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The H-2KbtsA58 transgenic mouse: A new tool for the rapid generation of novel cell lines

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Abstract

The ability to generate expanded populations of individual cell types able to undergo normal differentiationin vitro andin vivo is of critical importance in the investigation of the mechanisms that underly differentiation and in studies on the use of cell transplantation to repair damaged tissues. This review discusses the development of a strain of transgenic mice that allows the direct derivation of conditionally immortal cell lines from a variety of tissues, simply by dissociation of the tissue of interest and growth of cells in appropriate conditions. In these mice the tsA58 mutant of SV40 large T antigen is controlled by the interferon-inducible Class I antigen promoter. Cells can be grown for extended periodsin vitro simply by growing them at 33°C in the presence of interferon, while still retaining the capacity to undergo normal differentiationin vivo andin vitro. In addition, it appears that cell lines expressing mutant phenotypes can readily be generated by preparing cultures from appropriate offspring of matings between H-2KbtsA58 transgenic mice and mutant mice of interest.

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References

  • Baldwin, A.S. Jr. and Sharp, P.A. (1987) Binding of a nuclear factor to a regulatory sequence in the promoter of the mouse H-2Kb class I major histocompatibility gene.Mol. Cell. Biol. 7, 305–13.

    PubMed  Google Scholar 

  • Barr, E. and Leiden, J.M. (1991) Systemic delivery of recombinant proteins by genetically modified myoblasts.Science 254, 1507–9.

    PubMed  Google Scholar 

  • Basham, T.Y. and Merigan, T.C. (1983) Recombinant interferon-gamma increases HLA-DR synthesis and expression.J. Immunol. 130, 1492–4.

    PubMed  Google Scholar 

  • Beyreuther, K., Rodemann, H.P., Hommel, R., Dittmann, K., Albeiz, M. and Francz, P.I. (1988) Human skin fibroblastsin vitro differentiate along a terminal cell lineage.Proc. Natl Acad. Sci. USA 85, 5112–6.

    PubMed  Google Scholar 

  • Brinster, R.L., Chen, H.Y., Messing, A., Dyke, T. van, Levine, A.J. and Palmiter, R.D. (1984) Transgenic mice harboring SV40 T-antigen genes develop characteristic brain tumors.Cell 37, 367–79.

    Article  PubMed  Google Scholar 

  • Chambers, T.J., Owens, J.M., Hattersley, G., Jat, P.S. and Noble, M.D. (1993) Generation of osteoclast-inductive and osteoclastogenic cell lines from the H-2KbA58 transgenic mouse.Proc. Natl Acad. Sci. USA 90, 5578–82.

    PubMed  Google Scholar 

  • Colby, W.W. and Shenk, T. (1982) Fragments of SV40 transforming gene facilitate transformation of rat embryo fibroblasts.Proc. Natl Acad. Sci. USA 79, 5189–93.

    PubMed  Google Scholar 

  • Compere, S.J. (1989) Theras andmyc oncogenes cooperate in tumor induction in many tissues when introduced into midgestation mouse embryos by retroviral vectors.Proc. Natl Acad. Sci. USA 86, 2224–8.

    PubMed  Google Scholar 

  • Cristofalo, V.J. (1974). Animal cell cultures as a model system for the study of aging.Adv. Gerontol. Res. 4, 45–77.

    Google Scholar 

  • Cunningham, M.G., Nikkah, G. and McKay, R.D.G. (1993) Grafting immortalized hippocampal cells into the brain of the adult and newborn rat.Neuroprotocols 3, 260–72.

    Article  Google Scholar 

  • Dell'Orco, R.T., Mertens, J.G. and Kruse, P.F. Jr. (1973) Doubling potential, calender time, and senescence of human diploid cells in culture.Exptl Cell Res. 77, 356–60.

    Article  PubMed  Google Scholar 

  • Dhawan, J., Pan, L.C., Pavlath, G.K., Travis, M.A., Lanctot, A.M. and Blau, H.M. (1991) Systemic delivery of human growth hormone by injection of genetically engineered myoblasts.Science 254, 1509–11.

    PubMed  Google Scholar 

  • Efrat, S., Linde, S., Kofod, H., Spector, D., Delannoy, M., Grant, S., Hanahan, D. and Baekkeskov, S. (1988) Betacell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene.Proc. Natl Acad. Sci. USA 85, 9037–41.

