Description

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation E2F3p (08-JAN-04)   Donating Investigator Ana Zubiaga,   University of the Basque Country

Description
Mice that are homozygous for the targeted mutation are viable and normal in size. No gene product, mRNA or protein, was detected. At age 15 months mutant mice have a 27% survival rate due to diffuse autoimmune disease that resembles systemic lupus erythematosus (SLE). The phenotype includes splenomegaly by 8-12 weeks of age, glomerulonephritis, accumulated inflammatory infiltrates in the lung, liver, and skin abnormalities such as hair loss, skin wounds, erythema. Anti-dsDNA antibodies are detected in the serum. There are an increased number of mature CD8+ thymocytes and an abnormal accumulation of CD8+ Cd44high Cd69- T effector/memory cells that are autoreactive in peripheral lymphoid organs. E2F2 deficient mice appear to have normal negative selection of thymocytes but demonstrate defects in peripheral tolerance of T lymphoctes (especially Cd8+ T cells) leading to progressive autoimmune disease. This mutant mouse strain may be useful in studies of autoimmunity and may serve as model of systemic lupus erythematosus.

Development
A targeting vector containing neomycin resistance and thymidine kinase genes was used to disrupt the second exon which encodes the DNA binding and dimerization domains of the protein. The construct was electroporated into 129S1/Sv-p+Tyr+Kitl+ derived CJ7 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were backcrossed to C57BL/6 mice.

