Strain Name:

NOD.129(B6)-Ctla4tm1All/DoiJ

Stock Number:

005144

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Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Additional information on Congenic nomenclature.
Specieslaboratory mouse
Background Strain NOD/ShiLtJ
Donor Strain 129 (R1 ES cells)
H2 Haplotypeg7
Generation?+N1p (08-MAY-05)
Generation Definitions
 
Donating Investigator Christophe Benoist,   Joslin Diabetes Center

Appearance
pink-eyed abino
Related Genotype: A/? Tyrc/Tyrc

Description
Heterozygous Ctla4tm1All mice are viable, fertile, and normal in size and exhibit diabetes incidence comparable to NOD.

Ctla4tm1All homozygous mice on various backgrounds, including C57BL/6, BALB/c, 129 and NOD, die at 3-4 weeks of age due to massive polyclonal expansion of T-cells and massive lymphocyte infiltration into non-lymphoid organs, such as heart, liver, lung and pancreas. Treatment with murine Ctla4Ig or depletion of CD4+ T-cells blocks this lymphoproliferative disease. Splenic and lymph node T-cells display an activated phenotype characterized as CD69+, CD25+, CD44hi, Mel14lo, CD45RBlo and Sca1hi and have down regulated the TCR. Lymph node and spleen cells cultured from Ctla4tm1All homozygous mice spontaneously proliferate while wild-type controls do not. Cells from whole lymph nodes or purified T-cells are unresponsive to anti CD28mAb stimulation, while rIl2 increases the proliferative response. Homozygous Ctla4tm1All NOD mice also transgenically expressing the BDC2.5 alpha and beta TCR chains do not exhibit the lymphoproliferative phenotype. Other TCR transgenes exert a similar effect on differing backgrounds. However, all of the mice develop aggressive autoimmunity and rapidly develop diabetes by7 weeks of age.In contrast, mice heterozygous for Ctla4tm1All and transgenically expressing the BDC2.5 TCR have late and relatively rare diabetes.

NOD.129(B6)-Ctla4tm1All/DoiJ may be useful for studying the role of Ctla4/Cd28:Cd80/Cd86 in the regulation of self tolerance and susceptibility to autoimmune diseases.

Development
A construct containing a neomycin expression cassette inserted into exon 3 of Ctla4 (cloned from 129/Sv mouse) was transfected into R1 ((129X1/SvJ x 129S1/Sv)F1-Kitl +) embryonic stem cells (ES cells). These ES cells were injected into C57BL/6 blastocysts. To establish a colony and germ line transmission chimeric mice were backcrossed to C57BL/6 (Chambers et, al, 1997). Luhder et al. 2000, subsequently backcrossed this mutation to NOD/LtJ. In 2004, the Type 1 Diabetes Resource received NOD.129(B6)- Ctla4tm1All /DoiJ heterozygotes at generation N18.

Control Information

  Control
   Wild-type from the colony
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Ctla4
017607   B6.129S4-Cd28tm1Shr Ctla4tm1Shr/J
002980   C57BL/6-Tg(Cd152Ig)1Jbs/J
View Strains carrying other alleles of Ctla4     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Celiac Disease, Susceptibility to, 3; CELIAC3   (CTLA4)
Cytotoxic T Lymphocyte-Associated 4; CTLA4   (CTLA4)
Diabetes Mellitus, Insulin-Dependent, 12; IDDM12   (CTLA4)
Hashimoto Thyroiditis   (CTLA4)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX® Mice strain.

