B6.129S2-Aire^tm1.1Doi/J

Stock number: 004743
Product name: Aire-
Strain synonyms: Aireo, HD Aire-
Research areas: Immunology, Inflammation and Autoimmunity Research

Description

These autoimmune regulator knock-out mice may be useful in studies related autoimmune disease and tolerance induction.

Detailed description

Mice homozygous for the targeted allele are viable, normal in size and at birth do not display any gross physical or behavioral abnormalities, although they are infertile/subfertile (see below). While a transcript may be generated from the targeted locus, a functional protein is not translated. Homozygous mice display a phenotype consistent with a broad defect in immunological tolerance induction. By four weeks of age histological analysis reveals lymphocytic infiltrates in some organs. Infiltrates become more prevalent as the mouse ages. Serum autoantibodies are detected by 3-6 months. The thymic medullary epithelial cell (MEC) number is doubled. Similarly, a near doubling in the numbers of activated/memory CD44^hiCD62L^lo T lymphocytes is observed. A loss or reduction in expression occurs for a substantial number of genes in MECs, an observation consistent with the targeted gene's role as a transcriptional activator. The Donating Investigator reports that homozygotes are not fertile (most homozygous females are sterile due to ovarian autoimmunity, homozygous males can only breed for a short time and are subfertile). This mutant mouse strain may be useful in studies related autoimmune disease and tolerance induction.

Development

To create this mutant, the originating investigator employed a targeting vector bearing a loxP site-flanked Pgk-neo cassette inserted into intron 2. An additional single loxP site was placed in intron 1. The targeting construct was electroporated into 129S2/SvPas-derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric mice were mated with CMV-cre transgenic mice on a C57BL/6 background. Exon 2 and portions of introns 1 and 3 were excised in the offspring. The resulting chimeric animals were crossed to C57BL/6 mice. Heterozygous offspring were crossed to C57BL/6 for at least nine generations (October 2009).



A 48 SNP (single nucleotide polymorphism) panel analysis, with 43 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. One of the 43 markers, on Chromosome 12, was segregating with 129.

Allele

Symbol: Aire^tm1.1Doi
Name: targeted mutation 1.1, Christophe Benoist and Diane Mathis
MGI accession ID: MGI:2661910
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: Aire-; Aire^o; HD Aire^-
Marker symbol: Aire
Marker name: autoimmune regulator (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy)
Marker synonyms: AIRE1; APECED; APS1; APSI; PGA1
Chromosome: 10
Strain of origin: 129S2/SvPas
Molecular note: The floxed fragment containing exon 2, portions of the surrounding introns, and a neo cassette were excised via cre mediated recombination in vivo. While shortened transcript was detected by RT-PCR analysis of homozygous mutant thymii, sequence analysis of the transcript identified a frameshift mutation resulting from the splicing of exons 1 and 3 that precludes translation past exon 1.