These MRL/lpr NOS2-/- mice carry the Nos2tm1Lau targeted mutation and Faslpr spontaneous alleles on the MRL genetic background, and may be useful in studies of autoimmune glomerulonephritis.
James C. Oates, Medical University of South Carolina
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-Faslpr/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-Faslpr/J wildtype controls.
Mice carrying the Nos2tm1Lau 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-Nos2tm1Lau/J mice were crossed to MRL/MpJ-Faslpr/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-Faslpr/J (Stock No. 000485) at least once to establish the colony.
|Allele Type||Spontaneous (Hypomorph)|
|Allele Synonym(s)||Fas-; Fas-def; lpr; MRL/lpr; Tnfrf6lpr; Tnfrsf6lpr; Tnfrsf6lpr|
|Gene Symbol and Name||Fas, Fas (TNF receptor superfamily member 6)|
|Strain of Origin||MRL/Mp|
|General Note||Faslpr, 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 Faslpr 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 Cd72c haplotype is a modifier of Faslpr-induced autoimmune disease. J:204782|
|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.|
|Allele Name||targeted mutation 1, Victor E Laubach|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||iNOS-; iNOS KO; iNOS-; NOS2-; NOS2tm/Lau; Nos2tm1Lau|
|Gene Symbol and Name||Nos2, nitric oxide synthase 2, inducible|
|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.|
|Mutations Made By|| |
Dr. Victor Laubach, University of Virginia Health Sci. Ctr.
When maintaining a live colony, these mice can be bred as homozygotes for both alleles.
When using the MRL.Cg-Nos2tm1Lau Faslpr/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #022350 in your Materials and Methods section.