NSG-TLR4null mice carry the spontaneous mutation Tlr4Lps-del, which results in a defective response to LPS stimulation, combined with the features of the severe combined immune deficiency mutation or scid (B and T cell deficiency), and IL2 receptor gamma chain deficiency (NK cell deficiency).
Dr. Leonard D. Shultz, The Jackson Laboratory
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|Allele Type||Gene Symbol||Gene Name|
|Spontaneous||Prkdc||protein kinase, DNA activated, catalytic polypeptide|
|Allele Type||Gene Symbol||Gene Name|
|Targeted (Null/Knockout)||Il2rg||interleukin 2 receptor, gamma chain|
|Allele Type||Gene Symbol||Gene Name|
|Spontaneous (Null/Knockout)||Tlr4||toll-like receptor 4|
NSG-TLR4null mice combine the features of the severe combined immune deficiency mutation or scid (B and T cell deficiency) and IL2 receptor gamma chain deficiency (NK cell deficiency) with the spontaneous mutation Tlr4lps-del, a large deletion in the toll-like receptor 4 gene that completely removes the Tlr4 coding sequence. No Tlr4 mRNA or protein is expressed. The stimulation of TLR4 by lipopolysaccharide (LPS) induces the release of proinflammatory cytokines that activate immune responses. Toll signaling pathways are involved with inflammation, including susceptibility to various bacterial infections, effects of tissue ischemia (including cerebral and retinal ischemia), myocardial infarction, neurodegeneration, and tumor immune responses. Mice homozygous for Tlr4lps-del exhibit a defective response to LPS stimulation. The severe immunodeficiency of the NSG background allows the mice to be humanized by engraftment of human CD34+ hematopoietic stem cells (HSC), peripheral blood mononuclear cells (PBMC), patient derived xenografts (PDX), or adult stem cells and tissues. Mice homozygous for the three mutations are viable, fertile and normal in size; survival is similar to NSG mice.
The spontaneous mutation lps-del was identified as an abnormal response to lipopolysaccharide observed in the inbred strain C57BL/10ScN in the 1970s. The phenotype was subsequently identified as a 74723bp deletion in the Tlr4 gene. Mice on an unspecified background carrying the Tlr4lps-del allele were transferred to the laboratory of Dr. Leonard Shultz (The Jackson Laboratory) and the Tlr4 allele was introgressed into NOD.Cg-Prkdcscid Il2rgtm1Wjl/Sz for at least 10 generations.
|Allele Name||severe combined immunodeficiency|
|Gene Symbol and Name||Prkdc, protein kinase, DNA activated, catalytic polypeptide|
|Site of Expression||T and B lymphocytes.|
|Strain of Origin||C.BKa-Ighb/Icr|
|Molecular Note||A T-to-A transversion point mutation at a position corresponding to codon 4046 (codon 4095 in transcript ENSMUST00000023352.8) created a premature stop codon (p.Y4046*).|
|Allele Name||targeted mutation 1, Warren J Leonard|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||[KO]gammac; CD132-; gammac-; gc-; Il2rgtm1Wjll; IL2Rgammanull|
|Gene Symbol and Name||Il2rg, interleukin 2 receptor, gamma chain|
|Site of Expression||Primarily lymphoid cells.|
|Strain of Origin||129S4/SvJae|
|Molecular Note||A neomycin resistance cassette replaced part of exon 3 and all of exons 4 - 8 of the gene, resulting in the loss of most of the extracellular domain and all of the transmembrane and cytoplasmic domains of the protein.|
|Mutations Made By|| |
Dr. Warren Leonard, NHLBI, NIH
|Allele Name||defective lipopolysaccharide response, deletion|
|Allele Type||Spontaneous (Null/Knockout)|
|Allele Synonym(s)||Tlr4-; TLR4lps-; TLR4-KO|
|Gene Symbol and Name||Tlr4, toll-like receptor 4|
|Strain of Origin||C57BL/10ScN|
|General Note||C57BL/10ScN, C57BL/10ScNJ, and C57BL10/ScCr mice carry this allele.|
|Molecular Note||This allele has been characterized by lack of mRNA owing to a deletion of the locus. 74723bp of genomic DNA sequence have been removed, encompassing only the Tlr4 gene.|
When maintaining a live colony, these mice are bred as homozygous for all three alleles (Il2rg is X-linked). Specific and opportunistic pathogen free conditions are recommended.
When using the NSG-TLR4 KO , NSG-TLR4null , NSG-TLR4null mouse strain in a publication, please cite the originating article(s) and include JAX stock #033704 in your Materials and Methods section.
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