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Physiological relevance and functional potential of central nervous system-derived cell lines

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Abstract

Central nervous system (CNS)-derived neural cell lines have proven to be extremely useful for delineating mechanisms controlling such diverse phenomena as cell lineage choice and differentiation, synaptic maturation, neurotransmitter synthesis and release, and growth factor signalling. In addition, there has been hope that such lines might play pivotal roles in CNS gene therapy and repair. The ability of some neural cell lines to integrate normally into the CNS following transplantation and to express foreign, often corrective gene productsin situ might offer potential therapeutic approaches to certain neurodegenerative diseases. Five general strategies have evolved to develop neural cell lines: isolation and cloning of spontaneous or mutagenically induced malignancies, targeted oncogenesis in transgenic mice, somatic cell fusion, growth factor mediated expansion of CNS progenitor or stem cells, and retroviral transduction of neuroepithelial precursors. In this article, we detail recent progress in these areas, focusing on those cell lines that have enabled novel insight into the mechanisms controlling neuronal cell lineage choice and differentiation, both in vitro and in vivo.

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References

  1. Walsh C. (1993) Cell lineage and regional specification in the mammalian neocortex.Perspectives Dev. Neurobiol. 1, 75–80.

    CAS  Google Scholar 

  2. McKay R. D. G. (1989) The origins of cellular diversity in the mammalian central nervous system.Cell 58, 815–821.

    Article  PubMed  CAS  Google Scholar 

  3. Gage F. H., Ray J., and Fisher L. J. (1995) Isolation, characterization, and use of stem cells from the CNS.Ann. Rev. Neurosci. 18, 159–192.

    Article  PubMed  CAS  Google Scholar 

  4. McConnell S. K. (1991) The generation of neuronal diversity in the central nervous system.Ann. Rev. Neurosci. 14, 269–300.

    Article  PubMed  CAS  Google Scholar 

  5. Luskin M. B. (1994) Neuronal cell lineage in the vertebrate central nervous system.FASEB J. 8, 722–739.

    PubMed  CAS  Google Scholar 

  6. Cepko C. L., Ryder E. F., Austin C. P., Walsh C., and Fekete D. M. (1993) Lineage analysis using retrovirus vectors.Meth. Enzymol. 225, 933–960.

    Article  PubMed  CAS  Google Scholar 

  7. Cepko C. L. (1989) Immortalization of neural cells via retrovirus-mediated oncogene transduction.Ann. Rev. Neurosci. 12, 47–65.

    Article  PubMed  CAS  Google Scholar 

  8. Lendahl U. and McKay R. D. G. (1990) The use of cell lines in neurobiology.Trends Neurosci. 13, 132–137.

    Article  PubMed  CAS  Google Scholar 

  9. Whittemore S. R., White L. A., Shihabuddin L. S., and Eaton M. J. (1995) Phenotypic diversity in neuronal cell lines derived from raphe nucleus by retroviral transduction.Methods: Companion Meth. Enzymol. 7, 285–293.

    Article  CAS  Google Scholar 

  10. Snyder E. Y. (1995) Retroviral vectors for the study of neuroembryology: immortalization of neural cells, inViral Vectors: Tools for Analysis and Genetic Manipulation of the Nervous System (Kaplit M. G. and Loewy A. D., eds.) Academic, New York, pp. 435–475.

    Google Scholar 

  11. Whittemore S. R., Neary J. T., Kleitman N., Sanon H. R., Benigno A., Donahue R. P., and Norenberg M. D. (1994) Isolation and characterization of conditionally immortalized astrocyte cell lines derived from adult human spinal cord.Glia 10, 211–226.

    Article  PubMed  CAS  Google Scholar 

  12. Moura Neto V., Mallat M., Chneiweiss H., Premont J., Gros F., and Prochiantz A. (1986) Two simian virus 40 (SV40)-transformed cell lines from the mouse striatum and mesencephalon presenting astrocytic characteristics. I. Immunological and pharmacological properties.Dev. Brain Res. 26, 11–22.

    Article  CAS  Google Scholar 

  13. Trotter J., Boulter C. A., Sontheimer H., Schachner M., and Wagner E. F. (1989) Expression of v-src arrests murine glial cell differentiation.Oncogene 4, 457–464.

    PubMed  CAS  Google Scholar 

  14. Rabotti G. F., Gogusev J., Teutsch B., Mongiat-Lardemer F., and Haguenau F. (1978) Transformation in vitro of glial hamster cells by rous sarcoma virus.J. Natl. Cancer Inst. 60, 113–124.

    PubMed  CAS  Google Scholar 

  15. Geller H. M. and Dubois-Dalcq M. (1988) Antigenic and functional characterization of a rat central nervous system-derived cell line immortalized by a retroviral vector.J. Cell Biol. 107, 1977–1986.

    Article  PubMed  CAS  Google Scholar 

  16. Evrard C., Galiana E., and Rouget P. (1986) Establishment of ‘normal’ nervous cell lines after transfer of polyoma virus and adenovirus early genes into murine brain cells.EMBO J. 5, 3157–3162.

    PubMed  CAS  Google Scholar 

  17. Galiana E., Borde I., Marin P., Rassoulzadegan M., Cuzin F., Gros F., Rouget P., and Evrard C. (1990) Establishment of permanent astroglial cell lines, able to differentiate in vitro, from transgenic mice carrying the polyoma virus large T gene: an alternative approach to brain cell immortalization.J. Neurosci. Res. 26, 269–277.

    Article  PubMed  CAS  Google Scholar 

  18. Major E. O., Miller A. E., Mourrain P., Traub R. G., DeWidt E., and Sever J. (1985) Establishment of a line of human fetal glial cells that supports JC virus multiplication.Proc. Natl. Acad. Sci. USA 82, 1257–1261.

