NSG DR4 mice are NOD.scid.Il2Rγcnull ("NSG") animals with the DR4β(NT) transgene that encodes a human HLA-DRB1*0401 engineered to have amino acid mutations in the β2 domain for better interaction with murine CD4. The NSG platform is permissive for xenograft/human tumor growth, with the DR4β(NT) transgene allowing irradiated NSG DR4 mice to be engrafted with HLA-DR-matched hematopoietic stem cells (HSC) - resulting in humanized T cell and B cell populations.
Dr. Leonard D. Shultz, The Jackson Laboratory
Genetic Background | Generation |
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Allele Type | Gene Symbol | Gene Name |
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Spontaneous | Prkdc | protein kinase, DNA activated, catalytic polypeptide |
Allele Type | Gene Symbol | Gene Name |
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Targeted (Null/Knockout) | Il2rg | interleukin 2 receptor, gamma chain |
Allele Type |
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Transgenic (Inserted expressed sequence, Humanized sequence) |
NSG DR4 mice are NOD.scid.Il2Rγcnull ("NSG"; Stock No. 005557) animals with the DR4β(NT) transgene that encodes a human HLA-DRB1*0401 modified to have improved interaction with murine CD4.
The presence of the DR4β(NT) transgene allows irradiated NSG DR4 mice to be engrafted with HLA-DR-matched hematopoietic stem cells (HSC) - resulting in humanized T cell and B cell populations.
Females that are homozygous for both mutations and homozygous for the DR4β(NT) transgene, and males that are homozygous for scid, hemizygous for the X-linked Il2Rγcnull mutation and homozygous for the DR4β(NT) transgene, may be collectively referred to as homozygous NSG DR4 mice.
Although viable and fertile, homozygous NSG DR4 mice are immunodeficient: they have no mature T cells or B cells, lack functional natural killer (NK) cells, have reduced numbers of lymphocytes and myeloid dendritic cells, and are deficient in cytokine signaling. The NSG platform is permissive for xenograft/human tumor growth.
The DR4β(NT) transgene has the mouse H2-Eα promoter directing expression of the HLA class II antigen binding domain molecule (HLA-DRB1*0401) modified to have amino acid mutations in the β2 domain for better interaction with murine CD4. In humans, the HLA-DR4 genotype (HLA-DRA/HLA-DRB1*0401) is associated with the development of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type 1 diabetes, and lyme disease-induced arthritis.
Maintenance Note: Similar to other immunodeficient strains, maintaining homozygous NSG DR4 mice in high health status (specific pathogen-free) vivaria promotes overall colony health. If homozygous NSG DR4 animals are maintained in low health barrier rooms, the use of medicated water (e.g., sulfatrim/trimethoprim-sulfa or enrofloxacin/Baytril) is suggested to increase overall colony health.
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Resources for the NSG mouse model, including discussion forum, immunodeficient model comparison, and categorized, up-to-date references.
NSG DR4 mice are NOD.scid.Il2Rγcnull ("NSG") animals with the DR4β(NT) transgene. Each mutation/transgene is described below.
NSG mice are non-obese diabetic animals (NOD/ShiLtJ) harboring the spontaneous severe combined immunodeficiency mutation (Prkdcscid) on chromosome 16 and the Il2Rγcnull mutation at ~101 Mbp on the X chromosome (Il2rgtm1Wjl created by Dr. Warren J. Leonard [NIH]). NSG mice are described and available from The Jackson Laboratory Repository as Stock No. 005557.
