- reduction of tract numbers in cerebellothalamic (-49%), thalamocortical (-55%) and thalamostriatal (-86%) projection pathways

ectopic Purkinje cell
- heterotopic Purkinje cells are more frequent in the caudal cerebellum compared to the anterior cerebellum
- mutants exhibit 33% more heterotopic Purkinje cells in the cerebellum than controls

enlarged cerebellum
- however, no structural abnormality of deep cerebellar nuclei neurons or Purkinje cell numbers
- subtle enlargement of the cerebellum, with total volume of the cerebellum including granule cell layer, molecular cell layer, and deep cerebellar nuclei is slightly increased

behavior/neurological phenotype

behavior/neurological phenotype
- males do not display altered responses to drug challenge
- males exhibit normal motor activity in the open field and habituate similar to wild-type males, normal rotarod behavior and similar performance to wild-type on the beam-walking test

Genotype: Tor1a^tm2Wtd/Tor1a⁺
involves: 129S1/Sv

cellular phenotype

abnormal cell nucleus morphology
- nuclear envelope is normal compared to homozygous Tor1a homozygous or compound mutants

nervous system phenotype

abnormal neuron physiology
- hippocampal neurons exhibit a prolonged cytoplasmic calcium concentration decay, indicating that neurons experience calcium overload
- treatment with glutamate-receptor antagonist results in the ablation of this prolonged decay

behavior/neurological phenotype

behavior/neurological phenotype
- males have no apparent behavioral abnormalities

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * C57BL/6J

mortality/aging

neonatal lethality, complete penetrance
- Background Sensitivity - median lifespan is 0.5 days, shorter than on a 129S1/Sv background or other backgrounds studied

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

mortality/aging

neonatal lethality, complete penetrance
- Background Sensitivity - median survival is 1.5 days, longer than on a mixed 129S1/Sv and C57BL/6 background but shorter than on a mixed 129S1/Sv/CD-1/ICR or mixed 129S1/Sv and DBA/2J background
- homozygotes typically die within 48 hours after birth

cellular phenotype

abnormal cell nucleus morphology
- E18.5 mutants exhibit nuclear envelope bleb formation in the cortex (7%), striatum (1.2%), and cerebellum (81%)
- lumen of the nuclear envelope contains large numbers of vesicles that appear to derive from the inner nuclear membrane; ventral horn neurons are most affected

behavior/neurological phenotype

abnormal suckling behavior
- homozygous pups fail to feed after birth

decreased vocalization
- homozygous pups do not vocalize after birth

nervous system phenotype

abnormal neuron physiology
- hippocampal neurons exhibit an accelerated cytoplasmic calcium concentration decay compared to controls
- treatment with glutamate-receptor antagonist does not affect the accelerated decay seen in neurons

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * CD-1

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median lifespan is 2.5 days and all mutants die by P3.5; survival is longer than on the 129S1/Sv or mixed 129S1/Sv and C57BL/6 background

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
D2.129S1-Tor1a^tm2Wtd

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median survival is 1.5 days, similiar to survival on the 129S1/Sv background but longer than on a mixed 129S1/Sv and C57BL/6J background and shorter than on mixed 129S1/Sv/CD-1/ICR and mixed 129S1/Sv/DBA/2J backgrounds

cellular phenotype

abnormal cell nucleus morphology
- E18.5 mutants exhibit nuclear envelope bleb formation in the cortex (8%), striatum (6%), and cerebellum (71%)

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * DBA/2J

mortality/aging

postnatal lethality, complete penetrance
- Background Sensitivity - median survival is 3.5 days, although survival up to 21 days is seen and 13.2% live longer than 7 days; survival is longer than any of the other backgrounds studied, including on the 129S1/Sv or a mixed 129S1/Sv and C57BL/6J background

behavior/neurological phenotype

abnormal eating behavior
- pups do not feed well and appear generally ill

abnormal gait
- mutants that live through the end of the first postnatal week develop abnormal motor behavior, showing tremor and prolonged twisting movements gait, particularly of the hindlimbs

tremors
- mutants that live through the end of the first postnatal week develop abnormal motor behavior, showing tremor and prolonged twisting movements gait, particularly of the hindlimbs

