JAX Mouse Strain Datasheet - 004848

NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/SzJ

Stock No:: 004848 |; NOD/LtSz-Rag1nullPfpnull

Cryo Recovery

Overview

Also Known As: NOD/LtSz-Rag1nullPfpnull

These double knock-out mutant mice have no mature T or B lymphocytes, no detectable NK cell cytotoxic activity, and lack serum immunoglobulin. They also develop thymic lymphomas.

Donating Investigator

Dr. Leonard D. Shultz, The Jackson Laboratory

Genetic overview

Genetic Background	Generation

Prf1^tm1Sdz

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Prf1	perforin 1 (pore forming protein)

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Rag1	recombination activating gene 1

Research Applications

Cancer Research
Developmental Biology Research
Hematological Research
Immunology, Inflammation and Autoimmunity Research
Internal/Organ Research
Research Tools
Apoptosis Research

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Base Price

Starting at:

$2,595.00 Domestic price Cryo Recovery

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Details

Detailed Description

Mice that are homozygous for both targeted mutations are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities when housed under specific pathogen free conditions. These double homozygote mutant mice have no mature T or B lymphocytes, no detectable NK cell cytotoxic activity, and lack serum immunoglobulin. The number of nucleated spleen cells is significantly reduced in double mutant mice, when compared to the single homozygote, NOD.129S7(B6)-Rag1^tm1Mom/J (Stock No. 003729). Although an increased number of DX5⁺CD122⁺ NK cells are found in the spleens of double mutants, these NK cells have impaired cytotoxic activity. The disruption of Prf1 ablates NK cell cytotoxic activity resulting in increased engraftment levels over that observed with Stock No. 003729. All mutant mice develop thymic lymphomas. This double mutant mouse strain may be useful in studies involving engraftment of human hematolymphoid cells.

Development

Please see strain entries Stock No. 002407 and Stock No. 003729 for details regarding the construction of each mutant allele. This strain was produced by crossing female NOD.129S7(B6)-Rag1^tm1Mom/J (Stock No. 003729) to male C57BL/6-Prf1^tm1Sdz (Stock No. 002407). Resulting female progeny heterozygous for both mutant alleles were crossed to male NOD.129S7(B6)-Rag1^tm1Mom/J (Stock No. 003729). Mice homozygous for the Rag1 mutant allele and heterozygous for the Prf1 allele were crossed to NOD.129S7(B6)-Rag1^tm1Mom/J (Stock No. 003729) mice for 10 generations, and then intercrossed to produce double homozygotes.

Control Suggestions

Approximate Controls

001976 NOD/ShiLtJ

Additional Information

Considerations for Choosing Controls

Selected References

Shultz LD; Banuelos S; Lyons B; Samuels R; Burzenski L; Gott B; Lang P; Leif J; Appel M; Rossini A; Greiner DL. 2003. NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment. Transplantation 76(7):1036-42. PubMed: 14557749 MGI: J:109843

View All References

Genetics

Prf1^tm1Sdz

Allele Symbol: Prf1^tm1Sdz

Allele Name	targeted mutation 1, Sandoz Pharmaceuticals
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	P⁰; Pfn^-; Pfp^tm1Sdz; Prf1^-; Prf1^tm/Sdz; Prf^-; perf-; perforin 0; perforin-; pfp-; pfpKO; pko; prf1^tm1
Gene Symbol and Name	Prf1, perforin 1 (pore forming protein)
Gene Synonym(s)	Cyta; FLH2; HPLH2; P1; PFN1; PFP; Pfn; Pfp; Pfp; Prf-1; Prf-1; RATCYTA; perforin; perforin 1; pore forming protein
Strain of Origin	C57BL/6J
Chromosome	10
General Note	Phenotypic Similarity to Human Syndrome: hemophagocytic lymphohistiocytosis in mutants infected with lymphocytic choriomeningitic virus (J:92260)
Molecular Note	A neomycin selection cassette was inserted into exon 3. RT-PCR analysis on RNA derived from homozygous mice demonstrated that an abnormal transcript was produced from this allele. However, immunocytochemistry experiments on activated spleen cells derived from homozygous mice confirmed that no detectable protein was made from this allele.
Mutations Made By	Dr. Birgit Lederman, University of Zurich

Rag1^tm1Mom

Allele Symbol: Rag1^tm1Mom

Allele Name	targeted mutation 1, Peter Mombaerts
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	RAG-1-; RAG1^null; Rag-; Rag-1KO; Rag1^-; Rag^1tm1Mom
Gene Symbol and Name	Rag1, recombination activating gene 1
Gene Synonym(s)	RAG-1; RNF74; Rag-1; Rag-1
Site of Expression	expression is seen in bone marrow derived cell lines.
Strain of Origin	129S7/SvEvBrd-Hprt<+>
Chromosome	2
Molecular Note	A 1356 bp genomic fragment of the Rag1 gene, encoding the nuclear localization signal and the zinc-finger motif, was replaced by a neomycin cassette. A mutant transcript expressed from this allele was detected by Northern blot in bone marrow derived cell lines from homozygous mice.
Mutations Made By	Peter Mombaerts, Max Planck Research Unit for Neurogenetics