    Article  PubMed  CAS  Google Scholar 

  19. Giotta G. J., Heitzmann J., and Cohn M. (1980) Properties of two temperature-sensitive rous sarcoma virus transformed cerebellar cell lines.Brain Res. 202, 445–458.

    Article  PubMed  CAS  Google Scholar 

  20. Goodman M. N., Silver J., and Jacobberger J. W. (1993) Establishment and neurite outgrowth properties of neonatal and adult rat olfactory bulb glial cell lines.Brain Res. 619, 199–213.

    Article  PubMed  CAS  Google Scholar 

  21. Yoshida T. and Takeuchi M. (1993) Establishment of an astrocyte progenitor cell line: induction of glial fibrillary acidic protein and fibronectin by transforming growth factor-ß1.J. Neurosci. Res. 35, 129–137.

    Article  PubMed  CAS  Google Scholar 

  22. Kasai H., Fukuda J., and Segawa K. (1987) Transformation of glial cells in mouse embryonic brain cell in vitro with simian virus 40.Neurosci. Lett. 76, 239–244.

    Article  PubMed  CAS  Google Scholar 

  23. Jensen N. A., Smith G. M., Garvey J. S., Shine H. D., and Hood L. (1993) Cyclic AMP has a differentiative effect on an immortalized oligodendrocyte cell line.J. Neurosci. Res. 35, 288–296.

    Article  PubMed  CAS  Google Scholar 

  24. Verity A. N., Bredesen D., Vonderscher C., Handley V. W., and Campagnoni A. T. (1993) Expression of myelin protein genes and other myelin components in an oligodendrocytic cell line conditionally immortalized with a temperature-sensitive retrovirus.J. Neurochem. 60, 577–587.

    Article  PubMed  CAS  Google Scholar 

  25. Russo T., Mogavero A. R., Ammendola R., Mesuraca M., Fiore F., Fatatis A., Salvatore G., and Cimino F. (1993) Immortalization of a cell line showing some characteristics of the oligodendrocyte phenotype.Neurosci. Lett. 159, 159–162.

    Article  PubMed  CAS  Google Scholar 

  26. Almazan G. and McKay R. (1992) An oligodendrocyte precursor cell line from rat optic nerve.Brain Res. 579, 234–245.

    Article  PubMed  CAS  Google Scholar 

  27. Barnett S. C., Franklin R. J. M., and Blakemore W. F. (1993) In vitro and in vivo analysis of a rat bipotential O-2A progenitor cell line containing the temperature-sensitive mutant gene of the SV40 large T antigen.Eur. J. Neurosci. 5, 1247–1260.

    Article  PubMed  CAS  Google Scholar 

  28. Redies G., Lendahl U., and McKay R. G. D. (1991) Differentiation and heterogeneity in T-antigen immortalized precursor cell lines from mouse cerebellum.J. Neurosci. Res. 30, 601–615.

    Article  PubMed  CAS  Google Scholar 

  29. Aloisi F., Sun D., Levi G., and Wekerle H. (1990) Establishment of a permanent rat brain-derived glial cell line as a source of purified oligodendrocyte-type 2 astrocyte lineage cell populations.J. Neurosci. Res. 27, 16–24.

    Article  PubMed  CAS  Google Scholar 

  30. Trotter J., Crang A. J., Schachner M., and Blakemore W. F. (1993) Lines of glial precursor cells immortalised with a temperature-sensitive oncogene give rise to astrocytes and oligodendrocytes following transplantation into demyelinated lesions in the central nervous system.Glia 9, 25–40.

    Article  PubMed  CAS  Google Scholar 

  31. Galiana E., Bernard R., Borde I., Rouget P., and Evrard C. (1993) Proliferation and differentiation properties of bipotent glial progenitor cell lines immortalized with the adenovirus E1A gene.J. Neurosci. Res. 36, 133–146.

    Article  PubMed  CAS  Google Scholar 

  32. Louis J. C., Magal E., Muir D., Manthorpe M., and Varon S. (1995) CG-4, a new bipotential glial cell line from rat brain, is capable of differentiating in vitro into either mature oligo-dendrocytes or type-2 astrocytes.J. Neurosci. Res. 31, 193–204.

    Article  Google Scholar 

  33. Bocchini V., Mazzolla R., Barluzzi R., Blasi E., Sick P., and Kettenmann H. (1992) An immortalized cell line expresses properties of activated microglial cells.J. Neurosci. Res. 31, 616–621.

    Article  PubMed  CAS  Google Scholar 

  34. Calof A. L. and Guevara J. L. (1993) Cell lines derived from retrovirus-mediated oncogene transduction into olfactory epithelium cultures.Neuroprotocols 3, 222–231.

    Article  Google Scholar 

  35. Birren S. J. and Anderson D. J. (1990) A v-myc-immortalized sympathoadrenal progenitor cell line in which neuronal differentiation is initiated by FGF but not NGF.Neuron 4, 189–201.

    Article  PubMed  CAS  Google Scholar 

  36. Birren S. J., Verdi J. M., and Anderson D. J. (1992) Membrane depolarization induces p140trk and NGF responsiveness, but not p75LNGFR, in MAH cells.Science 257, 395–397.

    Article  PubMed  CAS  Google Scholar 

  37. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson S. J., Stahl N., and Yancopoulos G. D. (1992) CNTF and LIF act on neuronal cells via shared signaling pathways that involve IL-6 signal trans-ducing receptor component gp130.Cell 69, 1121–1132.

    Article  PubMed  CAS  Google Scholar 

  38. Ip N. Y., Boulton T. G., Li Y., Verdi J. M., Birren S. J., Anderson D. J., and Yancopoulos G. D. (1994) CNTF, FGF, and NGF collaborate to drive the terminal differentiation of MAH cells into postmitotic neurons.Neuron 13, 443–455.

    Article  PubMed  CAS  Google Scholar 

  39. Anderson D. J. (1994) Stem cells and transcription factors in the development of the mammalian neural crest.FASEB J. 8, 707–713.

