MRL.Cg-Nos2^tm1Lau Fas^lpr/J

Stock number: 022350
Research areas: Apoptosis Research, Cancer Research, Immunology, Inflammation and Autoimmunity Research, Mouse/Human Gene Homologs, Neurobiology Research

Description

These MRL/lpr NOS2-/- mice carry the Nos2^tm1Lau targeted mutation and Fas^lpr spontaneous alleles on the MRL genetic background, and may be useful in studies of autoimmune glomerulonephritis.

Detailed description

Mice that are homozygous for these targeted mutation and spontaneous mutant alleles are viable, fertile, and develop immune complex proliferative glomerulonephritis similar to that observed in MRL/MpJ-Fas^lpr/J (JAX Stock No. 000485) mice. Double mutant mice exhibit more superoxide production in the renal cortex and increased anti-dsDNA antibody production when compared to MRL/MpJ-Fas^lpr/J wildtype controls.

Development

Mice carrying the Nos2^tm1Lau allele on a mixed C57BL/6 and 129P2/OlaHsd background (Stock No. 002596) were obtained by the Donating Investigator from Dr. Victor Laubach (Glaxo Wellcome Inc.). Briefly, a targeting vector designed by Dr. Victor Laubach and containing a NEO cassette was used to replace exons 12 and 13, disrupting the calmodulin binding domain. The construct was electroporated into 129P2/OlaHsd-derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were crossed to C57BL/6 female mice. These B6;129P2-Nos2^tm1Lau/J mice were crossed to MRL/MpJ-Fas^lpr/J (JAX Stock No. 000485) mice for 9 generations using a marker assisted protocol. Upon arrival at The Jackson Laboratory, the mice were crossed to MRL/MpJ-Fas^lpr/J (Stock No. 000485) at least once to establish the colony.

Allele

Symbol: Nos2^tm1Lau
Name: targeted mutation 1, Victor E Laubach
MGI accession ID: MGI:1857228
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Nos2
Marker name: nitric oxide synthase 2, inducible
Chromosome: 11
Strain of origin: 129P2/OlaHsd
Molecular note: A neomycin cassette replaced exons 12 and 13 of the gene, which encode the calmodulin-binding domain. Northern and Western blots of IFNg/LPS-stimulated peritoneal macrophages showed no detectable Nos2 mRNA or protein, respectively.

Allele

Symbol: Fas^lpr
Name: lymphoproliferation
MGI accession ID: MGI:1856334
Generation method: Spontaneous
Attributes: Hypomorph
Marker symbol: Fas
Marker name: Fas (TNF receptor superfamily member 6)
Chromosome: 19
Strain of origin: MRL/Mp
Molecular note: Southern blotting experiments indicated that the mutation is a genomic rearrangement within the gene, probably within the second intron. Sequencing of genomic DNA and RT-PCR products from homozygous mutant mice revealed the insertion of an early transposable element (ETn) into intron 2. RT-PCR analysis of liver and thymus mRNA showed that the presence of the ETn leads to premature termination of transcription at the long terminal repeat (LTR) of the ETn and aberrant mRNA splicing. The mutation is "leaky," however, as full-length mRNA and a longer splice product incorporating a segment of the ETn as an extra intron are detected in the thymus at low levels.
General note: Fas^lpr, lymphoproliferation, recessive. This mutation was found during inbreeding of a strain MRL/Mp derived from crosses among strains LG, AKR, C3H, and C57BL/6. The resemblance has led to extensive use of Fas^lpr mice in attempts to determine the etiology of SLE and to evaluate therapies. However, the human APT1 gene (OMIM 134637) encodes the FAS antigen; Tnfrsf6 is not the homolog of the human (SLE) gene. The Cd72^c haplotype is a modifier of Fas^lpr-induced autoimmune disease. J:204782