C57BL/6-Isr(HSA6;TREM2*R47H)3Mdk/J

Stock number: 039173
Product name: TREM2-GR*R47H
Strain synonyms: R47H TREM2-GR
, C57BL/6-Tc(HSA6_TREM2*R47H)1Mdk/J
Research areas: Mouse/Human Gene Homologs, Neurobiology Research

Description

Humanized transchromosomal R47H TREM2-GR (gene replacement) mice are a knock-in/knock-out model in which a 289 kb region of mouse chromosome 17 including Trem2 (triggering receptor expressed on myeloid cells 2) is exchanged for 280 kb of the human TREML1 to NCR2 (including TREM2) genomic region on chromosome 6 (HSA6). In these mice, the human TREM2 carries the Alzheimer's disease R47H risk variant. These mice may serve as base models into which additional alterations can be introduced to explore more fully the role of the TREM gene cluster in Alzheimer's disease (AD).

Detailed description

The human TREM gene cluster (TREML1 to NCR2) is associated with Alzheimer's Disease pathogenesis and microglial function. Specifically, Trem2 (triggering receptor expressed on myeloid cells 2) encodes a protein that is a part of a receptor signaling complex with TYRO protein tyrosine kinase binding protein that activates macrophages and dendritic cells during immune responses. The TREM2 R47H mutation is a missense mutation in exon 2 that is one of the strongest genetic risk factors for late-onset Alzheimer's disease.

The humanized transchromosomal R27H TREM-GR (gene replacement) mice are a knock-in/knock-out model in which the mouse genomic region (Chr17:48,404,707-48,693,648) between Treml1 (triggering receptor expressed on myeloid cells like 1) to Trem1 (triggering receptor expressed on myeloid cells 1) is replaced by the human TREM gene cluster containing TREML1, TREM2, TREML2, TREML4, TREM1, and NCR2 (including promoter, regulatory and intergenic regions; Chr6:41,099,491-41,379,205). In these mice, the human TREM2 carries the Alzheimer's disease R47H risk variant (arginine to histidine). Homozygous mice are viable and fertile with no obvious anatomical or behavior issues.

Of note, a set of TREM2-GR strains are distributed as B6J.B6N-Tc(HSA6)1Mdk/J; WT-TREM2-GR (Stock No. 039172), B6J.B6N-Tc(HSA6_TREM2*R47H)1Mdk/J; R47H-TREM2-GR (this strain, Stock No. 039173), and B6J.B6N-Tc(HSA6*rs9357347-C)1Mdk/J; rs9357347-C-TREM2-GR (Stock No. 039174).

Development

A 289 kb deletion on mouse chromosome 17 is replaced by a 280 kb syntenic region from human chromosome 6 (HSA6). In this transchromosomal (Tc) strain, the mouse Trem (Treml1, Trem2, Treml2, Treml4, Trem1) gene cluster (Chr17:48,404,707-48,693,648) gene is replaced by the human TREM (triggering receptor expressed on myeloid cells) gene cluster including: TREML1, TREM2, TREML2, (TREML3P), TREML4, TREM1, and NCR2 (Chr6:41,099,491-41,379,205). The human TREM2 gene also carries the CGC to CAC mutation at position 47 resulting in an arginine to histidine mutation (R47H) in exon 2. In addition, there are also several pseudogenes and non-coding antisense RNAs in the human genome segment. The genomic sequences are from human assembly GRCh38.p14 and the mouse assembly GRCm39. The construct included a loxN-flanked neomycin selection cassette. The construct was electroporated into C57BL/6NTac derived PRX-B6N embryonic stem cells (ES). The transient expression of Cre removed the neomycin cassette. Correctly targeted ES cells were injected into blastocysts. Chimeric animals were backcrossed to C57BL/6J (Stock No. 000664)mice for at least 2 generations by the donating laboratory. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Allele

Symbol: Isr(HSA6;TREM2*R47H)3Mdk
Name: interspecies replacement, human Chr 6, Michael Koob 3
MGI accession ID: MGI:7865622
Generation method: Targeted
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: TREM2-GR*R47H; Tc(HSA6_TREM2*R47H)1Mdk
Marker symbol: Isr(HSA6;TREM2*R47H)3Mdk
Marker name: interspecies replacement, human Chr 6, Michael Koob 3
Marker synonyms: Tc(HSA6_TREM2*R47H)1Mdk
Chromosome: 17
Strain of origin: C57BL/6NTac
Molecular note: A 288 kb deletion on mouse chromosome 17 is replaced by a 280 kb syntenic region from human chromosome 6 (HSA6). The mouse Trem (Treml1, Trem2, Treml2, Treml4, Trem1) gene cluster (Chr17:48,404,707-48,693,648) gene is replaced by the human TREM (triggering receptor expressed on myeloid cells) gene cluster including: TREML1, TREM2, TREML2, (TREML3P), TREML4, TREM1, and NCR2 (Chr6:41,099,491-41,379,205). The human TREM2 gene also carries the CGC to CAC mutation at position 47 resulting in an arginine to histidine mutation (R47H) in exon 2. In addition, there are also several pseudogenes and non-coding antisense RNAs in the human genome segment.