Mouse Models

 

CuZnSOD knockout mice
MnSOD knockout mice
Inducible MnSOD transgenic mice
Inducible EC-SOD transgenic mice
Other mouse models used in the lab

CuZnSOD knockout mice Strain name: B6-Sod1tm2Cje Allele name: Sod1, CuZn superoxide dismutase Type: Targeted mutation Genetic Background: C57BL/6J Breeding: Heterozygous x C57BL/6J Description: This strain was generated in Charles Epstein’s laboratory at UCSF in 1996 via homologous recombination using the ES cell line CB1-4. Both heterozygous male and female mice are fertile. Homozygous females, on the other hand, are sterile and homozygous males have reduced fertility. Homozygous mice are smaller in size and roughly 30% would develop liver tumor between 18 and 21 months of age. Genotyping: PCR genotyping procedure for B6-Sod1tm2Cje (link to PDF protocol file) Availability: Cryopreserved by MMRRC (Mutant Mouse Regional Resource Center), strain number 000203-MU; live colony at Stanford University (contact Ting-Ting Huang at tthuang@stanford.edu) References:

  1. Huang TT, Yasunami M, Carlson EJ, Gillespie AM, Reaume AG, Hoffman EK, Chan PH, Scott RW, Epstein CJ (1997) Superoxide-mediated cytotoxicity in superoxide dismutase-deficient fetal fibroblasts. Arch Biochem Biophys 344, 424-432.
  2. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367-380.
  3. Busuttil RA, Garcia AM, Cabrera C, Rodriguez A, Suh Y, Kim WH, Huang TT, Vijg J (2005) Organ-specific increase in mutation accumulation and apoptosis rate in CuZnSOD-deficient mice. Cancer Research 65, 11271-11275.
  4. Muller FL, Song W, Liu Y, Chaudhuri A, Dahl SP, Strong R, Huang TT, Epstein CJ, Roberts II LJ, Faulkner JA, Richardson A, Van Remmen H (2006) Absence of CuZn-SOD causes severe oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med 40, 1993-2004.
  5. Erker, L, Schubert R, Elchuri S, Huang TT, Tarin D, Mueller K, Zielen S, Epstein CJ, Wynshaw-Boris A (2006) Effect of the reduction of superoxide dismutase 1 and 2 or treatment with alpha-tocopherol on tumorigenesis in Atm-deficient mice. Free Radic Biol Med 41, 590-600.
  6. Elchuri S, Naeemuddin M, Sharpe O, Robinson WH, Huang TT (2007) Identification of biomarkers associated with the development of hepatocellular carcinoma in CuZn superoxide dismutase deficient mice. Proteomics 7, 2121-2129.
  7. Fishman K, Baure J, Zou Y, Huang TT, Andres-Mach M, Rola R, Suarez T, Achaarya M, Limoli CL, Lamborn KR, Fike JR (2009) Radiation-Induced Reductions in Neurogenesis are Ameliorated in Mice Deficient in CuZnSOD or MnSOD. Free Radic Bio Med 47,1459-1467.

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MnSOD knockout mice Strain name: B6-Sod2tm1Cje Allele name: Sod2, Mn superoxide dismutase Type: Targeted mutation Genetic Background: C57BL/6J Breeding: Heterozygous x C57BL/6J Description: This strain was generated in Charles Epstein’s laboratory at UCSF in 1994 via homologous recombination using the ES cell line CB1-4. Both heterozygous male and female mice are fertile and show no overt abnormalities under normal laboratory conditions. Homozygous mice have an early lethal phenotype, and depending on the genetic backgrounds, they either die around E15 or within a few weeks after birth. Genotyping: PCR genotyping procedure for B6-Sod2tm1Cje (link to PDF protocol file) Availability: Cryopreserved by MMRRC (Mutant Mouse Regional Resource Center), strain number 000202-MU; live colony at Stanford University (contact Ting-Ting Huang at tthuang@stanford.edu) References:

  1. Li Y*, Huang TT*, Carlson EJ, Melov S, Ursell PC, Olson JL, Noble LJ, Yoshimura MP, Berger C, Chan PH, Epstein CJ (1995) Dilated cardiomyopathy and neonatal lethality in mutant mice lacking manganese superoxide dismutase. Nat Genet 11, 376-381.
  2. Williams MD, Van Remmen H, Conrad CC, Huang TT, Epstein CJ, Richardson A (1998) Increased oxidative damage is correlated to altered mitochondrial function in heterozygous manganese superoxide dismutase knockout mice. J Biol Chem 273, 28510-28515.
  3. Melov S, Coskun P, Patel M, Tuinstra R, Cottrell B, Jun AS, Zastawny TH, Dizdaroglu M, Goodman SI, Huang TT, Miziorko H, Epstein CJ, Wallace DC (1999) Mitochondrial disease in superoxide dismutase 2 mutant mice. Proc Natl Acad Sci U S A 96, 846-851.
  4. Van Remmen H, Salvador C, Yang H, Huang TT, Epstein CJ, Richardson A (1999) Characterization of the antioxidant status of the heterozygous manganese superoxide dismutase knockout mouse. Arch Biochem Biophys 363, 91-97.
  5. Friedman JS, Rebel VI, Derby R, Bell K, Huang TT, Kuypers FA, Epstein CJ, Burakoff SJ (2001) Absence of mitochondrial superoxide dismutase results in a murine hemolytic anemia responsive to therapy with a catalytic antioxidant. J Exp Med 193, 925-934.
  6. Huang TT, Carlson EJ, Kozy HM, Mantha S, Goodman SI, Ursell PC, Epstein CJ (2001) Genetic modification of prenatal lethality and dilated cardiomyopathy in Mn superoxide dismutase mutant mice. Free Radic Biol Med 31, 1101-1110.
  7. Van Remmen H, Williams MD, Guo Z, Estlack L, Yang H, Carlson EJ, Epstein CJ, Huang TT, Richardson A (2001) Knockout mice heterozygous for Sod2 show alterations in cardiac mitochondrial function and apoptosis. Am J Physiol Heart Circ Physiol 281, H1422-1432.
  8. Asikainen TM, Huang TT, Taskinen E, Levonen AL, Carlson E, Lapatto R, Epstein CJ, Raivio KO (2002) Increased sensitivity of homozygous Sod2 mutant mice to oxygen toxicity. Free Radic Biol Med 32,175-186.
  9. Zhao Y, Oberley TD, Chaiswing L, Lin SM, Epstein CJ, Huang TT, St Clair D (2002) Manganese superoxide dismutase deficiency enhances cell turnover via tumor promoter-induced alterations in AP-1 and p53-mediated pathways in a skin cancer model. Oncogene 21, 3836-3846.
  10. Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A (2003) Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging. Physiol Genomics 16, 29-37.
  11. Ali SS, Hardt JI, Quick KL, Kim-Han JS, Erlanger BF, Huang TT, Epstein CJ, Dugan LL (2004) A biologically effective fullerene (C60) derivative with superoxide dismutase mimetic properties. Free Radic Biol Med 37, 1191-1202.
  12. Lynn S, Huang EJ, Elchuri S, Naeemuddin M, Nishinaka Y, Yodoi J, Ferriero DM, Epstein CJ, Huang TT (2005) Selective neuronal vulnerability and inadequate stress response in MnSOD mutant mice. Free Radic Biol Med 38, 817-828.
  13. Huang TT, Naeemuddin M, Elchuri S, Kozy HM, Carlson EJ, Epstein CJ (2006) Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Human Molecular Genetics 15, 1187-1194.
  14. Fishman K, Baure J, Zou Y, Huang TT, Andres-Mach M, Rola R, Suarez T, Achaarya M, Limoli CL, Lamborn KR, Fike JR (2009) Radiation-Induced Reductions in Neurogenesis are Ameliorated in Mice Deficient in CuZnSOD or MnSOD. Free Radic Bio Med 47, 1459-1467.
  15. Kim A, Chen CH, Ursell P, Huang TT (2010) Genetic modifier of mitochondrial superoxide dismutase deficient mice delays heart failure and prolongs survival. Mammalian Genome 21, 534-542.