Disease/Phenotype

Disease Terms

Research Areas By Genotype

This mouse can be used to support research in many areas including:

Cancer Research
- Increased Tumor Incidence
  - Lymphomas
  - Lymphomas: thymic
- Toxicology
  - B and T cell deficiency, xenograft/transplant host
Developmental Biology Research
- Lymphoid Tissue Defects
  - hematopoietic defects
Hematological Research
- Immunological Defects
  - B and T cell deficiency
Immunology, Inflammation and Autoimmunity Research
- Autoimmunity
  - B and T cell deficiency
  - B cell deficiency
- Immunodeficiency
  - B and T cell deficiency
  - B cell deficiency
  - B, T, and NK cell deficiency
  - NK Cell Deficiency
  - multiple immune defects
- Inflammation
  - B and T cell deficiency
- Lymphoid Tissue Defects
  - B and T cell deficiency
  - hematopoietic development
Internal/Organ Research
- Lymphoid Tissue Defects
  - B and T cell deficiency
  - T cell deficiency
- Thymus Defects
  - B and T cell deficient
Research Tools
- Cancer Research
  - B and T cell deficiency, xenograft/transplant host
  - B cell deficiency
  - B, T, and NK cell deficiency, xenograft/transplant host
  - T cell deficiency
  - genes regulating lymphoma development
  - production of B and T cells, antibodies, and hybridomas
  - xenograft/transplant host
- Immunology, Inflammation and Autoimmunity Research
  - B and T cell deficiency
  - B cell deficiency
  - B, T, and NK cell deficiency
  - NK Cell Deficiency
  - T cell deficiency
  - T cell deficiency, xenograft/transplant host
  - production of B cells, antibodies T cell lines, and hybridomas
  - production of T cell lines and hybridomas
- Toxicology Research
  - B and T cell deficiency, xenograft transplant host
  - xenograft/transplant host

Genotype: Prf1^tm1Sdz related

Apoptosis Research
- Extracellular Modulators
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency Associated with Other Defects

Genotype: Rag1^tm1Mom related

Cancer Research
- Toxicology
  - B and T cell deficiency, xenograft/transplant host
Hematological Research
- Immunological Defects
  - B and T cell deficiency
Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - B and T cell deficiency
- Inflammation
  - B and T cell deficiency
- T Cell Receptor Signaling Defects
  - B and T cell deficiency
Internal/Organ Research
- Lymphoid Tissue Defects
  - B and T cell deficiency
Research Tools
- Cancer Research
  - B and T cell deficiency, xenograft/transplant host
- Toxicology Research
  - xenograft/transplant host

Mammalian Phenotype Terms by Genotype

Genotype: Prf1^tm1Sdz/Prf1^tm1Sdz Rag1^tm1Mom/Rag1^tm1Mom
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/SzJ

homeostasis/metabolism phenotype

increased circulating glucose level
- 70% of streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 negative human peripheral blood mononuclear cells exhibit increased glucose serum levelsels
- however, all of streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 positive human peripheral blood mononuclear cells exhibit euglycemia
- streptozotocin-treated mice exhibit increased serum glucose levels that can be restored transiently to euglycemia by transplanting islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice

immune system phenotype

abnormal response to transplant
- streptozotocin-treated mice transplanted with islet cells from Prkdc^scid/Prkdc^scid Tg(HLA-A2.1)1Enge Tg(B2M)55Hpl transgenic mice and HLA-A2 negative human peripheral blood mononuclear cells exhibit destruction of engrafted islet cellsls

Genotype: Rag1^tm1Mom/Rag1^tm1Mom Prf1^tm1Sdz/Prf1^tm1Sdz
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/Sz

mortality/aging

premature death
- mean lifespan is 262+/-21 days

immune system phenotype

abnormal level of surface class II molecules
- four to five-fold decrease in cells expressing I-A^g7 as compared to NOD control

abnormal lymph node cortex morphology
- lymph nodes lack follicles

abnormal response to transplant
- 6-8 weeks after IP injection, bone marrow exhibits a 12-fold increase in engraftment of human cord blood cells
- following IP injection of human PMBC, peripheral blood has a fivefold increase in the percentage of human lymphoid cells as compared to NOD-Rag^null controls
- peripheral blood has a 13-fold increase in engraftment of human CD4+ T cells
- spleens have a 9-fold increase in engraftment of human CD45+ cells and a 20-fold increase in human CD4+ cells as compared to control, although there is no significant difference in engraftment of human CD8+ cells

abnormal spleen white pulp morphology
- spleen lacks lymphoid follicles

abnormal thymus cortex morphology
- thymus lacks a clearly defined cortex

decreased CD4-positive, alpha beta T cell number
- spleens of 8-11 week old mice are deficient in CD3+ CD4+ T cells

decreased CD8-positive, alpha-beta T cell number
- spleens of 8-11 week old mice are deficient in CD3+ CD8+ T cells

decreased immunoglobulin level
- no serum immunoglobulin is detected in 176-362 day old mice

decreased mature B cell number
- spleens of 8-11 week old mice are deficient in Igkappa+ B220+ T cells