The DR4β(NT) transgene (also called DR4β(NT)/pDOI-5) was generated by Dr. Chella S. David (Mayo Clinic) as described in Pan et al. 1998 J Immunol 161:2925. This transgene has the mouse H2-Eα promoter (and rabbit β-globin intron) upstream of "DRB1*0401(NT)" - a human HLA-DRB1*0401 cDNA sequence engineered to have amino acid mutations (Q110N*K139T) in the β2 domain for better interaction with murine CD4. The transgene was microinjected into fertilized eggs from (SWR x B10)F1 mice. Mice from the founder line with five transgene copies were backcrossed to B10.RFB3 animals (C57BL/10-congenic Eβ0 Eαp mice lacking endogenous Eβ but expressing Eα intracytoplasmically). Next, Dr. David backcrossed them to NOD inbred mice for five generations. In 2009, the NOD-congenic DR4 Ab0 mice were sent to Dr. Leonard D. Shultz (The Jackson Laboratory). They were then bred to NSG mice (Stock No. 005557) for at least one generation, and the Ab0 mutation was replaced with the endogenous H2-Ab1 allele.
The resulting NSG DR4 animals were bred together for several generations, and then made available as Stock No. 029295.
Expressed Gene | HLA-DRB1, major histocompatibility complex, class II, DR beta 1, human |
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Site of Expression |
Depending upon the experiment, the following may be appropriate control strain(s):
--NOD.scid.IL2RγcKO ("NSG"; Stock No. 005557)
--NOD.scid (Stock No. 001303)
--NOD/ShiLtJ inbred mice (Stock No. 001976)
Allele Name | severe combined immunodeficiency |
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Allele Type | Spontaneous |
Allele Synonym(s) | SCID |
Gene Symbol and Name | Prkdc, protein kinase, DNA activated, catalytic polypeptide |
Gene Synonym(s) | |
Site of Expression | T and B lymphocytes. |
Strain of Origin | C.BKa-Ighb/Icr |
Chromosome | 16 |
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 |
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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 |
Gene Synonym(s) | |
Site of Expression | Primarily lymphoid cells. |
Strain of Origin | 129S4/SvJae |
Chromosome | X |
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 | transgene insertion 1, Chella David |
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Allele Type | Transgenic (Inserted expressed sequence, Humanized sequence) |
Allele Synonym(s) | DR4beta(NT) |
Gene Symbol and Name | Tg(H2-Ea-HLA-DRB1*0401*)1Dv, transgene insertion 1, Chella David |
Gene Synonym(s) | |
Promoter | H2-Ea, histocompatibility 2, class II antigen E alpha, |
Expressed Gene | HLA-DRB1, major histocompatibility complex, class II, DR beta 1, human |
Strain of Origin | (SWR x C57BL/10)F1 |
Chromosome | UN |
Molecular Note | This transgene has the mouse H2-Ealpha promoter (and rabbit beta-globin intron) upstream of a human HLA-DRB1*0401 cDNA sequence engineered to have amino acid mutations (Q110N and K139T) in the beta2 domain to provide an improved interaction with murine CD4. |
Females that are homozygous for both mutations and homozygous for the DR4β(NT) transgene, and males that are homozygous for scid (Prkdcscid), hemizygous for the X-linked Il2Rγcnull mutation (Il2rgtm1Wjl) and homozygous for the DR4β(NT) transgene, may be collectively referred to as homozygous NSG DR4 mice.
When maintaining a live colony, homozygous NSG DR4 females may be bred with homozygous NSG DR4 males.
Homozygous NSG DR4 mice are immunodeficient. As such, and similar to other immunodeficient strains, maintenance in high health status (specific pathogen-free) vivaria promotes overall colony health. If homozygous NSG DR4 animals are maintained in low health barrier rooms, the use of medicated water (e.g., sulfatrim/trimethoprim-sulfa or enrofloxacin/Baytril) is suggested to increase overall colony health. Also see additional NSG housing information.
When using the NSG DR4 mouse strain in a publication, please cite the originating article(s) and include JAX stock #029295 in your Materials and Methods section.
Facility Barrier Level Descriptions
Service/Product | Description | Price |
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Females will be Homozygous for Prkdc<scid> and Il2rg<tm1Wjl> and HemizygousTg(H2-Ea-HLA-DRB1*0401*)1Dv. Males will be will be Homozygous for Prkdc<scid>, and Hemizygous for Il2rg<tm1Wjl> and Tg(H2-Ea-HLA-DRB1*0401*)1Dv. |
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