    PubMed  CAS  Google Scholar 

  40. Heath J. K. and Smith A. G. (1988) Regulatory factors of embryonic stem cells.J. Cell. Sci. Suppl. 10, 257–266.

    PubMed  CAS  Google Scholar 

  41. MacPherson P. A. and McBurney M. W. (1995) P19 embryonal carcinoma cells: a source of cultured neurons amenable to genetic manipulation.Methods: Companion Meth. Enymol. 7, 222–237.

    Google Scholar 

  42. Stains W. A., Morassutti D. J., Reuhl K. R., Ally A. I., and McBurney M. W. (1994) Neurons derived from P19 embryonal carcinoma cells have varied morphologies and neurotransmitters.Neuroscience 58, 735–751.

    Article  Google Scholar 

  43. Morrassutti D. J., Stains W. A., Magnuson D. S. K., Marshall K. C., and McBurney M. W. (1994) Murine embryonal carcinoma-derived neurons survive and mature following transplantation into adult rat striatum.Neuroscience 58, 753–763.

    Article  Google Scholar 

  44. Wojcik B. E., Nothias F., Lazar M., Jouin H., Nicholas J.-F., and Peschanski M. (1993) Catecholaminergic neurons result from intracerebral implantation of embryonal carcinoma cells.Proc. Natl. Acad. Sci. USA 90, 1305–1309.

    Article  PubMed  CAS  Google Scholar 

  45. Andrews P. W., Damjanov I., Simon D., Banting G. S., Carlin C., Dracopoli N. C., and Fogh J. (1984) Pluripotent embryonal carcinoma clones derived from human teratocarcinoma cell line Tera-2.Lab. Invest. 50, 147–162.

    PubMed  CAS  Google Scholar 

  46. Pleasure S. J., Page C., and Lee V. M.-Y. (1992) Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons.J. Neurosci. 12, 1802–1815.

    PubMed  CAS  Google Scholar 

  47. Trojanowski J. Q., Mantione J. R., Lee J. H., Seid D. P., You T., Inge L. J., and Lee V. M.-Y. (1993) Neurons derived from a human teratocarcinoma cell line establish molecular and structural polarity following transplantation into the rodent brain.Exp. Neurol. 122, 283–294.

    Article  PubMed  CAS  Google Scholar 

  48. Kleppner S. R., Robinson K. A., Trojanowski J. Q., and Lee V. M.-Y. (1995) Transplanted human neurons derived from a teratocarcinoma cell line (NTera-2) mature, integrate, and survive for over one year in the nude mouse brain.J. Comp. Neurol. 357, 618–632.

    Article  PubMed  CAS  Google Scholar 

  49. Masayuki M., Lee V. M.-Y., and Trojanowski J. Q. (1995) Proliferation, cell death and neuronal survival in transplanted human teratocarcinoma (NTera2) cells depend on the graft site in nude and SCID mice.Lab. Invest. 73, 1–14.

    Google Scholar 

  50. Ronnett G. V., Hester L. D., Nye J. S., Connor K., and Snyder S. H. (1990) Human cortical neuronal cell line: establishment from a patient with unilateral megalencephaly.Science 248, 603–605.

    Article  PubMed  CAS  Google Scholar 

  51. Poltorak M., Isono M., Freed W. J., Ronnett G. V., and Snyder S. H. (1992) Human cortical neuronal cell line (HCN-1): further in vitro characterization and suitability for brain transplantation.Cell Transplant. 1, 3–15.

    PubMed  CAS  Google Scholar 

  52. Truckenmiller M. E., Kulaga H., Coggiano M., Wyatt R., Snyder S. H., and Sweetnam P. M. (1993) Human cortical neuronal cell line: a model for HIV-1 infection in an immature neuronal system.AIDS Res. Human Retroviruses 9, 445–453.

    Article  CAS  Google Scholar 

  53. Mizachi Y., Rodriguez I., Sweetnam P. M., Rubinstein A., and Volsky D. J. (1994) HIV type 1 infection of human cortical neuronal cells: enhancement by select neuronal growth factors.AIDS Res. Human Retroviruses 10, 1593–1596

    Google Scholar 

  54. White L. A., Keane R. W., and Whittemore S. R. (1994) Differentiation of an immortalized CNS neuronal cell line decreases their susceptibility to cytotoxic T lymphocyte cell lysis in vitro.J. Neuroimmunol. 49, 135–143.

    Article  PubMed  CAS  Google Scholar 

  55. Sorieul S. and Ephrussi B. (1961) Karylogical demonstration of hybridization of mammalian cells in vitro.Nature 190, 653–654.

    Article  Google Scholar 

  56. Pontecorvo G. (1975) Production of mammalian somatic cell hybrids by means of polyethylene glycol treatment.Som. Cell Genet. 1, 397–400.

    Article  CAS  Google Scholar 

  57. Lee H. J., Hammond D. N., Large T. H., Roback J. D., Sim J. A., Brown D. A., Otten U. H., and Wainer B. H. (1990) Neuronal properties and trophic activities of immortalized hippocampal cells from embryonic and young adult mice.J. Neurosci. 10, 1779–1767.

    PubMed  CAS  Google Scholar 

  58. Cashman N. R., Durham H. D., Blusztajn J. K., Oda K., Tabira T., Shar I. T., Dahrouge S., and Antel J. P. (1992) Neuroblastoma X spinal cord (NSC) hybrid cell lines resemble developing motor neurons.Devel. Dynam. 194, 209–221.

    CAS  Google Scholar 

  59. Choi H. K., Won L. A., Kontur P. J., Hammond D. N., Fox A. P., Wainer B. H., Hoffmann P. C., and Heller A. (1991) Immortalization of embryonic mesencephalic dopaminergic neurons by somatic cell fusion.Brain Res. 552, 67–76.

