B6;129S-Tnf^tm1Gkl/J

Stock number: 003008
Product name: TNFα^-
Research areas: Apoptosis Research, Cancer Research, Cardiovascular Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Hematological Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Neurobiology Research

Description

Homozygous TNFα KO mice are useful when studying the role of tumor necrosis factor (TNF) in various systems, including inflammatory responses as seen in lung immunopathology and inflammatory bowel disease.

Detailed description

Development of both lymph nodes and Peyer's patches is normal in these mice, with homozygous mutants exhibiting no apparent outward phenotypic abnormalities. Homozygous mice completely lack splenic primary B cell follicles and cannot form organized follicular dendritic cell networks and germinal centers. TNF-deficient mice treated to induce skin carcinogenesis develop significantly less benign and malignant tumors than treated wildtype mice. Nonobese homozygous mutant mice show modest decreases in body weight, epididymal fat depot weight, and percent body fat (statistically significant in males at 28 weeks of age). Further characterization indicates that 28 week old male mutant mice display lower insulin, triglyceride, and leptin levels compared to wildtype controls. Characterization of TNF deficient homozygotes injected with gold-thioglucose (GTG) to induce hyperphagic obesity indicates that the presence of TNF does not affect the degree of obesity. However, fasting plasma glucose and insulin levels, and the insulin response to an oral glucose load were significantly decreased in obese TNF deficient mice compared to obese wildtype controls. These results indicate TNF plays a role in lipid and glucose metabolism but is not sufficient to completely eliminate hyperglycemia and hyperinsulinemia in this induced obesity model. TNFα KO mice are viable and fertile.

Development

The targeting vector was constructed by replacing the coding region of the tumor necrosis factor (TnF) gene with an MC1neopA cassette in reverse orientation to the gene. The construct was electroporated into 129S/SvEv-Gpi1^c-derived CCE embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to C57BL/6 mice before being intercrossed to produce homozygotes. Upon arrival at The Jackson Laboratory, sperm was cryopreserved. To establish our live colony of TNFα KO mice, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664). Some mice were further backcrossed to C57BL/6J inbred mice to generate a C57BL/6J-congenic strain (Stock No. 005540).

Allele

Symbol: Tnf^tm1Gkl
Name: targeted mutation 1, George Kollias
MGI accession ID: MGI:2149024
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Tnf
Marker name: tumor necrosis factor
Chromosome: 17
Strain of origin: 129S/SvEv-Gpi1^c
Molecular note: Replacement of 40 bp of the 5' UTR, all the coding region, including the ATG translation initiation codon, of the first exon and part of the first intron with MC1neopA cassette. Northern blot analysis of LPS stimulated macrophages confirmed disruption of Tnf mRNA expression.