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Inducible MnSOD transgenic mice Strain name: Sod2-TRE-LacZ Allele name: Sod2, Mn superoxide dismutase; LacZ, β-galactosidase Type: Transgenic mouse Genetic Background: C57BL/6J Breeding: Hemizygous x C57BL/6J Description: This transgenic line was generated in Charles Epstien’s laboratory at UCSF in 2002. The transgenes are controlled by a bi-directional tet-responsive element (TRE). LacZ serves as a reporter for the expression of MnSOD in the opposite direction. The transgenic line was initially generated in fertilized B6D2F1 eggs by microinjection. The transgenic line has been crossed to LAP-tTA, CamKII-tTA, CamKII-rtTA, and α-MHC-tTA transgenics and showed LacZ expression in the target tissues. Hemizygous transgenic mice have no overt abnormalities under normal laboratory conditions. Genotyping: PCR genotyping procedure for Sod2-TRE-LacZ (link to PDF protocol file) Availability: Live colony at Stanford University (contact Ting-Ting Huang at tthuang@stanford.edu) Reference: Kim A, Joseph S, Khan A, Epstein CJ, Sobel R, Huang TT (2010) Enhanced expression of mitochondrial superoxide dismutase leads to prolonged in vivo cell cycle progression and up-regulation of mitochondrial thioredoxin. Free Radic Bio Med 48, 1501-1512

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Inducible EC-SOD transgenic mice Strain name: TRE-Sod3-GFP Allele name: Sod3, extracellular superoxide dismutase (EC-SOD); hrGFP, humanized green fluorescence protein Type: Transgenic mouse Genetic Background: C57BL/6J Breeding: Hemizygous x C57BL/6J Description: This transgenic line was generated in Ting-Ting Huang’s laboratory in 2007. DNA construct was injected directly in B6 embryos at the two-cell stage. Founders were then crossed to C57BL/6J to test germline transmission. Two independent transgenic lines were generated, and both show comparable levels of EC-SOD when crossed to transactivator transgenics. The transgenic lines have been crossed to CamKII-tTA, CamKII-rtTA, and LAP-tTA to test transgene expression. Genotyping: PCR genotyping procedure for TRE-Sod3-GFP (link to PDF protocol file) Availability: Live colony at Stanford University (contact Ting-Ting Huang at tthuang@stanford.edu) Reference: Zou Y, Chen, CH, Fike, JR, Huang TT (2009) A new mouse model for temporal and tissue-specific control of extracellular superoxide dismutase. Genesis 47, 142-154.

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Other mouse models used in the lab

  1. Floxed Sod2 mice. Can be used for tissue-and cell-specific deletion of MnSOD.
    Original Source: Professor Takuji Shirasawa, Tokyo Metropolitan Institute of Gerontology, Japan
    Original Reference: Ikegami T, Suzuki Y, Shimizu T, Isono K, Koseki H, Shirasawa T (2002) Model mice for tissue-specific deletion of the manganese superoxide dismutase (MnSOD) gene. Biochem Biophys Res Commun. 296,729-736.
  2. EC-SOD knockout mice. Ubiquitous deletion of EC-SOD. Homozygous knockout mice are viable and fertile. The lifespan is similar to that of C57BL/6J mice.
    Original Source: Professor Stephan Marklund, Umeå University, Sweden and Professor James Crapo, National Jewish Health, Denver, USA
    Original Reference: Carlsson LM, Jonsson J, Edlund T, Marklund SL (1995) Mice lacking extracellular superoxide dismutase are more sensitive to hyperoxia. Proc Natl Acad Sci 92, 6264-6268.
  3. EC-SOD transgenic mice. Ubiquitous overexpression of human EC-SOD transgene.
    Source: Professor James Crapo, National Jewish Health, Denver, USA
    Original Reference: Oury TD, Ho YS, Piantadosi CA, Crapo JD (1992) Extracellular superoxide dismutase, nitric oxide, and central nervous system O2 toxicity. Proc Natl Acad Sci 89, 9715-9719.
  4. HCV transgenic line FL-35. Liver-specific expression of full length hepatitis C virus polyprotein. Transgene expression is controlled by murine albumin enhancer/promoter.
    Source: Professor Stanley Lemon (UTMB, Galveston) and Professor Steven Weinman (University of Kansas Medical Center)
    Original Reference: Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology. 122, 352-365.
  5. HCV transgenic line SL-139. Liver-specific expression of hepatitis C virus structural proteins. Transgene expression is controlled by murine albumin enhancer/promoter.
    Source: Professor Stanley Lemon (UTMB, Galveston) and Professor Steven Weinman (University of Kansas Medical Center)
    Original Reference: Lerat H, Honda M, Beard MR, Loesch K, Sun J, Yang Y, Okuda M, Gosert R, Xiao SY, Weinman SA, Lemon SM (2002) Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology. 122, 352-365.

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