B6.FVB-Tg(Camk2a-MAPT*P301L)412677Jlws/J

Stock number: 041448
Product name: cTau^P301L
Research areas: Neurobiology Research

Description

cTau^P301L mice express the P301L mutant variant of the human MAPT gene, directed by the mouse Camk2a promoter. These mice may be useful when studying tauopathies, including frontotemporal lobar degeneration (FTLD-tau) and Alzheimer’s disease.

Detailed description

Tau protein, encoded by the microtubule associated protein tau (MAPT) gene, binds to tubulin and supports stabilization of microtubules that are implicated in the development and maintenance of neuronal axons and dendrites. MAPT mutations have been associated with frontotemporal dementia. These cTau^P301L transgenic mice express the P301L mutant variant of the human four-repeat microtubule-associated protein tau (MAPT gene), directed by the mouse calcium/calmodulin-dependent protein kinase II alpha (Camk2a) promoter.

Hemizygous cTau^P301L transgenic mice are viable and fertile; the viability of homozygous mice is not known. On a mixed B6;FVB genetic background, cTau^P301L hemizygotes demonstrate working memory deficits by 6 months of age and insoluble tau deposits including neurofibrillary tangles by 8 months of age. Notably, these cTau^P301L mice do not show any motor deficits prior to the onset of memory impairment, which is a phenotype seen in the Tet-controllable Camk2a P301L Tg (rTg4510) transgenic mouse line (Stock No. 024854). The donating laboratory has mapped the cTau^P301L transgene to chromosome 10 of the mouse genome via targeted locus amplification, where the insertion resulted in a 4.6kb deletion in a non-coding region of the mouse genome (GRCm39). Whereas the rTg4510 mouse line transgenes have been confirmed to have integrated into protein-coding loci on chromosomes 12 and 14 respectively. Specifically, the rTg4510 integrations have resulted in complete or partial deletions in the Vipr2, Wdr60, Esyt2, D430020J02Rik, Ncapg2 and Ptprn2 genes on chromosome 12 as well as the Fgf14 gene on chromosome 14. The additional mutations and unwanted deletions in the TET-inducible rTg4510 mouse line may affect onset of atrophy and tau pathology, as well as behavior.

The cTau^P301L transgenic mice may be useful when studying tauopathies, including frontotemporal lobar degeneration (FTLD-tau) and Alzheimer's disease.

Development

The cTau^P301L transgene was designed to have mouse calcium/calmodulin-dependent protein kinase II alpha (Camk2a) promoter driving expression of the human mutant ON4R tauP301L cDNA sequence. The transgene construct was created by removing the promoter sequences from the PrP.Xho vector and inserting a 4.5kb sequence that contained the entire promoter for the mouse Camk2a gene (GRCm38/10 Chr18:60,921,118-60,925,679). The ON4R tauP301L cDNA sequence encodes the human four-repeat microtubule-associated protein tau (MAPT) lacking the amino terminal sequence (ON4R) and containing the frontotemporal dementia-associated P301L mutation. The 0N4R tau P301L cDNA, which included an optimized Kozak sequence just upstream of the ATG start codon, was inserted into the unique Xho1 site in a CaMKII.PrP.Xho vector. The final cTau^P301L transgene was microinjected into fertilized FVB/N oocytes. The resulting mice were then backcrossed on to a C57BL/6J (Stock No. 000664) for at least 6 generations by the donating laboratory. Upon arrival at The Jackson Laboratory Repository, sperm was cryopreserved. To generate a live colony, an aliquot of the frozen sperm was used to fertilize C57BL/6J oocytes.

Of note, the donating laboratory has mapped the founder line 412677 cTau^P301L transgene to chromosome 10 of the mouse genome via targeted locus amplification. The insertion resulted in a 4.6kb deletion in a non-coding region of the mouse genome (GRCm39). The insertion is most closely flanked by upstream and downstream genes Gm47226 and Gm47227, respectively. Integration analysis also suggests that the single integration site possesses 20-135 vector copies (including partial copies).

Allele

Symbol: Tg(Camk2a-MAPT*P301L)412677Jlws
Name: transgene insertion 412677, Jada Lewis
MGI accession ID: MGI:8325608
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Marker symbol: Tg(Camk2a-MAPT*P301L)412677Jlws
Marker name: transgene insertion 412677, Jada Lewis
Chromosome: 10
Strain of origin: FVB/N
Molecular note: The transgene consists of the mouse calcium/calmodulin-dependent protein kinase II alpha (Camk2a) promoter driving expression of the human mutant ON4R tauP301L cDNA sequence.