    PubMed  Google Scholar 

  • Fallon, J.R. (1985) Preferential outgrowth of central nervous system neurites on astrocytes and Schwann cells as compared with nonglial cellsin vitro.J. Cell Biol. 100, 198–207.

    Article  PubMed  Google Scholar 

  • Fawcett, J.W. (1992) Intrinsic neuronal determinants of regeneration.Trends Neurosci. 15, 5–8.

    Article  PubMed  Google Scholar 

  • Fawcett, J.W., Housden, E., Smith-Thomas, L. and Meyer, R.L. (1989) The growth of axons in three-dimensional astrocyte cultures.Dev. Biol. 135, 449–58.

    Article  PubMed  Google Scholar 

  • Ffrench-Constant, C., Miller, R.H., Burne, J.F. and Raff, M.C. (1988) Evidence that that migratory oligodendrocyte-type-2 astrocyte (O-2A) progenitor cells are kept out of the rat retina by a barrier at the eye-end of the optic nerve.J. Neurocytol. 17, 13–25.

    Article  PubMed  Google Scholar 

  • Goldstein, S. (1990) Replicative senescence: the human fibroblast comes to age.Science 249, 1129–33.

    PubMed  Google Scholar 

  • Goldstein, S. and Singal, D.P. (1974) Senescence of cultured human fibroblasts: mitotic versus metabolic time.Exp. Cell Res. 88, 359–64.

    Article  PubMed  Google Scholar 

  • Gonos, E.S., Powell, A.J. and Jat, P.S. (1992) Human and rodent fibroblasts: Model systems for studying senescence and immortalisation.Internat. J. Oncol. 1, 209–13.

    Google Scholar 

  • Groves, A.K., Entwistle, A., Jat, P.S. and Noble, M. (1993) The characterisation of astrocyte cell lines that display properties of glial scar tissue.Dev. Biol. 159, 87–104.

    Article  PubMed  Google Scholar 

  • Hamilton, S.R. and Vogelstein, B. (1988) Point mutations in human neoplasia.J. Pathol. 154, 205–6.

    Article  PubMed  Google Scholar 

  • Hammang, J.P., Baetge, E.E., Behringer, R.R., Brinster, R.L., Palmiter, R.D. and Messing, A. (1990) Immortalized rat neurons derived from SV40 TAg induced tumors in transgenic mice.Neuron 4, 775–82.

    Article  PubMed  Google Scholar 

  • Hanahan, D. (1985) Heritable formation of pancreatic β-cell tumors in transgenic mice expressing recombinant insulin/ simian virus 40 oncogenes.Nature 315, 115–22.

    Article  PubMed  Google Scholar 

  • Harley, C.B. and Goldstein, S. (1978) Cultured human fibroblasts: distribution of cell generations and a critical limit.Cell Physiol. 97, 509–16.

    Article  Google Scholar 

  • Hattersley, G., Owens, J., Flanagen, A.M. and Chambers, T.J. (1991) Macrophage colony stimulating factor (M-CSF) is essential for osteoclast formationin vitro.Biochem. Biophys. Res. Commun. 177, 526–31.

    Article  PubMed  Google Scholar 

  • Hayflick, L. and Moorhead, P.S. (1961) The serial cultivation of human diploid cell strains.Exp. Cell. Res. 25, 585–621.

    Article  Google Scholar 

  • Hunter, T. (1991) Cooperation between oncogenes.Cell 64, 249–70.

    Article  PubMed  Google Scholar 

  • Ikram, Z., Norton, P. and Jat, P.S. (1994) The biological clock that measure the mitotic life-span of mouse embryo fibroblasts continues to function in the presence of simian virus 40 large T antigen.Proc. Natl Acad. Sci. USA 91, 6448–52.

    PubMed  Google Scholar 

  • Israel, A., Kimura, A., Fournier, A., Fellous, M. and Kourilsky, P. (1986) Interferon response sequence potentiates activity of an enhancer in the promoter of a mouseH-2 gene.Nature 322, 743–746.

    Article  PubMed  Google Scholar 

  • James, C.D., Carlbom, E., Dumanski, J.P., Hansen, M., Nordenskjold, M., Collins, V.P. and Cavenee, W.K. (1988) Clonal genomic alterations in glioma malignancy stages.Cancer Res. 48, 5546–51.