    Article  PubMed  CAS  Google Scholar 

  60. Smith R. G., Alexianu M. E., Crawford G., Nyormoi O., Stefani E., and Appel S. H. (1994) Cytotoxicity of immunoglobulins from amyotrophic lateral sclerosis patients on a hybrid motoneuron cell line.Proc. Natl. Acad. Sci. USA 91, 3393–3397.

    Article  PubMed  CAS  Google Scholar 

  61. Choi H. K., Won L., Roback J. D., Wainer B. H., and Heller A. (1992) Specific modulation of dopamine expression in neuronal hybrid cells by primary cells from different brain regions.Proc. Natl. Acad. Sci. USA 89, 8943–8947.

    Article  PubMed  CAS  Google Scholar 

  62. Crawford G. D. Jr., Le W.-D., Smith R. G., Xie W.-J., Stefani E., and Appel S. H. (1992) A novel N18TG2 X mesencephalon cell hybrid expresses properties that suggest a dopaminergic cell line of substantia nigra origin.J. Neurosci. 12, 3392–3398.

    PubMed  CAS  Google Scholar 

  63. Blusztajn J. K., Venturini A., Jackson D. A., Lee H. J., and Wainer B. H. (1992) Acetylcholine synthesis and release is enhanced by dibutyryl cyclic AMP in a neuronal cell line derived from mouse septum.J. Neurosci. 12, 793–799.

    PubMed  CAS  Google Scholar 

  64. Hammond D. N., Wainer B. H., Tonsgard J. H., and Heller A. (1986) Neuronal properties of clonal hybrid cell lines derived from central cholinergic neurons.Science 234, 1237–1240.

    Article  PubMed  CAS  Google Scholar 

  65. Lee H. J., Hammond D. N., Large T. H., and Wainer B. H. (1990) Immortalized young adult neurons from the septal region: generation and characterization.Dev. Brain Res. 52, 219–228.

    Article  CAS  Google Scholar 

  66. Eves E. M., Marsden K. M., Downen M., Sheman L., Rosner M. R., and Wainer B. H. (1993) A novel hybrid immortalization strategy yields a more mature neuronal phenotype.Absts. Am. Soc. Neurosci. 19, 243.

    Google Scholar 

  67. Botteri F. M., van der Putter H., Wong, D. F., Sauvage C. A., and Evans R. M. (1987) Unexpected thymic hyperplasia in transgenic mice harboring a neuronal promoter fused with simian virus 40 large T antigen.Mol. Cell. Biol. 7, 3178–3184.

    PubMed  CAS  Google Scholar 

  68. Efrat S., Teitelman G., Anwar M., Ruggiero D., and Hanahan D. (1988) Glucagon gene regulatory region directs oncoprotein expression to neurons and pancreatic α-cells.Neuron 1, 605–613.

    Article  PubMed  CAS  Google Scholar 

  69. Baetge E. E., Behringer R. R., Messing A., Brinster R. L., and Palmiter R. D. (1988) Transgenic mice express the human phenylethanolamine N-methyltransferase gene in adrenal medulla and retina.Proc. Natl. Acad. Sci. USA 85, 3648–3652.

    Article  PubMed  CAS  Google Scholar 

  70. Hammang J. P., Baetge E. E., Behringer R. R., Brinster R. L., Palmiter R. D., and Messing A. (1990) Immortalized retinal neurons derived from SV40 T-antigen-induced tumors in transgenic mice.Neuron 4, 775–782.

    Article  PubMed  CAS  Google Scholar 

  71. Mandel G. and McKinnon D. (1993) Molecular basis of neural-specific gene expression.Ann. Rev. Neurosci. 164, 323–345.

    Article  Google Scholar 

  72. 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  CAS  Google Scholar 

  73. Martinez de la Escalera G., Choi A. L., and Weiner R. I. (1992) Beta 1-adrenergic regulation of the GT1 gonadotrophin-releasing hormone (GnRH) neuronal cell lines: stimulation of GnRH release via receptors positively coupled to adenylate cyclase.Endocrinology 131, 1397–1402.

    Article  PubMed  CAS  Google Scholar 

  74. Martinez de la Escalera G., Gallo F., Choi A. L., and Weiner R. I. (1992) Dopaminergic regulation of the GT1 gonadotrophin-releasing hormone (GnRH) neuronal cell lines: stimulation of GnRH release via D1-receptors positively coupled to adenylate cyclase.Endocrinology 131, 2965–2971.

    Article  PubMed  CAS  Google Scholar 

  75. Milenkovic L., D’Angelo G., Kelly P. A., and Weiner R. I. (1994) Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors.Proc. Natl. Acad. Sci. USA 91, 1244–1247.

    Article  PubMed  CAS  Google Scholar 

  76. Martinez de la Escalera G., Choi A. L. H., and Weiner R. I. (1994) Biphasic GABAergic regulation of GnRH secretion in GT1 cell lines.Neuronal Reg. 59, 420–425.

    CAS  Google Scholar 

  77. Wetsel W. C., Eraly S. A., Whyte D. B., and Mellon P. L. (1993) Regulation of gonadotropin-releasing hormone by protein kinase-A and-C in immortalized hypothalamic neurons.Endocrinology 132, 2360–2370.

    Article  PubMed  CAS  Google Scholar 

  78. Mellon P. L., Eraly S. A., Belsham D. D., Lawson M. A., Clark M. E., Whyte D. B., and Windle J. J. (1995) An immortal cell culture model of hypothalamic gonadotropin-releasing hormone neurons.Methods: Companion Meth. Enzymol. 7, 303–310.

    Article  CAS  Google Scholar 

  79. Miller G. M., Silverman A.-J., Roberts J. L., Dong K. W., and Gibson M. J. (1993) Functional assessment of intrahypothalamic implants of immortalized gonadotropin-releasing hormone-secreting cells in female hypogonadal mice.Cell Transplant. 2, 251–257.

