NOD.Cg-Tlr4^lps-del Prkdc^scid Il2rg^tm1Wjl/SzJ

Stock number: 033704
Product name: NSG-TLR4 KO , NSG-TLR4null , NSG-TLR4^null
Research areas: Cancer Research, Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research, Internal/Organ Research, Research Tools, Virology Research

Description

NSG-TLR4^null mice carry the spontaneous mutation Tlr4^Lps-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).

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Detailed description

NSG-TLR4^null 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 Tlr4^lps-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 Tlr4^lps-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.

Development

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 Tlr4^lps-del allele were transferred to the laboratory of Dr. Leonard Shultz (The Jackson Laboratory) and the Tlr4 allele was introgressed into NOD.Cg-Prkdc^scid Il2rg^tm1Wjl/Sz for at least 10 generations.

Allele

Symbol: Tlr4^lps-del
Name: defective lipopolysaccharide response, deletion
MGI accession ID: MGI:1860755
Generation method: Spontaneous
Attributes: Null/Knockout
Marker symbol: Tlr4
Marker name: toll-like receptor 4
Chromosome: 4
Strain of origin: C57BL/10ScN
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.
General note: C57BL/10ScN, C57BL/10ScNJ, and C57BL10/ScCr mice carry this allele.

Allele

Symbol: Prkdc^scid
Name: severe combined immunodeficiency
MGI accession ID: MGI:1857113
Generation method: Spontaneous
Marker symbol: Prkdc
Marker name: protein kinase, DNA activated, catalytic polypeptide
Chromosome: 16
Strain of origin: C.BKa-Igh^b/Icr
Site of expression: T and B lymphocytes.
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

Symbol: Il2rg^tm1Wjl
Name: targeted mutation 1, Warren J Leonard
MGI accession ID: MGI:1857455
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Il2rg
Marker name: interleukin 2 receptor, gamma chain
Chromosome: X
Strain of origin: 129S4/SvJae
Site of expression: Primarily lymphoid cells.
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.