Ctla4tm1All/Ctla4tm1All

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * NOD
  • mortality/aging
  • premature death
    • mice die at 3 to 4 weeks of age   (MGI Ref ID J:109887)
  • immune system phenotype
  • increased acute inflammation
    • at 3 weeks, mice exhibit extensive infiltration of the heart, liver, and pancreas unlike in wild-type mice   (MGI Ref ID J:109887)
View Research Applications

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

Ctla4tm1All related

Cancer Research
Growth Factors/Receptors/Cytokines

Diabetes and Obesity Research
Type 1 Diabetes (IDDM) Analysis Strains
      NOD Congenics with Mutations Affecting Cytokine Production by Autoreactive T Cells

Immunology, Inflammation and Autoimmunity Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
Growth Factors/Receptors/Cytokines

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Ctla4tm1All
Allele Name targeted mutation 1, James P Allison
Allele Type Targeted (knock-out)
Common Name(s) CTLA-4 KO; CTLA-4-; Ctla4o; Ctla4o;
Mutation Made By James Allison,   Mem. Sloan-Kettering Cancer Ctr., HHMI
Strain of Origin(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line NameR1
ES Cell Line Strain(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name Ctla4, cytotoxic T-lymphocyte-associated protein 4
Chromosome 1
Gene Common Name(s) CD; CD152; CD152 antigen; CELIAC3; CTLA-4; Cd152; Ctla-4; GRD4; GSE; IDDM12; Ly-56; cytotoxic T lymphocyte-associated protein 4; sCTLA4;
Molecular Note The insertion of neomycin selection cassette under the control of a PGK promoter disrupted exon 3. [MGI Ref ID J:42481]

Genotyping

Genotyping Information

Genotyping Protocols

Ctla4tm1All, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Luhder F; Chambers C; Allison JP; Benoist C; Mathis D. 2000. Pinpointing when T cell costimulatory receptor CTLA-4 must be engaged to dampen diabetogenic T cells. Proc Natl Acad Sci U S A 97(22):12204-9. [PubMed: 11035773]  [MGI Ref ID J:109887]

Additional References

Chambers CA; Cado D; Truong T; Allison JP. 1997. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A 94(17):9296-301. [PubMed: 9256476]  [MGI Ref ID J:42481]

Tivol EA; Borriello F; Schweitzer AN; Lynch WP; Bluestone JA; Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541-7. [PubMed: 7584144]  [MGI Ref ID J:30393]

Waterhouse P; Bachmann MF; Penninger JM; Ohashi PS; Mak TW. 1997. Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor-transgenic CTLA-4-deficient mice. Eur J Immunol 27(8):1887-92. [PubMed: 9295023]  [MGI Ref ID J:42659]

Ctla4tm1All related

Chambers CA; Cado D; Truong T; Allison JP. 1997. Thymocyte development is normal in CTLA-4-deficient mice. Proc Natl Acad Sci U S A 94(17):9296-301. [PubMed: 9256476]  [MGI Ref ID J:42481]

Chambers CA; Kang J; Wu Y; Held W; Raulet DH; Allison JP. 2002. The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by an inhibitory NK cell receptor. Blood 99(12):4509-16. [PubMed: 12036882]  [MGI Ref ID J:77052]

Chambers CA; Kuhns MS; Allison JP. 1999. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci U S A 96(15):8603-8. [PubMed: 10411922]  [MGI Ref ID J:119845]

Chambers CA; Sullivan TJ; Allison JP. 1997. Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 7(6):885-95. [PubMed: 9430233]  [MGI Ref ID J:111523]

Chambers CA; Sullivan TJ; Truong T; Allison JP. 1998. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol 28(10):3137-43. [PubMed: 9808182]  [MGI Ref ID J:114212]

Chen Z; Stockton J; Mathis D; Benoist C. 2006. Modeling CTLA4-linked autoimmunity with RNA interference in mice. Proc Natl Acad Sci U S A 103(44):16400-5. [PubMed: 17060611]  [MGI Ref ID J:115599]

Gattinoni L; Ranganathan A; Surman DR; Palmer DC; Antony PA; Theoret MR; Heimann DM; Rosenberg SA; Restifo NP. 2006. CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent. Blood 108(12):3818-23. [PubMed: 16882704]  [MGI Ref ID J:140448]

