FVB/N-Tg(HTT*97Q)LXwy/ChdiJ

Stock number: 027433
Product name: FVB.BAC HD ; BACHD on FVB/NJ back ground ; CHDI-81001011
Research areas: Mouse/Human Gene Homologs, Neurobiology Research, Research Tools

Description

The FVB/N-congenic BAC HD transgenic line L expresses multiple copies of a transgene encoding the full-length human huntingtin gene (HTT; HD or Hdh) modified to have a floxed exon 1 containing 97 mixed CAA-CAG repeats. These FVB.BAC HD (or FVB.BACHD-L) mice may be useful for studying Huntington's disease on a defined congenic background, as well as for exploring the effect of interrupted CAG tracts versus non-interrupted CAG tracts on somatic instability and RNA structure mechanisms in HD pathophysiology.

Detailed description

Stock No. 027433 was formerly associated with CHDI Foundation colony Stock No. 370192 [CHDI-81001011].

Huntington's disease (HD) is an autosomally dominant, fatal neurodegenerative disorder characterized by uncontrolled movements, psychiatric disturbances and cognitive impairment. HD is caused by an unstable trinucleotide (polyglutamine) repeat expansion in the huntingtin gene (HTT; HD or Hdh).


The BAC HD transgenic mouse line L expresses multiple copies of full-length human HTT with a mutant exon 1 containing a 97 glutamine repeat tract (mixed CAG-CAA repeats) at levels 1.5 to 2 times higher than the endogenous mouse Htt; a function of higher numbers of transgene copies inserted. Of note, the mutant exon 1 is flaked with loxP sites.

Stock No. 027433: The FVB/N-congenic BAC HD transgenic mouse line L is called FVB.BAC HD or FVB.BACHD-L. Hemizygous mice are viable, fertile and normal in size. Hemizygous mice are viable and fertile, with activity defects (hyperactivity in ~8 week old females but hyperactivity by 8 weeks [mainly in females)), abnormal gait, and motor impairment (rotarod deficit ~4 weeks of age). These mice exhibit weight gain (which can confound motor endpoint evaluation) evident in both sexes from ~4 weeks of age. Overall survival is similar to wildtype (noncarrier) mice up to 1 year of age or longer. The FVB.BACHD-L mice are not further characterized to date (April 2014).


While genetic background may lead to variations in disease severity/progression, these FVB.BACHD-L mice may exhibit a phenotype similar to that of BAC HD mice from the same founder line with less backcrossing onto the FVB/N genetic background (described and available as Stock No. 017487. Briefly, mutant HTT protein is detected in cortex, striatum, and cerebellum by Western blot analysis. qPCR results indicated that there are tandem integrations of approximately 5 copies of the transgene. The 97 CAA-CAG repeat length is stable in maternal and paternal germline transmission, as well as in brain tissue from 12 month old transgenic mice. Onset of progressive motor deficits is 2 months of age. Transgenic mice weigh 8-14% more than wildtype controls. In transgenic mice 12 months of age, a few mutant HTT protein aggregates are observed in the cortical neuropil, with tiny aggregates in the striatum, which is similar to the pattern seen in adult onset Huntington's Disease.

Importantly, if a behavioral testing battery includes cognitive tests that require the animals to use visual cues, the C57BL/6 genetic background mice may be preferred as the FVB/N genetic background imparts the Pde6b^rd1 mutation causing retinal degeneration and blindness at an early age. In addition, the relatively high aggression levels in FVB/N mice, especially males, may cause problems during experiments that require long-term group-housing. Conversely, mice on the C57BL/6-congenic background may exhibit age-related hearing loss and become deaf to certain frequencies.

This Huntington's disease mouse model is available by way of a collaborative effort between CHDI Foundation, Dr. X. William Yang (University of California, Los Angeles) and The Jackson Laboratory.

Development

The BAC HD transgene was designed by Dr. X. William Yang (University of California, Los Angeles). The 240 kbp human bacterial artificial chromosome (BAC) RP11-866L6 containing the entire 170 kbp human HTT gene, and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences, was modified by replacing exon 1 with a loxP-flanked fragment containing 97 mixed CAA-CAG repeats. The transgenic construct was microinjected into the pronucleus of FVB/N fertilized eggs. Founder line L was subsequently established and maintained on the FVB/NJ background. BAC HD mice were sent to the CHDI Foundation colony, where they were backcrossed with FVB/N inbred mice for several generations to create the FVB/N-congenic colony (FVB.BAC HD or FVB.BACHD-L), called CHDI Foundation colony Stock No. 370192 [CHDI-81001011]. In 2015, FVB.BAC HD animals from backcross generation N21-N22 were sent from the CHDI Foundation colony to The Jackson Laboratory Repository, from which FVB.BAC HD hemizygous mice are available as Stock No. 027433.

Allele

Symbol: Tg(HTT*97Q)LXwy
Name: transgene insertion L, X William Yang
MGI accession ID: MGI:4438228
Generation method: Transgenic
Attributes: Conditional ready (e.g. floxed); Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(HTT*97Q)LXwy
Marker name: transgene insertion L, X William Yang
Chromosome: UN
Strain of origin: FVB
Expressed genes: 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). Two lines were created (line I and L) that exhibit the same phenotype.