FVB/N-Tg(HTT*)NXwy/J

Stock number: 027379
Product name: BACHD-ΔN17
Research areas: Developmental Biology Research, Neurobiology Research

Description

BACHD-ΔN17 transgenic mice express a mutant human HTT (huntingtin) gene that produces a pathogenic protein with a 97 polyQ repeat expansion. They also contain a deletion of the N17 domain. These mice are important when studying the regulation of mutant HTT nucleocytoplasmic trafficking, aggregation, and disease pathogenesis.

Detailed description

BACHD-ΔN17 transgenic mouse model expresses a modified human HTT (mHTT) BAC that contains an exon 1 with 97 mixed CAA-CAG repeats, but lacking the sequence encoding the residues 2-16 in the first 17 amino acid domain (N17) of mHTT. The mHTT exon 1 is also flanked by two loxP sites, similar to the construct design of BACHD (see Stock No. 008197), allowing for cre-mediated reduction of mHTT expression. The ΔN17 form of mHTT expressed in BACHD-ΔN17 mice can rescue the embryonic lethality phenotype of murine Htt knockout mice. Compared to BACHD mice (see Stock No. 008197), BACHD-ΔN17 mice exhibit earlier disease onset and recapitulates several features reminiscent of clinically manifest HD, including adult-onset chorea and dystonia-like movement, progressive neurological and general health decline, robust cortical and striatal atrophy, and marked striatal medium spiny neuron loss. In addition, the model also showed HD-like peripheral pathology including skeletal muscle atrophy and testicular degeneration. Finally, BACHD-ΔN17 mice show HD-like transcriptional dysregulation in the striatum, and evidence for neuroinflammation that is similar to both HD and Alzheimer's disease. Both the male and female hemizygous transgenic mice are fertile at young adult age (2-4 months), but show decreased fertility and eventually become infertile at older ages. Homozygotes are viable but infertile.

Development

The 240 kb human bacterial artificial chromosome (BAC) RP11-866L6 containing the entire 170kb 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, encoding a continuous polyglutamine (polyQ) stretch. This BAC was also modified to have a deletion of residues 2-16 in the N17 domain in exon 1, upstream of the polyQ sequence. The transgenic construct was microinjected into the pronucleus of FVB/NJ fertilized eggs. Founder line N was subsequently established and maintained on the FVB/NJ background. Upon arrival at The Jackson Laboratory, the mice were crossed to FVB/NJ (Stock No. 001800) at least once to establish the colony.

Allele

Symbol: Tg(HTT*)NXwy
Name: transgene insertion N, X William Yang
MGI accession ID: MGI:5635152
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(HTT*)NXwy
Marker name: transgene insertion N, X William Yang
Chromosome: UN
Strain of origin: FVB/NJ
Expressed genes: HTT,huntingtin,human
Molecular note: The 240 kb human bacterial artificial chromosome (BAC RP11-866L6), containing the entire 170 kb human Huntingtin genomic locus and approximately 20 kbp of 5' and 50 kbp of 3' flanking sequences and modified to replace 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 stretch was further modified to delete the first 17-amino-acid domain (N17; residues 2-16). This modified BAC containing both the 97Q and the deleted N17 domain was microinjected into FVB/NJ fertilized eggs. Three founders were established; N, L, and A. Line N and L show a similar level of expression.