    Google Scholar 

  80. Suri C., Fung B. P., Tischler A. S., and Chikaraishi D. M. (1993) Catecholaminergic cell lines from the brain and adrenal glands of tyrosine hydroxylase-SV40 T antigen transgenic mice.J. Neurosci. 13, 1280–1291.

    PubMed  CAS  Google Scholar 

  81. Largent B. L., Sosnowski R. G., and Reed R. R. (1993) Directed expression of an oncogene to the olfactory neuronal lineage in transgenic mice.J. Neurosci. 13, 300–312.

    PubMed  CAS  Google Scholar 

  82. Jat P. S., Noble M. D., Ataliotis P., Tanaka Y., Yannoutsos N., Larsen 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, 5096–5100.

    Article  PubMed  CAS  Google Scholar 

  83. Kershaw T. R., Rashid-Doubell F., and Sinden J. D. (1994) Immunocharacterization of H-2Kb-tsA58 transgenic mouse hippocampal neuroepithelial cells.Neuroreport 5, 2197–2200.

    Article  PubMed  CAS  Google Scholar 

  84. Eves E. M., Kwon J., Downen M., Tucker M. S., Wainer B. H., and Rosner M. R. (1994) Conditional immortalization of neuronal cells from postmitotic cultures and adult CNS.Brain Res. 656, 396–404.

    Article  PubMed  CAS  Google Scholar 

  85. Kilpatrick T. J. and Bartlett P. F. (1995) Cloned multipotential precursors from the mouse cerebrum require FGF-2, whereas glial restricted precursors are stimulated with either FGF-2 or EGF.J. Neurosci. 15, 3563–3661.

    Google Scholar 

  86. Cattaneo E. and McKay R. (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor.Nature 347, 762–765.

    Article  PubMed  CAS  Google Scholar 

  87. Deloulme J. C., Baudier J., and Sensenbrenner M. (1991) Establishment of pure neuronal cultures from fetal rat spinal cord and proliferation of the neuronal precursor cells in the presence of fibroblast growth factor.J. Neurosci. Res. 29, 499–509.

    Article  PubMed  CAS  Google Scholar 

  88. Ray J. and Gage F. H. (1994) Spinal cord neuroblasts proliferate in response to basic fibroblast growth factor.J. Neurosci. 14, 3548–3564.

    PubMed  CAS  Google Scholar 

  89. Murphy M., Drago J., and Bartlett P. F. (1990) Fibroblast growth factor stimulates the proliferation and differentiation of neural precursors in vitro.J. Neurosci. Res. 25, 463–475.

    Article  PubMed  CAS  Google Scholar 

  90. Ray J., Peterson D. A., Schinstine M., and Gage F. H. (1993) Proliferation, differentiation, and long-term culture of primary hippocampal neurons.Proc. Natl. Acad. Sci. USA 90, 3602–3606.

    Article  PubMed  CAS  Google Scholar 

  91. Vicario-Abejon C., Johe K. K., Hazel T. G., Collazo D., and McKay R. D. G. (1995) Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons.Neuron 15, 105–114.

    Article  PubMed  CAS  Google Scholar 

  92. DeHamer M. K., Guevera J. L., Hannon K., Olwin B. B., and Calof A. L. (1994) Genesis of olfactory receptor neurons in vitro: regulation of progenitor cell divisions by fibroblast growth factors.Neuron 13, 1083–1097.

    Article  PubMed  CAS  Google Scholar 

  93. Reynolds B. A., Tetzlaff W., and Weiss S. (1992) A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes.J. Neurosci. 12, 4565–4574.

    PubMed  CAS  Google Scholar 

  94. Davis A. A. and Temple S. (1994) A self-renewing multipotential stem cell in embryonic rat cerebral cortex.Nature 372, 263–266.

    Article  PubMed  CAS  Google Scholar 

  95. Reynolds B. A. and Weiss S. (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.Science 255, 1707–1710.

    Article  PubMed  CAS  Google Scholar 

  96. Frederiksen K. and McKay R. D. G. (1988) Proliferation and differentiation of rat neuro-epithelial precursor cells in vivo.J. Neurosci. 8, 1144–1151.

    PubMed  CAS  Google Scholar 

  97. Richards L. J., Kilpatrick T. J., and Bartlett P. F. (1992) De novo generation of neuronal cells from the adult mouse brain.Proc. Natl. Acad. Sci. USA 89, 8591–8595.

    Article  PubMed  CAS  Google Scholar 

  98. Kilpatrick T. J. and Bartlett P. F. (1993) Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation.Neuron 10, 255–265.

    Article  PubMed  CAS  Google Scholar 

  99. Temple S. and Davis A. A. (1994) Isolated rat cortical progenitor cells are maintained in division in vitro by membrane-associated factors.Development 120, 999–1008.

    PubMed  CAS  Google Scholar 

  100. Drago J., Murphy M., Carrol S. M., Harvey R. P., and Bartlett P. F. (1991) Fibroblast growth factor-mediated proliferation of central nervous system precursors depends on endogenous production of insulin-like growth factor.Proc. Natl. Acad. Sci. USA 88, 2199–2203.

    Article  PubMed  CAS  Google Scholar 

  101. Drago J., Nurcombe V., Pearse M. J., Murphy M., and Bartlett P. F. (1991) Basic fibroblast growth factor upregulates steady state levels of laminin B1 and B2 chain mRNA in cultured neuroepithelial cells.Exp. Cell Res. 196, 246–254.

    Article  PubMed  CAS  Google Scholar 

  102. Vescovi A. L., Reynolds B. A., Fraser D. D., and Weiss S. (1993) bFGF regulates the proliferative fate of unipotent (neuronal) and bipotent (neuronal/astroglial) EGF-generated CNS progenitor cells.Neuron 11, 951–966.

