B6.129S-Atxn1^tm1Hzo/J

Stock number: 005601
Product name: Sca1^154Q/2Q, Atxn1[154Q], Atxn1^154Q/2Q
Research areas: Developmental Biology Research, Neurobiology Research

Description

These mice carry a knock-in mutation of the Atxn1 (formerly Sca1) and exhibit growth retardation, lack of motor coordination, cognitive defects, and muscle wasting, ataxia and an abnormal gait. They may be useful in studies of neurodegenerative diseases.

Detailed 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 7 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 7. 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.

Allele

Symbol: Atxn1^tm1Hzo
Name: targeted mutation 1, Huda Y Zoghbi
MGI accession ID: MGI:2429435
Generation method: Targeted
Attributes: Humanized sequence
Synonyms: Atx1-KI; atxn1^154Q; Sca1^154Q; Sca1-KI
Marker symbol: Atxn1
Marker name: ataxin 1
Marker synonyms: 2900016G23Rik; Atx1; D6S504E; Sca1
Chromosome: 13
Strain of origin: 129S7/SvEvBrd-Hprt1^b-m2
Molecular note: An expanded tract of 154 CAG repeats was engineered and knocked into exon 7 by replacing the PPPQQ codons with 154 glutamine (Q) codons. Additionally, a loxP site flanked neomycin resistance gene cassette was inserted into intron 6 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 due to the mutant protein accumulating into nuclear aggregates as mice age.