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

E2f2^tm1Zubi/E2f2^tm1Zubi

        involves: 129S1/Sv * C57BL/6

• life span-post-weaning/aging
• premature death (MGI Ref ID J:76318)
  • at 15 months, only 27% of mice are alive compared to 67% of wild-type mice
• immune system phenotype
• abnormal immune system morphology (MGI Ref ID J:76318)
• abnormal T cell differentiation (MGI Ref ID J:76318)
  • the fraction of mature (CD4+ and, especially, CD8+) thymocytes in the thymus is increased with a decreased in immature double positive thymocytes
• increased T cell proliferation (MGI Ref ID J:76318)
  • in response to IL-2 treatment, effector/memory cell (CD44^hiCD69-) T cell proliferation is increased relative to in wild-type mice by 2 times at weeks 8 to 12, and 13 times at 15 months
  • T cell proliferation stimulated by CD3 antibody is increased compared to in stimulated wild-type mice and is more prominent at suboptimal CD3 antibody concentrations
• abnormal T cell subpopulation ratio (MGI Ref ID J:76318)
  • there is an increase in the number of CD8+ T cells relative to CD4+ T cells (CD4+/CD8+ ratio: 0.79+/-0.1 compared to 1.43+/-0.3 in wild-type mice)
  • however, the T to B cells ratio is normal
• abnormal spleen white pulp morphology (MGI Ref ID J:76318)
  • at 15 months, mice display white pulp hyperplasia and increased sinusoidal cellularity
• enlarged spleen (MGI Ref ID J:76318)
  • at 15 months, mice exhibit splenomegaly with spleen size 2 to 5 times greater than that of wild-type mice
• increased spleen weight (MGI Ref ID J:76318)
  • at week 8 to 12, spleen weight is increased 2-fold (1445+/-250 mg) relative to in wild-type mice (668+/-108 mg) and continues to increase at 15 months (3340+/-540 mg compared to 722+/-125 mg in wild-type mice)
• increased memory T cell number (MGI Ref ID J:76318)
  • at 3 to 4 weeks and at 15 months, the number of CD44^hiCD69- memory T cells is increased
• abnormal immune system physiology (MGI Ref ID J:76318)
• increased anti-double stranded DNA antibody level (MGI Ref ID J:76318)
  • the amount of double stranded DNA antibodies is increased relative to in wild-type mice and corresponds to the severity of organ damage
• increased inflammatory response (MGI Ref ID J:76318)
  • at 15 months, mice exhibit features of autoimmune disease
  • in elderly mice, increased mononuclear infiltrate is observed in the lung, kidney and liver
• glomerulonephritis (MGI Ref ID J:76318)
  • elderly mice exhibit membranoproliferative glomerulonephritis that is focal and of moderate intensity
  • affected glomeruli are enlarged with a thickened basement membrane and contain perivascular aggregates of inflammatory infiltrate and immune complex deposition
• liver inflammation (MGI Ref ID J:76318)
  • in elderly mice, inflammatory infiltrate accumulates in the liver and perivascular infiltrates are observed
• lung inflammation (MGI Ref ID J:76318)
  • in elderly mice, inflammatory infiltrate accumulates in the lung
• increased susceptibility to autoimmune disorder (MGI Ref ID J:76318)
  • at 15 months, mice exhibit features of autoimmune disease including inflammatory infiltrate, adnormal accumulation of effector/memory T cells, and double stranded DNA antibodies
• skin/coat/nails phenotype
• abnormal skin condition/ morphology (MGI Ref ID J:76318)
  • elderly mice exhibit skin wounds
• reddish skin (MGI Ref ID J:76318)
  • elderly mice exhibit erythema affecting the head and neck
• partial hair loss (MGI Ref ID J:76318)
  • elderly mice exhibit considerable hair loss
• liver/biliary system phenotype
• liver inflammation (MGI Ref ID J:76318)
  • in elderly mice, inflammatory infiltrate accumulates in the liver and perivascular infiltrates are observed
• renal/urinary system phenotype
• glomerulonephritis (MGI Ref ID J:76318)
  • elderly mice exhibit membranoproliferative glomerulonephritis that is focal and of moderate intensity
  • affected glomeruli are enlarged with a thickened basement membrane and contain perivascular aggregates of inflammatory infiltrate and immune complex deposition
• respiratory system phenotype
• lung inflammation (MGI Ref ID J:76318)
  • in elderly mice, inflammatory infiltrate accumulates in the lung
• hematopoietic system phenotype
• abnormal T cell differentiation (MGI Ref ID J:76318)
  • the fraction of mature (CD4+ and, especially, CD8+) thymocytes in the thymus is increased with a decreased in immature double positive thymocytes
• increased T cell proliferation (MGI Ref ID J:76318)
  • in response to IL-2 treatment, effector/memory cell (CD44^hiCD69-) T cell proliferation is increased relative to in wild-type mice by 2 times at weeks 8 to 12, and 13 times at 15 months
  • T cell proliferation stimulated by CD3 antibody is increased compared to in stimulated wild-type mice and is more prominent at suboptimal CD3 antibody concentrations
• abnormal T cell subpopulation ratio (MGI Ref ID J:76318)
  • there is an increase in the number of CD8+ T cells relative to CD4+ T cells (CD4+/CD8+ ratio: 0.79+/-0.1 compared to 1.43+/-0.3 in wild-type mice)
  • however, the T to B cells ratio is normal
• abnormal spleen white pulp morphology (MGI Ref ID J:76318)
  • at 15 months, mice display white pulp hyperplasia and increased sinusoidal cellularity
• enlarged spleen (MGI Ref ID J:76318)
  • at 15 months, mice exhibit splenomegaly with spleen size 2 to 5 times greater than that of wild-type mice
• increased spleen weight (MGI Ref ID J:76318)
  • at week 8 to 12, spleen weight is increased 2-fold (1445+/-250 mg) relative to in wild-type mice (668+/-108 mg) and continues to increase at 15 months (3340+/-540 mg compared to 722+/-125 mg in wild-type mice)
• increased memory T cell number (MGI Ref ID J:76318)
  • at 3 to 4 weeks and at 15 months, the number of CD44^hiCD69- memory T cells is increased
• cellular phenotype
• abnormal cell physiology (MGI Ref ID J:75726)
  • adenovirus-Myc fails to induce S phase as it does in wild-type mouse embryonic fibroblasts
• abnormal cell death (MGI Ref ID J:75726)
  • cell death induced by Myc expression in primary fibroblast cells is somewhat less efficient than in wild-type primary fibroblast

View Research Applications

Research Applications

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

E2f2^tm1Zubi related

Apoptosis Research
Endogenous Regulators (Autoimmune Lymphroliferatve syndrome)

Cancer Research
Genes Regulating Growth and Proliferation
Increased Tumor Incidence (Lymphomas: B cell lymphomas)
Increased Tumor Incidence (Lymphomas: thymic)

Cell Biology Research
Cell Cycle Regulation
Genes Regulating Growth and Proliferation

Dermatology Research
Skin and Hair Texture Defects

Developmental Biology Research
Lymphoid Tissue Defects (hematopoietic defects)

Hematological Research
Hematopoietic Defects
Immunological Defects (B and T cell deficiency)

Immunology and Inflammation Research
Autoimmunity (lupus erythematosus)
Immunodeficiency (T cell deficiency)
Inflammation
Lymphoid Tissue Defects (B and T cell deficiency)
Lymphoid Tissue Defects (hematopoietic development)
Lymphoid Tissue Defects (myeloid hyperplasia)
T Cell Receptor Signaling Defects (B and T cell deficiency)

Internal/Organ Research
Lymphoid Tissue Defects (T cell deficiency)
Spleen Defects
Thymus Defects (B and T cell deficient)