    Article  PubMed  CAS  Google Scholar 

  103. Ahmed S., Reynolds B. A., and Weiss S. (1995) BDNF enhances the differentiation but not the survival of CNS stem cell-derived neuronal precursors.J. Neurosci. 15, 5765–5778.

    PubMed  CAS  Google Scholar 

  104. Ghosh A. and Greenberg M. E. (1995) Distinct roles for bFGF and NT-3 in the regulation of cortical neurogenesis.Neuron 15, 89–103.

    Article  PubMed  CAS  Google Scholar 

  105. Guillemot, F., Lo L.-C., Johnson J. E., Auerbach A., Anderson D. J., and Joyner A. L. (1993) Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons.Cell 75, 463–476.

    Article  PubMed  CAS  Google Scholar 

  106. Lee J. E., Hollenberg S. M., Snider L., Turner D. L., Lipnick N., and Weintraub H. (1995) Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein.Science 12, 836–843.

    Article  Google Scholar 

  107. Gage F. H., Coates P. W., Palmer T. D., Kuhn H. G., Fisher L. J., Suhonen J. O., Peterson D. A., Suhr S. T., and Ray J. (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain.Proc. Natl. Acad. Sci. USA 92, 11,879–11,883.

    Article  CAS  Google Scholar 

  108. Ray J., Fisher L. J., Kuhn H. G., Peterson D. A., Tuszynski M., and Gage F. H. (1994) Neuroblasts cultured from embryonic hippocampus and spinal cord can survive and express neural markers after grafting in the adult CNS.Absts. Am. Soc. Neurosci. 20, 670.

    Google Scholar 

  109. Nishikawa R., Xiang-Dong J., Harmon R. C., Lazar C. S., Gill G. N., Cavenee W. K., and Su Huang J. S. (1994) A mutant epidermal growth factor receptor common in human gliomas confers enhanced tumorigenicity.Proc. Natl. Acad. Sci. USA 91, 7727–7731.

    Article  PubMed  CAS  Google Scholar 

  110. Schlegel J., Merdes A., Stumm G., Albert F. K., Forsting M., Hynes N., and Kiessling M. (1994) Amplification of the epidermal-growth-factor-receptor gene correlates with different growth behaviour in human glioblastoma.Int. J. Cancer 56, 72–77.

    Article  PubMed  CAS  Google Scholar 

  111. Rolelj S., Weinberg R. A., Fanning P., and Klagsbrun M. (1988) Basic fibroblast growth factor fused to a signal peptide transforms cells.Nature 331, 173–175.

    Article  Google Scholar 

  112. Calof A. L., ed. (1993)Neuroprotocols, vol. 3: Immortalizing Neural Cells. Academic, San Diego, CA.

    Google Scholar 

  113. Cepko C. L. (1992) Transduction of genes using retrovirus vectors, inCurrent Protocols in Molecular Biology (Ausubel F. M., Brent R., Kingston R. E., Moore D. D., Seidman J. G., Smith J. A., and Struhl K., eds.), Wiley, New York, pp. 9.10.1–9.14.3.

    Google Scholar 

  114. Miller D. G., Adam M. A., and Miller A. D. (1990) Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection.Mol. Cell. Biol. 10, 4239–4242.

    PubMed  CAS  Google Scholar 

  115. Bartlett P. F., Reid H. H., Bailey K. A., and Bernard O. (1988) Immortalization of mouse neural precursor cells by the c-myc oncogene.Proc. Natl. Acad. Sci. USA 85, 3255–3259.

    Article  PubMed  CAS  Google Scholar 

  116. Murphy M., Bernard O., Reid K., and Bartlett P. F. (1990) Cell lines derived from mouse neural crest are representative of cells at various stages of differentiation.J. Neurobiol. 22, 522–535.

    Article  Google Scholar 

  117. Bernard O., Reid H. H., and Bartlett P. F. (1992) Role of the c-myc and the N-myc proto-oncogenes in the immortalization of neural precursors.J. Neurosci. Res. 24, 9–20.

    Article  Google Scholar 

  118. Ryder E. F., Snyder E. Y., and Cepko C. L. (1990) Establishment and characterization of multipotent neural cell lines using retrovirus vector-mediated oncogene transfer.J. Neurobiol. 21, 356–375.

    Article  PubMed  CAS  Google Scholar 

  119. Eves E. M., Tucker M. S., Roback J. D., Downen M., Rosner M. R., and Wainer B. H. (1992) Immortal rat hippocampal cell lines exhibit neuronal and glial lineages and neurotrophin gene expression.Proc. Natl. Acad. Sci. USA 89, 4373–4377.

    Article  PubMed  CAS  Google Scholar 

  120. Giordano M., Takashima H., Herranz A., Poltorak M., Geller H. M., Marone M., and Freed W. J. (1993) Immortalized GABAergic cell lines derived from rat striatum using a temperature-sensitive allele of the SV40 large T antigen.Exp. Neurol. 124, 395–400.

    Article  PubMed  CAS  Google Scholar 

  121. Pessac B., Girard A., Romey G., Crisanti P., Lorinet A. M., and Calothy G. (1983) A neuronal clone derived from a rous sarcoma virus-transformed quail embryo neuroretina established culture.Nature 302, 616–618.

    Article  PubMed  CAS  Google Scholar 

  122. DeVitry F., Camier M., Czernichow P., Benda P. H., Cohen P., and Tixier-Vidal A. (1974) Establishment of a clone of mouse hypothalamic neurosecretory cells synthesizing neurophysin and vasopressin.Proc. Natl. Acad. Sci. USA 71, 3575–3579.

    Article  CAS  Google Scholar 

  123. Frederiksen K., Jat P. S., Valtz N., Levy D., and McKay R. (1988) Immortalization of precursor cells from the mammalian CNS.Neuron 1, 439–448.