Genotype: Tor1a^tm2Wtd/Tor1a^tm4.2Wtd
involves: 129S/SvEv * 129S1/Sv * C57BL/6

behavior/neurological phenotype

abnormal reflex
- sustained forepaw straining during tail suspension
- truncal twisting during tail suspension

decreased grip strength
- impaired ability to remain suspended in horizontal grid hang test (decreased latency to fall)

hunched posture
- hunched posture on balance beam

impaired balance
- balance beam crossing using forepaws and dragging hind paws
- increased number of footslips on balance beam as compared to control

impaired coordination
- balance beam crossing using forepaws and dragging hind paws
- increased number of footslips on balance beam as compared to control

limb grasping
- forelimb clasping during tail suspension

tremors

weakness

growth/size/body region phenotype

decreased body weight
- reduced body weight beginning at P7 as compared to controls

mortality/aging

premature death
- 47.37% survival rate
- most of loss occurs by 30 days of age

nervous system phenotype

abnormal cerebellum deep nucleus morphology
- reduced numbers of deep cerebellar nuclei

abnormal neuron morphology
- ubiquitin accumulation found in deep cerebellar nuclei, cortex, thalamus, red nucleus and facial motor nucleus

gliosis
- regions of gliosis found in deep cerebellar nuclei, cortex, thalamus, red nucleus and facial motor nucleus

neurodegeneration

vision/eye phenotype

delayed eyelid opening

The following phenotype relates to a compound genotype created using this strain

Genotype: Tor1a^tm1Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

cellular phenotype

abnormal cell nucleus morphology
- lumen of the nuclear envelope contains large numbers of vesicles that appear to derive from the inner nuclear membrane

References

Goodchild RE; Kim CE; Dauer WT. 2005. Loss of the dystonia-associated protein torsinA selectively disrupts the neuronal nuclear envelope. Neuron 48(6):923-32. PubMed: 16364897 MGI: J:107596

Additional - Tor1a^tm2Wtd related

Bode N; Massey C; Gonzalez-Alegre P. 2012. DYT1 knock-in mice are not sensitized against mitochondrial complex-II inhibition. PLoS One 7(8):e42644. PubMed: 22880064 MGI: J:189823
Dominguez Gonzalez B; Billion K; Rous S; Pavie B; Lange C; Goodchild R. 2018. Excess LINC complexes impair brain morphogenesis in a mouse model of recessive TOR1A disease. Hum Mol Genet 27(12):2154-2170. PubMed: 29868845 MGI: J:263180
Gordon KL; Glenn KA; Bode N; Wen HM; Paulson HL; Gonzalez-Alegre P. 2012. The ubiquitin ligase F-box/G-domain protein 1 promotes the degradation of the disease-linked protein torsinA through the ubiquitin-proteasome pathway and macroautophagy. Neuroscience 224:160-71. PubMed: 22917612 MGI: J:192485
Iwabuchi S; Kakazu Y; Koh JY; Harata NC. 2013. Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model. Neurosci Lett 548:61-6. PubMed: 23748075 MGI: J:201535
Iwabuchi S; Koh JY; Wang K; Ho KW; Harata NC. 2013. Minimal Change in the cytoplasmic calcium dynamics in striatal GABAergic neurons of a DYT1 dystonia knock-in mouse model. PLoS One 8(11):e80793. PubMed: 24260480 MGI: J:209674
Kim CE; Perez A; Perkins G; Ellisman MH; Dauer WT. 2010. A molecular mechanism underlying the neural-specific defect in torsinA mutant mice. Proc Natl Acad Sci U S A 107(21):9861-6. PubMed: 20457914 MGI: J:160544
Liang CC; Tanabe LM; Jou S; Chi F; Dauer WT. 2014. TorsinA hypofunction causes abnormal twisting movements and sensorimotor circuit neurodegeneration. J Clin Invest 124(7):3080-92. PubMed: 24937429 MGI: J:213785
Richter F; Gerstenberger J; Bauer A; Liang CC; Richter A. 2017. Sensorimotor tests unmask a phenotype in the DYT1 knock-in mouse model of dystonia. Behav Brain Res 317:536-541. PubMed: 27769743 MGI: J:242639
Scarduzio M; Zimmerman CN; Jaunarajs KL; Wang Q; Standaert DG; McMahon LL. 2017. Strength of cholinergic tone dictates the polarity of dopamine D2 receptor modulation of striatal cholinergic interneuron excitability in DYT1 dystonia. Exp Neurol 295:162-175. PubMed: 28587876 MGI: J:262125
Sciamanna G; Napolitano F; Pelosi B; Bonsi P; Vitucci D; Nuzzo T; Punzo D; Ghiglieri V; Ponterio G; Pasqualetti M; Pisani A; Usiello A. 2015. Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons. Neurobiol Dis 78:146-61. PubMed: 25818655 MGI: J:223351
Song CH; Bernhard D; Bolarinwa C; Hess EJ; Smith Y; Jinnah HA. 2013. Subtle microstructural changes of the striatum in a DYT1 knock-in mouse model of dystonia. Neurobiol Dis 54:362-71. PubMed: 23336980 MGI: J:197748
Song CH; Bernhard D; Hess EJ; Jinnah HA. 2014. Subtle microstructural changes of the cerebellum in a knock-in mouse model of DYT1 dystonia. Neurobiol Dis 62:372-80. PubMed: 24121114 MGI: J:201962
Tanabe LM; Martin C; Dauer WT. 2012. Genetic background modulates the phenotype of a mouse model of DYT1 dystonia. PLoS One 7(2):e32245. PubMed: 22393392 MGI: J:185289
Ulug AM; Vo A; Argyelan M; Tanabe L; Schiffer WK; Dewey S; Dauer WT; Eidelberg D. 2011. Cerebellothalamocortical pathway abnormalities in torsinA DYT1 knock-in mice. Proc Natl Acad Sci U S A 108(16):6638-43. PubMed: 21464304 MGI: J:171370
Weisheit CE; Dauer WT. 2015. A novel conditional knock-in approach defines molecular and circuit effects of the DYT1 dystonia mutation. Hum Mol Genet 24(22):6459-72. PubMed: 26370418 MGI: J:225567