Mouse/Human Gene Homologs
systemic lupus erythematosus

Research Tools
Apoptosis Research
Cancer Research (B and T cell deficiency) (xenograft/transplant host)
Cancer Research (genes regulating lymphoma development)
Genetics Research (Mutagenesis and Transgenesis: Production of Targeted Mutations ("Knockouts"))
Genetics Research (Mutagenesis and Transgenesis: transcriptional activation)
Hematological Research
Immunology and Inflammation Research (B cell lymphomas)
Immunology and Inflammation Research (T cell deficiency)

Genes & Alleles

Gene & Allele Information

Allele Symbol		E2f2tm1Zubi
Allele Name		targeted mutation 1, Ana Zubiaga
Allele Type		Targeted (knock-out)
Common Name(s)		E2f2tm1Gle;
Mutation Made By		Ana Zubiaga,   University of the Basque Country
Strain of Origin		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
ES Cell Line Name		CJ7
ES Cell Line Strain		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Gene Symbol and Name		E2f2, E2F transcription factor 2
Chromosome		4
Gene Common Name(s)		E2F-2;
Molecular Note		Disruption of this gene was achieved via gene targeting. A PGK-neo cassette was inserted into exon 3. Southern and Northern analysis was utilized to confirm the targeting event and lack of transcript in homozygous mutant animals, respectively. [MGI Ref ID J:75726] [MGI Ref ID J:76318]

Genotyping

Genotyping Information

Genotyping Protocols

E2f2^tm1Zubi, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Murga M; Fernandez-Capetillo O; Field SJ; Moreno B; Borlado LR; Fujiwara Y; Balomenos D; Vicario A; Carrera AC; Orkin SH; Greenberg ME; Zubiaga AM. 2001. Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity. Immunity 15(6):959-70. [PubMed: 11754817]  [MGI Ref ID J:76318]

Additional References

Wu L; Timmers C; Maiti B; Saavedra HI; Sang L; Chong GT; Nuckolls F; Giangrande P; Wright FA; Field SJ; Greenberg ME; Orkin S; Nevins JR; Robinson ML; Leone G. 2001. The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414(6862):457-62. [PubMed: 11719808]  [MGI Ref ID J:73374]

Zhu JW; Field SJ; Gore L; Thompson M; Yang H; Fujiwara Y; Cardiff RD; Greenberg M; Orkin SH; DeGregori J. 2001. E2F1 and E2F2 Determine Thresholds for Antigen-Induced T-Cell Proliferation and Suppress Tumorigenesis. Mol Cell Biol 21(24):8547-64. [PubMed: 11713289]  [MGI Ref ID J:72952]

E2f2^tm1Zubi related

Andrechek ER; Mori S; Rempel RE; Chang JT; Nevins JR. 2008. Patterns of cell signaling pathway activation that characterize mammary development. Development 135(14):2403-13. [PubMed: 18550711]  [MGI Ref ID J:137644]

Bilousova G; Marusyk A; Porter CC; Cardiff RD; DeGregori J. 2005. Impaired DNA replication within progenitor cell pools promotes leukemogenesis. PLoS Biol 3(12):e401. [PubMed: 16277552]  [MGI Ref ID J:103814]

Chen D; Opavsky R; Pacal M; Tanimoto N; Wenzel P; Seeliger MW; Leone G; Bremner R. 2007. Rb-Mediated Neuronal Differentiation through Cell-Cycle-Independent Regulation of E2f3a. PLoS Biol 5(7):e179. [PubMed: 17608565]  [MGI Ref ID J:124204]

DeRyckere D; DeGregori J. 2005. E2F1 and E2F2 are differentially required for homeostasis-driven and antigen-induced T cell proliferation in vivo. J Immunol 175(2):647-55. [PubMed: 16002659]  [MGI Ref ID J:101673]

Dirlam A; Spike BT; Macleod KF. 2007. Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts. Mol Cell Biol 27(24):8713-28. [PubMed: 17923680]  [MGI Ref ID J:129010]

Iglesias A; Murga M; Laresgoiti U; Skoudy A; Bernales I; Fullaondo A; Moreno B; Lloreta J; Field SJ; Real FX; Zubiaga AM. 2004. Diabetes and exocrine pancreatic insufficiency in E2F1/E2F2 double-mutant mice. J Clin Invest 113(10):1398-407. [PubMed: 15146237]  [MGI Ref ID J:91105]

Leone G; Sears R; Huang E; Rempel R; Nuckolls F; Park CH; Giangrande P; Wu L; Saavedra HI; Field SJ; Thompson MA; Yang H; Fujiwara Y; Greenberg ME; Orkin S; Smith C; Nevins JR. 2001. Myc requires distinct E2F activities to induce S phase and apoptosis. Mol Cell 8(1):105-13. [PubMed: 11511364]  [MGI Ref ID J:75726]