Hegel JK; Knieke K; Kolar P; Reiner SL; Brunner-Weinzierl MC. 2009. CD152 (CTLA-4) regulates effector functions of CD8+ T lymphocytes by repressing Eomesodermin. Eur J Immunol 39(3):883-93. [PubMed: 19224637]  [MGI Ref ID J:146787]

Hoff H; Kolar P; Ambach A; Radbruch A; Brunner-Weinzierl MC. 2010. CTLA-4 (CD152) inhibits T cell function by activating the ubiquitin ligase Itch. Mol Immunol 47(10):1875-81. [PubMed: 20417562]  [MGI Ref ID J:160620]

Inobe M; Schwartz RH. 2004. CTLA-4 engagement acts as a brake on CD4+ T cell proliferation and cytokine production but is not required for tuning T cell reactivity in adaptive tolerance. J Immunol 173(12):7239-48. [PubMed: 15585846]  [MGI Ref ID J:94863]

Ise W; Kohyama M; Nutsch KM; Lee HM; Suri A; Unanue ER; Murphy TL; Murphy KM. 2010. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol 11(2):129-35. [PubMed: 20037585]  [MGI Ref ID J:158400]

Khattri R; Cox T; Yasayko SA; Ramsdell F. 2003. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337-42. [PubMed: 12612581]  [MGI Ref ID J:128566]

Miska J; Bas E; Devarajan P; Chen Z. 2012. Autoimmunity-mediated antitumor immunity: Tumor as an immunoprivileged self. Eur J Immunol 42(10):2584-96. [PubMed: 22777737]  [MGI Ref ID J:188006]

Pandiyan P; Gartner D; Soezeri O; Radbruch A; Schulze-Osthoff K; Brunner-Weinzierl MC. 2004. CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J Exp Med 199(6):831-42. [PubMed: 15007096]  [MGI Ref ID J:90481]

Pandiyan P; Hegel JK; Krueger M; Quandt D; Brunner-Weinzierl MC. 2007. High IFN-gamma production of individual CD8 T lymphocytes is controlled by CD152 (CTLA-4). J Immunol 178(4):2132-40. [PubMed: 17277117]  [MGI Ref ID J:143993]

Pedicord VA; Montalvo W; Leiner IM; Allison JP. 2011. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc Natl Acad Sci U S A 108(1):266-71. [PubMed: 21173239]  [MGI Ref ID J:169010]

Peggs KS; Quezada SA; Chambers CA; Korman AJ; Allison JP. 2009. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J Exp Med 206(8):1717-25. [PubMed: 19581407]  [MGI Ref ID J:151491]

Quandt D; Hoff H; Rudolph M; Fillatreau S; Brunner-Weinzierl MC. 2007. A new role of CTLA-4 on B cells in thymus-dependent immune responses in vivo. J Immunol 179(11):7316-24. [PubMed: 18025174]  [MGI Ref ID J:154822]

Rudolph M; Hebel K; Miyamura Y; Maverakis E; Brunner-Weinzierl MC. 2011. Blockade of CTLA-4 decreases the generation of multifunctional memory CD4+ T cells in vivo. J Immunol 186(10):5580-9. [PubMed: 21478403]  [MGI Ref ID J:173092]

Simpson TR; Li F; Montalvo-Ortiz W; Sepulveda MA; Bergerhoff K; Arce F; Roddie C; Henry JY; Yagita H; Wolchok JD; Peggs KS; Ravetch JV; Allison JP; Quezada SA. 2013. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med 210(9):1695-710. [PubMed: 23897981]  [MGI Ref ID J:202359]

Sojka DK; Hughson A; Fowell DJ. 2009. CTLA-4 is required by CD4+CD25+ Treg to control CD4+ T-cell lymphopenia-induced proliferation. Eur J Immunol 39(6):1544-51. [PubMed: 19462377]  [MGI Ref ID J:149528]

Stohl W; Jacob N; Quinn WJ 3rd; Cancro MP; Gao H; Putterman C; Gao X; Pricop L; Koss MN. 2008. Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. J Immunol 181(1):833-41. [PubMed: 18566449]  [MGI Ref ID J:137391]