impaired natural killer cell mediated cytotoxicity
- poly I:C stimulated spleen cells exhibit extremely low levels of NK cell cyotoxic activity

increased NK cell number
- numbers of NK cells are increased in comparison to NOD controls

increased granulocyte number
- numbers of granulocytes are increased in comparison to NOD controls, however, in comparison to NOD-Rag^null numbers are decreased

increased immature B cell number
- IgLkappa- B220+ immature B cells are increased six-fold as compared to NOD controls

increased macrophage cell number
- numbers of macrophages are increased in comparison to NOD controls

spleen hypoplasia
- nucleated spleen cells are reduced 14 fold in 8-11 week old mice as compared to NOD control

thymus hypoplasia
- lymphoid cells are severely reduced in thymuses

neoplasm

increased T cell derived lymphoma incidence

hematopoietic system phenotype

abnormal level of surface class II molecules
- four to five-fold decrease in cells expressing I-A^g7 as compared to NOD control

abnormal spleen white pulp morphology
- spleen lacks lymphoid follicles

abnormal thymus cortex morphology
- thymus lacks a clearly defined cortex

decreased CD4-positive, alpha beta T cell number
- spleens of 8-11 week old mice are deficient in CD3+ CD4+ T cells

decreased CD8-positive, alpha-beta T cell number
- spleens of 8-11 week old mice are deficient in CD3+ CD8+ T cells

decreased immunoglobulin level
- no serum immunoglobulin is detected in 176-362 day old mice

decreased mature B cell number
- spleens of 8-11 week old mice are deficient in Igkappa+ B220+ T cells

impaired natural killer cell mediated cytotoxicity
- poly I:C stimulated spleen cells exhibit extremely low levels of NK cell cyotoxic activity

increased NK cell number
- numbers of NK cells are increased in comparison to NOD controls

increased granulocyte number
- numbers of granulocytes are increased in comparison to NOD controls, however, in comparison to NOD-Rag^null numbers are decreased

increased immature B cell number
- IgLkappa- B220+ immature B cells are increased six-fold as compared to NOD controls

increased macrophage cell number
- numbers of macrophages are increased in comparison to NOD controls

spleen hypoplasia
- nucleated spleen cells are reduced 14 fold in 8-11 week old mice as compared to NOD control

thymus hypoplasia
- lymphoid cells are severely reduced in thymuses

endocrine/exocrine gland phenotype

abnormal thymus cortex morphology
- thymus lacks a clearly defined cortex

increased T cell derived lymphoma incidence

thymus hypoplasia
- lymphoid cells are severely reduced in thymuses

References

Shultz LD; Banuelos S; Lyons B; Samuels R; Burzenski L; Gott B; Lang P; Leif J; Appel M; Rossini A; Greiner DL. 2003. NOD/LtSz-Rag1nullPfpnull mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment. Transplantation 76(7):1036-42. PubMed: 14557749 MGI: J:109843

Additional - Prf1^tm1Sdz related

Abdool K; Cretney E; Brooks AD; Kelly JM; Swann J; Shanker A; Bere EW Jr; Yokoyama WM; Ortaldo JR; Smyth MJ; Sayers TJ. 2006. NK cells use NKG2D to recognize a mouse renal cancer (Renca), yet require intercellular adhesion molecule-1 expression on the tumor cells for optimal perforin-dependent effector function. J Immunol 177(4):2575-83. PubMed: 16888019 MGI: J:138353
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Also Known As: NOD/LtSz-Rag1nullPfpnull

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Prf1tm1Sdz

Allele Symbol: Prf1tm1Sdz

Rag1tm1Mom

Allele Symbol: Rag1tm1Mom

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This mouse can be used to support research in many areas including:

Genotype: Prf1tm1Sdz related

Genotype: Rag1tm1Mom related

Mammalian Phenotype Terms by Genotype

Genotype: Prf1tm1Sdz/Prf1tm1Sdz Rag1tm1Mom/Rag1tm1MomNOD.Cg-Rag1tm1Mom Prf1tm1Sdz/SzJ

homeostasis/metabolism phenotype

immune system phenotype

Genotype: Rag1tm1Mom/Rag1tm1Mom Prf1tm1Sdz/Prf1tm1SdzNOD.Cg-Rag1tm1Mom Prf1tm1Sdz/Sz

mortality/aging

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neoplasm

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Additional - Rag1tm1Mom related

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Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

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Prf1^tm1Sdz

Allele Symbol: Prf1^tm1Sdz

Rag1^tm1Mom

Allele Symbol: Rag1^tm1Mom

Genotype: Prf1^tm1Sdz related

Genotype: Rag1^tm1Mom related

Genotype: Prf1^tm1Sdz/Prf1^tm1Sdz Rag1^tm1Mom/Rag1^tm1Mom
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/SzJ

Genotype: Rag1^tm1Mom/Rag1^tm1Mom Prf1^tm1Sdz/Prf1^tm1Sdz
NOD.Cg-Rag1^tm1Mom Prf1^tm1Sdz/Sz

Additional - Prf1^tm1Sdz related

Additional - Rag1^tm1Mom related