STOCK Arg2^tm1Weo/J

Stock number: 020286
Research areas: Cardiovascular Research, Metabolism Research, Neurobiology Research, Sensorineural Research

Description

This strain carries a targeted mutation of the Arg2 (arginase type II) gene and may be helpful in studies of arginine homeostasis, vascular dysfunction, and neurodegeneration associated with retinopathy of prematurity.

Detailed description

ARG2 (arginase type II) protein, found in mitochondria, catalyzes the hydrolysis of arginine to ornithine and urea. It is widely distributed, but most highly expressed in the prostate and kidney.

This strain carries a targeted mutation of Arg2. Homozygous mutant mice exhibit hyperargininemia but are normal with respect to several related amino acids (Cit, Orn, Pro). When treated with streptozotocin to induce diabetes, homozygotes show less stiffening of the carotid artery than wildtype diabetic mice. In a model of retinopathy of prematurity (ROP) that employs Oxygen-Induced Retinopathy (OIR), homozygous mutant mice show reduced neuro-glial injury and improved retinal function. Neuronal survival and function are significantly improved and there's an inhibition of retinal thinning, preservation of rod bipolar cells and prevention of glial activation in retinas.

While homozygous mice are viable and generally fertile, it should be noted that unpublished studies suggest that there may be diminished fertility in homozygous males. Functional inactivation of the gene was confirmed by assaying the enzyme in the kidney, but Northern blotting of mRNA reveals the presence of a band similar in both intensity and size to the normal gene product. This strain may be useful in applications related to the study of arginine homeostasis, vascular dysfunction, and neurodegeneration associated with retinopathy of prematurity.

Development

A targeting vector was designed to introduce a neomycin resistance cassette to exon 4 of the gene. The targeting vector was introduced to embryonic stem (ES) cells and resultant male chimeras with germline transmission were bred to C57BL/6J females. Heterozygous mice were interbred, yielding predicted Mendelian genotypic ratios. This strain was backcrossed to C57BL/6J for more than 20 generations (See SNP note below).

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. Five of 27 markers throughout the genome were segregating from an unknown source. Three of 5 markers that determine C57BL/6J from C57BL/6N, were found to be segregating. This suggests a contamination from an unknown source or incomplete backcross.

Allele

Symbol: Arg2^tm1Weo
Name: targeted mutation 1, William E O'Brien
MGI accession ID: MGI:2180319
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: argII^mut
Marker symbol: Arg2
Marker name: arginase type II
Marker synonyms: AII
Chromosome: 12
Strain of origin: Not Specified
Expressed genes: Arg2,arginase type II,mouse, laboratory
Molecular note: A neomycin resistance gene under the control of an RNA polymerase II promoter replaced portions of exons 4 and 5. The insertion resulted in a frameshift that ablated the enzymatic activity of the protein product in the kidneys of homozygous mutant mice. The enzymatic activity was higher than expected in heterozygous animals but the authors noted a large statistical variation.