Stohl W; Xu D; Kim KS; David CS; Allison JP. 2004. MHC class II-independent and -dependent T cell expansion and B cell hyperactivity in vivo in mice deficient in CD152 (CTLA-4). Int Immunol 16(7):895-904. [PubMed: 15136557]  [MGI Ref ID J:90671]

Sugita S; Futagami Y; Horie S; Mochizuki M. 2007. Transforming growth factor beta-producing Foxp3(+)CD8(+)CD25(+) T cells induced by iris pigment epithelial cells display regulatory phenotype and acquire regulatory functions. Exp Eye Res 85(5):626-36. [PubMed: 17720157]  [MGI Ref ID J:132325]

Sugita S; Keino H; Futagami Y; Takase H; Mochizuki M; Stein-Streilein J; Streilein JW. 2006. B7+ iris pigment epithelial cells convert T cells into CTLA-4+, B7-expressing CD8+ regulatory T cells. Invest Ophthalmol Vis Sci 47(12):5376-84. [PubMed: 17122127]  [MGI Ref ID J:123098]

Sugita S; Ng TF; Lucas PJ; Gress RE; Streilein JW. 2006. B7+ iris pigment epithelium induce CD8+ T regulatory cells; both suppress CTLA-4+ T cells. J Immunol 176(1):118-27. [PubMed: 16365402]  [MGI Ref ID J:126250]

Sugita S; Ng TF; Schwartzkopff J; Streilein JW. 2004. CTLA-4+CD8+ T cells that encounter B7-2+ iris pigment epithelial cells express their own B7-2 to achieve global suppression of T cell activation. J Immunol 172(7):4184-94. [PubMed: 15034031]  [MGI Ref ID J:88713]

Sugita S; Streilein JW. 2003. Iris pigment epithelium expressing CD86 (B7-2) directly suppresses T cell activation in vitro via binding to cytotoxic T lymphocyte-associated antigen 4. J Exp Med 198(1):161-71. [PubMed: 12835481]  [MGI Ref ID J:84466]

Sullivan TJ; Letterio JJ; van Elsas A; Mamura M; van Amelsfort J; Sharpe S; Metzler B; Chambers CA; Allison JP. 2001. Lack of a role for transforming growth factor-beta in cytotoxic T lymphocyte antigen-4-mediated inhibition of T cell activation. Proc Natl Acad Sci U S A 98(5):2587-92. [PubMed: 11226283]  [MGI Ref ID J:135466]

Winstead CJ; Reilly CS; Moon JJ; Jenkins MK; Hamilton SE; Jameson SC; Way SS; Khoruts A. 2010. CD4(+)CD25(+)Foxp3(+) regulatory T cells optimize diversity of the conventional T cell repertoire during reconstitution from lymphopenia. J Immunol 184(9):4749-60. [PubMed: 20357265]  [MGI Ref ID J:160453]

Zheng SG; Wang JH; Stohl W; Kim KS; Gray JD; Horwitz DA. 2006. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 176(6):3321-9. [PubMed: 16517699]  [MGI Ref ID J:129539]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & HusbandryHomozygotes die at 3-4 weeks of age. Heterozygotes become diabetic similar to NOD/LtJ. A footpad injection of Complete Freund s Adjuvant (CFA) administered once at weaning will delay diabetes onset, thus extending the lifespan of breeders. Use of Complete Freund s Adjuvant in NOD mice can be found in Current Protocols in Immunology page 15.9.19, Reproduction.
Diet Information LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2450.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Embryos

Price (US dollars $)
Frozen Embryo $1600.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. 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, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3185.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Embryos

Price (US dollars $)
Frozen Embryo $2080.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. 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, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.
    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 11 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

    Cryorecovery to establish a Dedicated Supply for greater quantities of mice
    Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

General Supply Notes

Control Information

  Control
   Wild-type from the colony
   001976 NOD/ShiLtJ
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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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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