    Article  PubMed  CAS  Google Scholar 

  124. Evrard C., Borde I., Marin P., Galiana E., Prèmont F., Gros F., and Rouget P. (1990) Immortalization of bipotential and plastic glio-neuronal precursor cells.Proc. Natl. Acad. Sci. USA 87, 3062–3066.

    Article  PubMed  CAS  Google Scholar 

  125. Mehler M. F., Rozental R., Dougherty M., Spray D. C., and Kessler J. A. (1993) Cytokine regulation of neuronal differentiation of hippocampal progenitor cells.Nature 362, 62–65.

    Article  PubMed  CAS  Google Scholar 

  126. Soula C., Foulquier F., Duprat A. M., and Cochard P. (1993) Lineage analysis of early neural plate cells: cells with purely neuronal fate coexist with bipotential neuroglial progenitors.Dev. Biol. 159, 196–207.

    Article  PubMed  CAS  Google Scholar 

  127. Turner D. L. and Cepko C. L. (1987) A common progenitor for neurons and glia persists in rat retina late in development.Nature 328, 131–136.

    Article  PubMed  CAS  Google Scholar 

  128. Leber S. M., Breedlove S. M., and Sanes J. R. (1990) Lineage, arrangement, and death of clonally related motoneurons in chick spinal cord.J. Neurosci. 10, 2451–2462.

    PubMed  CAS  Google Scholar 

  129. Turner D. L., Snyder E. Y., and Cepko C. L. (1990) Lineage-independent determination of cell type in the embryonic mouse retina.Neuron 4, 833–845.

    Article  PubMed  CAS  Google Scholar 

  130. White L. A., Eaton M. J., Castro M. C., Klose K. J., Globus M. Y., Shaw G., and Whittemore S. R. (1994) Distinct regulatory pathways control neurofilament expression and neurotransmitter synthesis in immortalized serotonergic neurons.J. Neurosci. 14, 6744–6753.

    PubMed  CAS  Google Scholar 

  131. Eaton M. J., Staley J. K., Globus M. Y.-T., and Whittemore S. R. (1995) Developmental regulation of early serotonergic neuronal differentiation: the role of brain-derived neurotrophic factor and membrane depolarization.Dev. Biol. 170, 169–182.

    Article  PubMed  CAS  Google Scholar 

  132. Eaton M. J. and Whittemore S. R. (1995) ACTH activation of adenylate cyclase in raphe neurons: multiple regulatory pathways control serotonergic neuronal differentiation.J. Neurobiol. 28, 465–481.

    Article  PubMed  CAS  Google Scholar 

  133. Azmitia E. C. and de Kloet E. R. (1987) ACTH neuropeptide stimulation of serotonergic neuronal maturation in tissue culture: modulation by hippocampal cells, inProgress in Brain Research (de Kloet E. R., Wiegant V. M., and de Wied D., eds.), Elsevier, Amsterdam, pp. 311–318.

    Google Scholar 

  134. Ramaekers F., Rigter H., and Leonard B. E. (1978) Parallel changes in behavior and hippocampal monoamine metabolism in rats after administration of ACTH analogues.Pharmacol. Biochem. Behav. 8, 547–551.

    Article  PubMed  CAS  Google Scholar 

  135. Kitchens D. L., Snyder E. Y., and Gottlieb D. I. (1994) FGF and EGF are mitogens for immortalized neural progenitors.J. Neurobiol. 25, 797–807.

    Article  PubMed  CAS  Google Scholar 

  136. Kornblum H. I., Raymon H. K., Morrison R. S., Cavanaugh K. P., Bradshaw R. A., and Leslie F. M. (1990) Epidermal growth factor and basic fibroblast growth factor: effects on an overlapping population of neocortical neurons in vitro.Brain Res. 535, 255–263.

    Article  PubMed  CAS  Google Scholar 

  137. Whittemore S. R. and White L. A. (1993) Target regulation of neuronal differentiation in a temperature-sensitive cell line derived from medullary raphe.Brain Res. 615, 27–40.

    Article  PubMed  CAS  Google Scholar 

  138. Gao W.-Q. and Hatten M. E. (1994) Immortalizing oncogenes subvert the establishment of granule cell identity in developing cerebellum.Development 120, 1059–1070.

    PubMed  CAS  Google Scholar 

  139. Snyder E. Y. (1994) Grafting immortalized neurons to the CNS.Curr. Opin. Neurobiol. 4, 742–751.

    Article  PubMed  CAS  Google Scholar 

  140. Suhr S. and Gage F. H. (1994) Gene therapy for neurological disorders.Trends Genet. 10, 210–214.

    Article  Google Scholar 

  141. Snyder E. Y. (1996) Use of non-neuronal cells for gene delivery.Neuroreport (in press).

  142. 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 mammalian brain.Cell 66, 713–729.

    Article  PubMed  CAS  Google Scholar 

  143. Snyder E. Y., Deitcher D. L., Walsh C., Arnold-Aldea S., Hartwieg E. A., and Cepko C. L. (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum.Cell 66, 33–51.

    Article  Google Scholar 

  144. Shihabuddin L. S., Hertz J. A., Holets V. R., and Whittemore S. R. (1995) The adult CNS retains the potential to direct region-specific differentiation of a transplanted neuronal precursor cell line.J. Neurosci. 15, 6666–6678.

    PubMed  CAS  Google Scholar 

  145. Shihabuddin L. S., Brunschwig J.-P., Holets V. R., Bunge M. B., and Whittemore S. R. (1996) Induction of mature neuronal properties in immortalized neuronal precursor cells following grafting in the neonatal CNS.J. Neurocytol. 25, 101–111.

    Article  PubMed  CAS  Google Scholar 

  146. Snyder E. Y., Yandava B. D., Pan Z.-H., Yoon C., and Macklis J. D. (1993) Immortalized postnatally-derived cerebellar progenitors can engraft and participate in the development of multiple structures at multiple stages along the mouse neuraxis.Absts. Am. Soc. Neurosci. 19, 613.