    PubMed  Google Scholar 

  • Jat, P.S. and Sharp, P.A. (1986) Large T antigens of simian virus 40 and polyomavirus efficiently establish primary fibroblasts.J. Virol. 59, 746–50.

    PubMed  Google Scholar 

  • Jat, P.S. and Sharp, P.A. (1989) Cell lines established by a temperature-sensitive simian virus 40 large-T-antigen are growth restricted at the nonpermissive temperature.Mol. Cell. Biol. 9, 1672–81.

    PubMed  Google Scholar 

  • Jat, P.S., Noble, M.D., Ataliotis, P., Tanaka, Y., Yannoutsos, N., Larssen, L. and Kioussis, D. (1991) Direct derivation of conditionally immortal cell lines from an H-2Kb-tsA58 transgenic mouse.Proc. Natl Acad Sci. USA 88, 5096–100.

    PubMed  Google Scholar 

  • Kimura, A., Israel, A., Le Bail, O. and Kourilsky, P. (1986) Detailed analysis of the mouse H-2Kb promoter: enhancerlike sequences and their role in the regulation of Class I gene expression.Cell 44, 261–72.

    Article  PubMed  Google Scholar 

  • Kodama, H., Nose, M., Niida, S. and Yamasaki, A. (1991) Essential role of macrophage colony-stimulating factor in the osteoclast differentiation supported by stromal cells.J. Exp. Med. 173, 269–72.

    Article  PubMed  Google Scholar 

  • Lan, S. (1971) Cellular changes during the establishment and neoplastic transformation of mouse cell lines in tissue culture. PhD Thesis, University of London.

  • Land, H., Parada, L.F. and Weinberg, R.A. (1983a) Cellular oncogenes and multistep carcinogenesis.Science 222, 771–8.

    PubMed  Google Scholar 

  • Land, H., Parada, L.F. and Weinberg, R.A. (1983b) Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes.Nature 304, 596–602.

    Article  PubMed  Google Scholar 

  • Laywell, E. and Steindler, D. (1991) Boundaries and wounds, glia and glycoconjugates: cellular and molecular analyses of developmental partitions and adult brain lesions.Ann. NY Acad Sci. 633, 122–41.

    PubMed  Google Scholar 

  • Laywell, E., Dörries, U., Bartsch, U., Faissner, A., Schachner, M. and Steindler, D. (1992) Enhanced expression of the developmentally regulated extracellular matrix molecule tenascin following adult brain injury.Proc. Natl Acad Sci. USA 89, 2634–8.

    PubMed  Google Scholar 

  • Liesi, P. (1985a) Do neurons in the vertebrate CNS migrate on laminin?EMBO J. 4, 1163–70.

    PubMed  Google Scholar 

  • Liesi, P. (1985b) Laminin-immunoreactive glia distinguish regenerative adult CNS systems from non-regenerative ones.EMBO J. 4, 2505–11.

    PubMed  Google Scholar 

  • Liesi, P., Dahl, D. and Vaheri, A. (1983) Laminin is produced by early rat astrocytes in primary culture.J. Cell Biol. 96, 920–4.

    Article  PubMed  Google Scholar 

  • MacKay, K., Striker, L.J., Elliot, S., Pinkert, C.A., Brinster, R.L. and Striker, G.E. (1988) Glomerular epithelial mesangial, and endothelial cell lines from transgenic mice.Kidney Int. 33, 677–84.

    PubMed  Google Scholar 

  • McKeon, R.J., Schreiber, R.C., Rudge, J.S. and Silver, J. (1991) Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes.J. Neurosci. 11, 3398–411.

    PubMed  Google Scholar 

  • Mellon, P.L., Windle, J.J., Goldsmith, P.C., Padula, C.A., Roberts, J.L. and Weiner, R.I. (1990) Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis.Neuron 5, 1–10.

    Article  PubMed  Google Scholar 

  • Messing, A., Chen, H.Y., Palmiter, R.D. and Brinster, R.L. (1985) Peripheral neuropathies, hepatocellular carcinomas and islet cell adenomas in transgenic mice.Nature 316, 461–3.

    Article  PubMed  Google Scholar 

  • Morgan, J.E., Hoffman, E.P. and Partridge, T.A. (1990) Normal myogenic cells from newborn mice restore normal histology to degenerating muscles of the mdx mouse.J. Cell Biol. 111, 2437–49.