Service	Genotype	Price
	Heterozygous or wildtype for Tor1a<tm2Wtd>

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Tor1atm2Wtd

Allele Symbol: Tor1atm2Wtd

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Tor1atm2Wtd/Tor1a+B6.129S1-Tor1atm2Wtd

nervous system phenotype

behavior/neurological phenotype

Genotype: Tor1atm2Wtd/Tor1a+involves: 129S1/Sv

cellular phenotype

nervous system phenotype

behavior/neurological phenotype

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * C57BL/6J

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv

mortality/aging

cellular phenotype

behavior/neurological phenotype

nervous system phenotype

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * CD-1

mortality/aging

Genotype: Tor1atm2Wtd/Tor1atm2WtdD2.129S1-Tor1atm2Wtd

mortality/aging

cellular phenotype

Genotype: Tor1atm2Wtd/Tor1atm2Wtdinvolves: 129S1/Sv * DBA/2J

mortality/aging

behavior/neurological phenotype

Genotype: Tor1atm2Wtd/Tor1atm4.2Wtdinvolves: 129S/SvEv * 129S1/Sv * C57BL/6

behavior/neurological phenotype

growth/size/body region phenotype

mortality/aging

nervous system phenotype

vision/eye phenotype

Genotype: Tor1atm1Wtd/Tor1atm2Wtdinvolves: 129S1/Sv

cellular phenotype

References

Additional - Tor1atm2Wtd related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

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Tor1a^tm2Wtd

Allele Symbol: Tor1a^tm2Wtd

Genotype: Tor1a^tm2Wtd/Tor1a⁺
B6.129S1-Tor1a^tm2Wtd

Genotype: Tor1a^tm2Wtd/Tor1a⁺
involves: 129S1/Sv

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * C57BL/6J

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * CD-1

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
D2.129S1-Tor1a^tm2Wtd

Genotype: Tor1a^tm2Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv * DBA/2J

Genotype: Tor1a^tm2Wtd/Tor1a^tm4.2Wtd
involves: 129S/SvEv * 129S1/Sv * C57BL/6

Genotype: Tor1a^tm1Wtd/Tor1a^tm2Wtd
involves: 129S1/Sv

Additional - Tor1a^tm2Wtd related