    Google Scholar 

  147. Onifer S. M., Whittemore S. R., and Holets V. R. (1993) Variable morphological differentiation of a raphe-derived neuronal cell line following transplantation into the adult rat CNS.Exp. Neurol. 122, 130–142.

    Article  PubMed  CAS  Google Scholar 

  148. Macklis J. D. (1993) Transplanted neocortical neurons migrate selectively into regions of neuronal degeneration produced by chromophore-targeted laser photolysis.J. Neurosci. 13, 3848–3863.

    PubMed  CAS  Google Scholar 

  149. Sheen V. L. and Macklis J. D. (1994) Apoptotic mechanisms in targeted photolytic neuronal cell death by chromophore-activated photolysis.Exp. Neurol. 130, 67–81.

    Article  PubMed  CAS  Google Scholar 

  150. Macklis J. D., Yoon C. H., and Snyder E. Y. (1994) Immortalized neural progenitors differentiate toward repletion of a neuronal population selectively eliminated from adult mouse neocortex by targeted photolysis.Exp. Neurol. 127, 9.

    Article  Google Scholar 

  151. Gage F. H., Kawaja M. D., and Fisher L. J. (1991) Genetically modified cells: applications for intracerebral grafting.Trends Neurosci. 14, 328–333.

    Article  PubMed  CAS  Google Scholar 

  152. Glorioso J. C., Goins W. F., Meany C. A., Fink D. A., and DeLuca N. A. (1994) Gene transfer to brain using herpes simplex virus vectors.Ann. Neurol. 35, S28-S34.

    Article  PubMed  CAS  Google Scholar 

  153. Freese A., Geller A. I., and Neve R. (1990) HSV-1 vector mediated neuronal gene delivery.Biochem. Pharmacol. 40, 2189–2199.

    Article  PubMed  CAS  Google Scholar 

  154. Le Gal La Salle G., Robert J. J., Berrard S., Ridous V., Stratford-Perricaudet L. D., Perricaudet M., and Mallet J. (1993) An adenovirus vector for gene transfer into neurons and glia in the brain.Science 259, 988–990.

    Article  Google Scholar 

  155. Anton R., Kordower J. H., Maidment N. T., Manaster J. S., Kane D. J., Rabizadeh S., Schueller S. B., Yang J., Edwards R. H., Markham C. H., and Bredesen D. E. (1994) Neural-targeted gene therapy for rodent and primate hemiparkinsonism.Exp. Neurol. 127, 207–218.

    Article  PubMed  CAS  Google Scholar 

  156. Snyder E. Y., Taylor R. M., and Wolfe J. H. (1995) Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain.Nature 374, 367–370.

    Article  PubMed  CAS  Google Scholar 

  157. Lacorazza H. D., Flax J. D., Snyder E. Y., and Jendoubi M. (1996) Expression of human β-hexosaminidase α-subunit gene (the gene defect of Tay Sachs disease) in mouse brains upon engraftment of transduced progenitor cells.Nat. Med. 2, 424–429.

    Article  PubMed  CAS  Google Scholar 

  158. Martinez-Serrano A., Lundberg C., Horellou P., Fischer W., Bentiage C., Campbell K., McKay R. D. G., Mallet J., and Björklundt A. (1995) CNS-derived neural progenitor cells for gene transfer of nerve growth factor to the adult brains complete rescue of axotomized cholinergic neurons after transplantation into the septum.J. Neurosci. 15, 5668–5680.

    PubMed  CAS  Google Scholar 

  159. Martinez-Serrano A., Fischer W., and Björklund A. (1995) Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain.Neuron 15, 473–484.

    Article  PubMed  CAS  Google Scholar 

  160. Snyder E. Y. and Flax J. D. (1995) Transplantation of neural progenitors and stem-like cells as a strategy for gene therapy and repair of neurodegenerative diseases.Mental Retard. Dev. Disabil. Res. Rev. 1, 27–38.

    Article  Google Scholar 

  161. Wright W. E., Pereira-Smith O. M., and Shay J. W. (1989) Reversible cellular senescence: implications for immortalization of normal human diploid fibroblasts.Mol. Cell. Biol. 9, 3088–3092.

    PubMed  CAS  Google Scholar 

  162. Stewart N. and Bacchetti S. (1991) Expression of SV40 large T antigen, but not small tantigen, is required for the induction of chromosomal aberrations in transformed human cells.Virology 180, 49–57.

    Article  PubMed  CAS  Google Scholar 

  163. Ray F. A., Peabody D. S., Cooper J. L., Cram I. S., and Kraemer P. M. (1990) SV40 antigen alone drives karyotype instability that precedes neoplastic transformation of human diploid fibroblasts.J. Cell Biochem. 42, 13–31.

    Article  PubMed  CAS  Google Scholar 

  164. Wainwright M. S., Perry B. D., Won L. A., O’Malley K. L., Wang W.-Y., Ehrlich M. E., and Heller A. (1995) Immortalized murine striatal neuronal cell lines expressing dopamine receptors and cholinergic properties.J. Neurosci. 15, 676–688.

    PubMed  CAS  Google Scholar 

  165. Bottenstein J. E. and Sato G. H. (1979) Growth of a rat neuroblastoma cell line in serum-free supplemented media.Proc. Natl. Acad. Sci. USA 76, 514–517.

    Article  PubMed  CAS  Google Scholar 

  166. Rudge J. S., Eaton M. J., Mather P., Lindsay R. M., and Whittemore S. R. (1996) CNTF induces raphe neuronal precursors to switch from a serotonergic to a cholinergic phenotype in vitro.Mol. Cell Neurosci., in press.

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Whittemore, S.R., Snyder, E.Y. Physiological relevance and functional potential of central nervous system-derived cell lines. Mol Neurobiol 12, 13–38 (1996). https://doi.org/10.1007/BF02740745

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