    Article  PubMed  Google Scholar 

  • Morgan, J.E., Mouse, S.E., Walsh, F.S. and Partridge, T.A. (1992) Formation of skeletal musclein vivo from the mouse C2 cell line.J. Cell Sci. 102, 779–787.

    PubMed  Google Scholar 

  • Morgan, J.E., Beauchamp, J.R., Peckham, M., Ataliotis, P., Jat, P., Noble, M., Farmer, K. and Partridge, T. (1994) Myogenic cells derived from H-2KbtsA58 transgenic mice are conditionally immortalin vitro but differentiate normallyin vivo.Devel. Biol. 162, 486–498.

    Article  Google Scholar 

  • Noble, M.D., Fok-Seang, J. and Cohen, J. (1984) Glia are a unique substrate for thein vitro growth of central nervous system neurons.J. Neurosci. 4, 1892–903.

    PubMed  Google Scholar 

  • Noble, M.d., Murray, K., Stroobant, P., Waterfield, M.D. and Riddle, P. (1988) Platelet-derived growth factor promotes division and inhibits premature differentiation of the oligodendrocyte/type-2 astrocyte progenitor cell.Nature 333, 560–2.

    Article  PubMed  Google Scholar 

  • Orgel, L.E. (1963) The maintenance of the accuracy of protein synthesis and its relevance to aging.Biochemistry 49, 517–21.

    Google Scholar 

  • Orgel, L.E. (1963) The maintenance of the accuracy of protein synthesis and its relevance to aging.Biochemistry 49, 517–21.

    Google Scholar 

  • Orgel, L.E. (1973) Aging of clones of mamalian cells.Nature 243, 441–5.

    PubMed  Google Scholar 

  • Partridge, T.A., Morgan, J.E., Coulton, G.R., Hoffman, E.P. and Kunkel, L.M. (1989) Conversion of mdx myofibres from dystrophic-negative to-positive by injection of normal myoblasts.Nature 337, 176–8.

    Article  PubMed  Google Scholar 

  • Partridge, T.A., Morgan, J.E., Moore, S.E. and Walsh, F.S. (1988) Myogenesisin vivo from the mouse C2 muscle cell-line.J. Cell Biochem. Suppl. 12C, 331.

    Google Scholar 

  • Pereira-Smith, O.M., Spiering, A.L. and Smith J.R. (1989) Cellular senescence: the result of a genetic program: in Wang, E. and Warner, H.R. “Growth Control during Cell Aging” eds. pp. 123–136. Boca Raton, USA: CRC Press.

    Google Scholar 

  • Petit, C.A., Gardes, M. and Feunteun, J. (1983) The immortalization of rodent embryo fibroblasts by SV40 is maintained by the A gene.Virology 127, 74–82.

    Article  PubMed  Google Scholar 

  • Price, J., Turner, D. and Cepko, C.L. (1987) Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer.Proc. Natl Acad Sci. USA 84, 156–160.

    PubMed  Google Scholar 

  • Raff, M.C., Miller, R.H. and Noble, M. (1983) A glial progenitor cell that developsin vitro into an astrocyte or an oligodendrocyte depending on the culture medium.Nature 303, 390–6.

    Article  PubMed  Google Scholar 

  • Reier, P.J., Stensaas, L.J. and Guth, L. (1983) The astrocytic scar as an impediment to regeneration in the central nervous system.Spinal Cord Reconstruction In: Kao, C.C., Bunge, R.P. and Reier, P.J. eds. pp. 163–195 New York, USA: Raven Press.

    Google Scholar 

  • Renfranz, P.J., Cunningham, M.G. and McKay, R.D.G. (1991) Region-specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing brain.Cell 66, 713–29.

    Article  PubMed  Google Scholar 

  • Richardson, W.D., Pringle, N., Mosley, M., Westermark, B. and Dubois-Dalcq, M. (1988) A role for platelet-derived growth factor in normal gliogenesis in the central nervous system.Cell 53, 309–19.

    Article  PubMed  Google Scholar 

  • Ridley, A., Paterson, H., Noble, M. and Land, H. (1988) Rans-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation.EMBO J. 7, 1635–45.

    PubMed  Google Scholar 

  • Rudge, J.S., Smith, G.M. and Silver, J. (1989) Anin vitro model of wound healing in the CNS: analysis of cell reaction and interaction at different ages.Exp. Neurol. 103, 1–16.

