B6N.Cg-Ifng^tm1.1Hayg/J

Stock number: 037495
Product name: ARE-del
Research areas: Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Mouse/Human Gene Homologs

Description

IFN-γ ARE-del KI mice have 162 nucleotides of the adenylate-uridylate rich element (ARE) sequence deleted in the 3' UTR of the Ifng (interferon gamma) gene. Mice homozygous for the ARE-del mutation develop multiple autoimmune diseases with a female bias including lupus like disease, primary biliary cholangitis and ovarian failure syndrome. In addition, ARE-del mice develop symptoms of aplastic anemia.

Detailed description

Ifng (interferon gamma) encodes a cytokine involved in innate and adaptive immunity. Aberrant expression of IFN-γ is associated with autoimmune disease. IFN-γ ARE-del KI mice have 162 nucleotides of the adenylate-uridylate rich element (ARE) sequence deleted in the 3' UTR of the Ifng gene. The ARE-del mutation stabilizes Ifng mRNA and results in constitutive expression of a low level of IFN-γ (approx. 40 pg/mL in serum) in bone marrow, liver, thymus, spleen, lungs, and kidneys. Mice homozygous for the ARE-del mutation develop multiple autoimmune diseases with a female bias including lupus like disease, primary biliary cholangitis, and ovarian failure syndrome. Male mice have altered heart function seen after exercise. Homozygous mice do not breed and heterozygous mice must be used in breeding, however, homozygous sperm can be used for in vitro fertilization.

Specifically, ARE-del mice exhibit lupus like symptoms including neutrophilia, monocytosis, anti-nuclear antibodies, serum hypocomplementemia, glomerular immunoglobulin and complement deposition, and mesangioproliferative glomerulonephritis. Homozygotes develop portal and lobular inflammation, bile duct damage, fibrosis, and granuloma formation characteristic of human primary biliary cholangitis (PBC). The phenotype is more severe in females.

The constant low-level expression of IFN-γ disrupts the generation of myeloid progenitors and lineage differentiation. This alteration in hematopoiesis results in aplastic anemia (AA). Mice homozygous for the ARE-del mutation exhibit AA-like symptoms including: hypocellular bone marrow (25% of control), a decrease in the numbers of megakaryocytes, peripheral blood pancytopenia with low white and red blood cells and platelet counts.

In contrast to IFN-γ ARE-del KI mice on a BALB/C genetic background, this mouse line on a C57BL/6 genetic background does not exhibit aplastic anemia.

Development

The targeting vector was designed to replace the 162 nucleotides of the ARE (adenylate-uridylate rich element) sequence in the 3' untranslated region of the Ifng (interferon, gamma) gene, on chromosome 10, with a loxP-flanked neomycin resistance cassette. The construct was electroporated into (C57BL/6J X 129S4/SvJae)F1-derived V6.4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts and the resulting chimeric males were bred with C57BL/6NTac-Tg(ACTB-cre)3Mrt females to remove the neo cassette. Mice were backcrossed to C57BL/6NCrl for at least 10 generations and the cre bred out. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6NJ oocytes (Stock No. 005304).

Allele

Symbol: Ifng^tm1.1Hayg
Name: targeted mutation 1.1, Howard A Young
MGI accession ID: MGI:5751448
Generation method: Targeted
Attributes: Not Applicable
Synonyms: ARE-del
Marker symbol: Ifng
Marker name: interferon gamma
Marker synonyms: If2f; Ifg; IFI; IFNG2; IFN-gamma; IMD69
Chromosome: 10
Strain of origin: (C57BL/6J x 129S4/SvJae)F1
Molecular note: A loxP site flanked neomycin resistance gene cassette replaced 162 nt of the adenylate-uridylate rich element (ARE) sequence. Cre-mediated recombination removed the neo cassette. Deletion of the ARE increases the half-life of the mRNA and results in constitutive expression of a low level of IFN-gamma under normal physiologic conditions.