B6.129P2-Cnr2^tm1Dgen/J

Stock number: 005786
Product name: CB2R KO
Research areas: Immunology, Inflammation and Autoimmunity Research, Neurobiology Research

Description

CB₂ is normally up-regulated following pro-inflammatory and nociceptive stimuli, and in human brain tissues affected by Alzheimer's disease (AD), multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). These CB₂ knockout mice (CB₂^-, CB₂R^- or Cnr2^-) may be useful for studying these diseases, pain management and drug/antibody therapeutics.

Detailed description

Cannabinoid receptor 2 (CB₂ or CB₂R) is normally expressed in cells of the haematopoietic lineage, central nervous system, and bone. In immune cells, CB₂ is expressed on leukocytes and localized in intracellular membranous structures. Endogenous expression is up-regulated by pro-inflammatory and nociceptive stimuli. CB₂ activation reduces expression of adhesion molecules in brain endothelium, decreasing leukocyte engagement and recruitment.
In these CB₂ knockout mice (CB₂^-/-, CB₂R^-/-, Cnr2^-/- or Cnr2^tm1Dgen), CB₂ agonists have no effect on minimizing leukocyte-endothelial cell interaction. After treatment with lipopolysaccharide (LPS), CB₂ null mice fail to show complete resolution of inflammation compared to wild type controls. An increase in leukocyte adhesion is seen when Cnr2^-/- leukocytes are transferred into wildtype recipient mice.

This CB₂ knockout mutant was created and characterized by Deltagen, Inc. View phenotypic data developed by Deltagen.

J20 transgenic amyloid mice express the K670N/M671L/V717F mutant form of amyloid precursor protein under control of the human platelet-derived growth factor β polypeptide promoter (Stock No. 006293). Hemizygous J20 mice are a Familial Alzheimer's Disease model with progressive amyloid deposition as they age (significant reactive microgliosis by 8 months of age). C57BL/6 mice homozygous for Cnr2^tm1Dgen and also harboring the J20 transgene (J20 CNR2^/-/) exhibit increased amyloid pathology (increased soluble Aβ42, plaque deposition and plaque associated microglia), but altered tau processing (suppressed total tau), when compared to J20 mice alone.

Of note, another published CB₂ knockout allele (Cnr2^tm1Zim) has been used to show CB₂-deficient macrophages are resistant to the inhibitory effects of δ-9 tetrahydrocannabinol (THC) and CB₂ knockout mice have increased severity in experimental autoimmune encephalitis. Homozygous Cnr2^tm1Zim mice also harboring the R6/2 transgene (encoding human mutant Huntington exon 1) have increased microglial activation and exacerbated Huntington disease progression/excitotoxicity compared to R6/2 mice alone.

Development

The CB₂ knockout allele (CB₂^-, CB₂R^-, Cnr2^- or Cnr2^tm1Dgen) was created by Deltagen. Specifically, the "Neo555T" construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Targeted mutant cell line 655 had homologous recombination of the "Neo555T" construct resulting in a 334 bp deletion in the coding exon of cannabinoid receptor 2 [macrophage] locus (CB₂; Cnr2) on chromosome 4. The donating investigator reported the Cnr2^- mice were backcrossed at least five generations to C57BL/6 mice (see SNP note below) prior to sending to The Jackson Laboratory Repository.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 2 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Allele

Symbol: Cnr2^tm1Dgen
Name: targeted mutation 1, Deltagen
MGI accession ID: MGI:3604531
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Cnr2
Marker name: cannabinoid receptor 2 (macrophage)
Chromosome: 4
Strain of origin: 129P2/OlaHsd
Molecular note: This gene was disrupted by homologous recombination. Normally, RNA transcripts are detectable in lung, liver, thymus, spleen, lymph nodes, bone marrow, skin and testis.