    Article  PubMed  Google Scholar 

  • Rudge, J.S. and Silver, J. (1990) Inhibition of neurite outgrowth on astroglial scarsin vitro.J. Neurosci. 10, 3594–603.

    PubMed  Google Scholar 

  • Ruley, H.E. (1983) Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture.Nature 304, 602–6.

    Article  PubMed  Google Scholar 

  • Szilard, L. (1959) On the nature of the aging process.Proc. Natl Acad. Sci. USA 45, 30–45.

    Google Scholar 

  • Tegtmeyer, P. (1975) Function of simian virus 40 gene A in transforming infection.J. Virol. 15, 613–8.

    PubMed  Google Scholar 

  • Thompson, T.C., Southgate, J., Kitchener, G. and Land, H. (1989) Multistage carcinogenesis induced byras andmyc oncogenes in a reconstituted organ.Cell 56, 917–30.

    Article  PubMed  Google Scholar 

  • Todaro, G.J. and Green, H. (1963) Quantitative studies of the growth of mouse embryo cells in culture and their development into established cell-lines.J. Cell Biol. 17, 299–313.

    Article  PubMed  Google Scholar 

  • Vogelstein, B., Fearon, E.R., Hamilton, S.R., Kern, S.E., Preisinger, A.C., Leppert, M., Nakamura, Y., White, R., Smits, A.M. and Bos, J.L. (1988) Genetic alterations during colorectal cancer development.N. Engl. J. Med. 319, 525–32.

    PubMed  Google Scholar 

  • Wakeford, S., Watt, D.J. and Partridge, T.A. (1991) X-irradiation improves mdx mouse muscle as a model of muscle fibre loss in DMD.Muscle & Nerve 14, 42–49.

    Google Scholar 

  • Wallach, D., Fellous, M. and Revel, M. (1982) Preferential effort of γ interferon on the synthesis of HLA antigens and their mRNAs in human cells.Nature 299, 833–6.

    Article  PubMed  Google Scholar 

  • Weiss, E.H., Mellor, A., Golden, L., Fahrner, K., Simpson, E., Hurst, J. and Flavell, R.A. (1983) The structure of the mutant H-2 gene suggests that the generation of polymorphism inH-2 genes may occur by gene conversion-like events.Nature 301, 671–4.

    Article  PubMed  Google Scholar 

  • Wernig, A., Irintchev, A., Hartling, A., Stephan, G., Zimmerman, K. and Stariznski-Powitz, A. (1991) Formation of new muscle fibres and tumours after injection of cultured myogenic cells.J. Neurocytol. 20, 982.

    Article  PubMed  Google Scholar 

  • Whitehead, R.H., VanEeden, P.E., Noble, M.D., Ataliotis, P. and Jat, P.S. (1993) The establishment of conditionally immortalised epithelial cell lines from both colon and small intestine of H-2KbtsA58 transgenic mice.Proc. Natl Acad. Sci. USA 90, 587–91.

    PubMed  Google Scholar 

  • Wiktor-Jedrzejczak, W., Bartocci, A., Ferrante, A.W., Jr., Ahmed-Ansari, A., Sell, K.W., Pollard, J.W. and Stanley, E.R. (1990) Total absence of colony-stimulating factor 1 in macrophage-deficient osteopetrotic (op/op) mice.Proc. Natl Acad. Sci. USA 87, 4828–32.

    PubMed  Google Scholar 

  • Yoshida, H., Hayashi, S.-I., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., Sudo, T., Shultz, L.D. and Nishikawa, S.I. (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene.Nature 345, 442–4.

    Article  PubMed  Google Scholar 

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  1. Ludwig Institute for Cancer Research, 91 Riding House Street, W1P 8BT, London, UK

    Mark Noble, Zebbie Ikram & Parmjit S. Jat

  2. Department of Biochemistry & Molecular Biology and Department of Anatomy & Development Biology, University College London, UK

    Mark Noble

  3. Division of Biology, California Institute of Technology, 91225, Pasadena, CA, USA

    Andrew K. Groves

  4. Department of Cellular and Molecular Physiology, Harvard Medical School, 02115, Boston, MA, USA

    Paris Ataliotis

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  1. Mark Noble
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Noble, M., Groves, A.K., Ataliotis, P. et al. The H-2KbtsA58 transgenic mouse: A new tool for the rapid generation of novel cell lines. Transgenic Research 4, 215–225 (1995). https://doi.org/10.1007/BF01969114

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