B6J.B6N(CBA)-Tc(HSA17)1Mdk/J

Stock number: 033668
Product name: MAPT(H2.1)-GR
Strain synonyms: MAPT-GR wt(H2.1)
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

MAPT(H2.1)-GR mice express the human MAPT (H2 haplotype) and MAPT-AS1 transcripts and the typical MAPT protein isoforms.

Detailed description

The transchromosomal (Tc) MAPT(H2.1)-GR (Gene Replacement) mice contain a syntenic 190 kb region from human chromosome 17 (HSA17) that includes SPPLC2 (signal peptide peptidase 2C) and MAPT (microtubule-associated protein tau), specifically the H2 haplotype. The region replaces ~157 kb on mouse chromosome 11 stretching from, but not including, Crhr1 to Kansl1. The SPPL2C sequence is included because it is embedded entirely in the MAPT-AS1 transcribed region.

Human MAPT (microtubule-associated protein tau) is found within a 900 kb inversion on Chr 17q21 that defines two haplotypes, H1 and H2, found in Caucasians. The haplotypes are distinguished by a series of polymorphisms that include the MAPT sequence. A227A (GCA to GCG), is a silent point mutation in exon 9 of the MAPT isoform 441. The minor G allele is carried by H2 and the A allele is found in the more common H1 haplotype. H1 is linked with late onset Alzheimer's disease (AD) risk, progressive supranuclear palsy, Parkinson's disease, and corticobasal degeneration. H2 is associated with decreased risk of late onset AD, and lower MAPT levels in the cerebellum and temporal cortex.

Homozygous mice are viable and fertile and exhibit no obvious phenotype. These mice express the human MAPT (H2 haplotype), MAPT-AS1 transcripts and the typical MAPT protein isoforms. A modified H1 haplotype carrying the pathogenic N279K mutation is distributed as Stock No. 035794; a second strain, distributed as Stock No. 037420, carries the risk variant P30L. The H1 haplotype is distributed as Stock No. 035398 C57BL/6-Tc(HSA17)2Mdk/J. MAPT IVS10+16 C>T mice, distributed as Stock No. 036664, express the H1 haplotype and contain a non-coding C to T (rs63751011) mutation in intron 10.

Development

A 156.5 kb deletion on mouse chromosome 11 (Chr11:104,066,949-104,223,491) stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190.5 kb region from human chromosome 17 (HSA17; Chr17:45,838,648-46,029,144). The genomic sequences are from mouse assembly GRCm39 and human assembly GRCh38.p14 [PMID:38343132 Benzow et al., 2024 Alzheimers Dement. 20:3080]. In this transchromosomal (Tc) strain, the mouse Sppl2c (signal peptide peptidase 2C) and Mapt (microtubule-associated protein tau) genes are replaced by human SPPL2C and MAPT (H2 haplotype) genes. The genomic sequences are from human assembly GRCh38.p14 and the mouse assembly GRCm39. The deletion/insertion was made using C57BL/6N-PRX-B6N embryonic stem cells (ES) and loxN-flanked hygromycin resistance cassette. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to B6.Cg-Edil3^{Tg(Sox2-cre)1Amc}/J (Stock No. 008454) to remove the hygro cassette and then backcrossed to C57BL/6J for at least 5 generations. The Cre transgene was removed by breeding. Upon arrival, mice were bred to C57BL/6J for at least 1 generation to establish the colony.

Allele

Symbol: Tc(HSA17)1Mdk
Name: transchromosomal, human 17, line 1, Michael D Koob
MGI accession ID: MGI:6363617
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: MAPT-GR
Marker symbol: Tc(HSA17)1Mdk
Marker name: transchromosomal, human 17, line 1, Michael Koob
Chromosome: 11
Strain of origin: C57BL/6NTac
Site of expression: neurons of the central nervous system and at low levels in astrocytes and oligodentrocytes

Molecular note: A 157 kb deletion on mouse chromosome 11 stretching from, but not including, Crhr1 to Kansl1 is replaced by a syntenic 190 kb region from human chromosome 17 (HSA17). In this transchromosomal (Tc) strain, the mouse Sppl2c (signal peptide peptidase 2C) and Mapt (microtubule-associated protein tau) genes are replaced by human SPPL2C and MAPT genes and a loxN-flanked hygromycin cassette. Cre-mediated recombination removed the hygromycin cassette.