Li FX; Zhu JW; Hogan CJ; DeGregori J. 2003. Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1/E2F2 mutant mice. Mol Cell Biol 23(10):3607-22. [PubMed: 12724419]  [MGI Ref ID J:83284]

Li FX; Zhu JW; Tessem JS; Beilke J; Varella-Garcia M; Jensen J; Hogan CJ; DeGregori J. 2003. The development of diabetes in E2f1/E2f2 mutant mice reveals important roles for bone marrow-derived cells in preventing islet cell loss. Proc Natl Acad Sci U S A 100(22):12935-40. [PubMed: 14566047]  [MGI Ref ID J:86404]

Opavsky R; Tsai SY; Guimond M; Arora A; Opavska J; Becknell B; Kaufmann M; Walton NA; Stephens JA; Fernandez SA; Muthusamy N; Felsher DW; Porcu P; Caligiuri MA; Leone G. 2007. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc Natl Acad Sci U S A 104(39):15400-5. [PubMed: 17881568]  [MGI Ref ID J:125304]

Palmero I; Murga M; Zubiaga A; Serrano M. 2002. Activation of ARF by oncogenic stress in mouse fibroblasts is independent of E2F1 and E2F2. Oncogene 21(19):2939-47. [PubMed: 12082524]  [MGI Ref ID J:126187]

Redmond WL; Wei CH; Kreuwel HT; Sherman LA. 2008. The apoptotic pathway contributing to the deletion of naive CD8 T cells during the induction of peripheral tolerance to a cross-presented self-antigen. J Immunol 180(8):5275-82. [PubMed: 18390708]  [MGI Ref ID J:134242]

Saenz-Robles MT; Markovics JA; Chong JL; Opavsky R; Whitehead RH; Leone G; Pipas JM. 2007. Intestinal hyperplasia induced by simian virus 40 large tumor antigen requires E2F2. J Virol 81(23):13191-9. [PubMed: 17855529]  [MGI Ref ID J:129937]

Sharma N; Timmers C; Trikha P; Saavedra HI; Obery A; Leone G. 2006. Control of the p53-p21CIP1 Axis by E2f1, E2f2, and E2f3 is essential for G1/S progression and cellular transformation. J Biol Chem 281(47):36124-31. [PubMed: 17008321]  [MGI Ref ID J:117634]

Tessem JS; Jensen JN; Pelli H; Dai XM; Zong XH; Stanley ER; Jensen J; DeGregori J. 2008. Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration. Diabetes 57(6):1605-17. [PubMed: 18375440]  [MGI Ref ID J:136898]

Tsai SY; Opavsky R; Sharma N; Wu L; Naidu S; Nolan E; Feria-Arias E; Timmers C; Opavska J; de Bruin A; Chong JL; Trikha P; Fernandez SA; Stromberg P; Rosol TJ; Leone G. 2008. Mouse development with a single E2F activator. Nature 454(7208):1137-41. [PubMed: 18594513]  [MGI Ref ID J:138289]

Wu L; Timmers C; Maiti B; Saavedra HI; Sang L; Chong GT; Nuckolls F; Giangrande P; Wright FA; Field SJ; Greenberg ME; Orkin S; Nevins JR; Robinson ML; Leone G. 2001. The E2F1-3 transcription factors are essential for cellular proliferation. Nature 414(6862):457-62. [PubMed: 11719808]  [MGI Ref ID J:73374]

Yan Z; Choi S; Liu X; Zhang M; Schageman JJ; Lee SY; Hart R; Lin L; Thurmond FA; Williams RS. 2003. Highly coordinated gene regulation in mouse skeletal muscle regeneration. J Biol Chem 278(10):8826-36. [PubMed: 12477723]  [MGI Ref ID J:82190]

Zhang J; Bahi N; Zubiaga AM; Comella JX; Llovera M; Sanchis D. 2007. Developmental silencing and independency from E2F of apoptotic gene expression in postmitotic tissues. FEBS Lett 581(30):5781-6. [PubMed: 18037375]  [MGI Ref ID J:129205]

Zhu JW; Field SJ; Gore L; Thompson M; Yang H; Fujiwara Y; Cardiff RD; Greenberg M; Orkin SH; DeGregori J. 2001. E2F1 and E2F2 Determine Thresholds for Antigen-Induced T-Cell Proliferation and Suppress Tumorigenesis. Mol Cell Biol 21(24):8547-64. [PubMed: 11713289]  [MGI Ref ID J:72952]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129 background and is maintained on the same as a homozygote.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Induced Mutant Resource Colony collection.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

Contact information

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phone:	207-288-6470
fax:	207-288-6655

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“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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