Mice homozygous for this knock-out mutation display abnormal osteoclast development and physiology. They also exhibit an abnormal inflammatory response.
Dr. Richard A. Flavell, Yale University School of MedicineRead More +
Homozygous Irak3 (interleukin-1 receptor-associated kinase 3; also called IRAK-M) deficient mice develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Mice also exhibit increased cytokine production upon TLR/IL1 stimulation and bacterial challenge, and show increased inflammatory responses to bacterial infection. Endotoxin tolerance is significantly reduced. Absence of gene expression was confirmed by Western blot using an antibody directed against the C terminus of the gene. Homozygotes are viable and fertile.
The targeting vector was designed to replace a 1.2 kb region of the gene (containing three exons encoding two-thirds of the kinase domain) with a loxP-flanked neomycin resistance cassette. The targeting vector was linearized and electroporated into 129S1/Sv-derived W9.5 embryonic stem (ES) cells. Targeted clones were injected into C57BL/6 blastocysts and resulting chimeric males were bred to C57BL/6 females. Interbreeding of heterozygotes was performed to generate homozygotes. This line has been backcrossed to C57BL/6 eleven times by the donating laboratory.
|Allele Name||targeted mutation 1, Richard A Flavell|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Irak3, interleukin-1 receptor-associated kinase 3|
|Gene Synonym(s)||4833428C18Rik; 4833428C18Rik; AI563835; ASRT5; IRAK-M; IRAKM; RIKEN cDNA 4833428C18 gene; expressed sequence AI563835|
|Strain of Origin||129S1/Sv-Oca2<+> Tyr<+> Kitl<+>|
|Molecular Note||1.2 kb of sequence were replaced with a floxed neo cassette. The deleted region contained 3 exons encoding two thirds of the kinase domain. While Western blot analysis of LPS-stimulated bone marrow macrophage extracts using a carboxy terminal antibody confirmed the absence of normal protein in homozygous mutant mice, truncated transcript was detected by Northern blot analysis using an amino terminal probe. Sequence analysis of RT-PCR products revealed an in frame stop codon generated by aberrant splicingof the endogenous gene and the neo transgene.|
|Mutations Made By|| |
Dr. Richard Flavell, Yale University School of Medicine
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