B6.129P2-Htt^tm2Detl/200J

Stock number: 016523
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

These huntingtin knock-in mice (originally termed HdhQ200) carry a mutant allele with a 200 CAG/polyQ repeat mutation, and exhibit a more aggressive and earlier onset of the behavioral and neurological phenotype as compared to the HdhQ150 strain (STOCK no. 4595) with progressive motor deficits starting at 50 weeks of age. This mutant strain may be useful in studies related to Huntington's disease.

Detailed description

As early as 9 weeks of age heterozygous mice exhibit cytoplasmic aggregation foci of HTT (huntingtin) protein, and by 20 weeks of age exhibit striatal neuronal intranuclear inclusions (NIIs). By 40 weeks of age, the striatal aggregation foci are perinuclear and exhibit increased immunoreactivity for ubiquitin and autophagosome marker LC3. Heterozygotes exhibit impaired balance and diminished motor coordination by 50 weeks of age, and abnormal gait by 60 weeks. By 80 weeks of age, heterozygotes display loss of grip strength, striatal and cortical astrogliosis, and a loss of approximately 50% of striatal dopamine receptor binding with increased glial fibrillary acidic protein immunoreactivity. Increased glial fibrillary acidic protein immunoreactivity is present in the striatum and ubiquititin- and huntingtin-positive neuronal intranuclear inclusions (NIIs) are detected throughout the dorsal striatum, nucleus accumbens and to a lesser extent other regions of the brain. Mutant CAG/polyQ repeat expression is slightly lower than wildtype levels as detected by Western blot analysis and qRTPCR of brain tissue. Mutant mice may be noticeably smaller than wild-type littermates. Mice homozygous for the targeted allele are viable and fertile. Onset of symptoms occurs earlier for homozygotes than for heterozygotes. Motor deficits are detected in homozygotes as early as 20 weeks of age. After 30 weeks of age mutant mice may become infertile.

This strain is one of a set of different CAG/polyQ repeat length mutants derived from HdhQ150 (STOCK no. 004595 ). The set includes, STOCK numbers: 016521, 016522, 016523, 016524, 016525.

Development

In the first step of a two step procedure, exon 1 was replaced with the selectable marker Hprt in 129P2/OlaHsd-derived HM1 embryonic stem (ES) cells. A second round of targeting was performed to replace Hprt with exon 1 sequence including a 150 CAG repeat segment. Correctly targeted ES cells were injected into C57BL/6J blastocysts. Before being donated to the Repository, the mice were backcrossed to C57BL/6J for 12 generations while being selectively bred for the 200 CAG repeat segment which arose due to repeat instability. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony. The mice must be monitored for CAG repeat length due to the instability of the repeat segment.

Allele

Symbol: Htt^tm2Detl
Name: targeted mutation 2, Peter J Detloff
MGI accession ID: MGI:2177757
Generation method: Targeted
Marker symbol: Htt
Marker name: huntingtin
Chromosome: 5
Strain of origin: 129P2/OlaHsd-Hprt1^b-m3
Molecular note: This allele carries 150 CAG repeat units in the first exon of the endogenous gene. CAG repeat numbers in this gene are highly unstable. Mice carrying this allele may have more or fewer repeats than stated in the original description.