Gene Transfer into the Nervous System

  • Xandra O. Breakefield
  • Alfred I. Geller
Part of the Molecular Neurobiology book series (MN)


Several techniques have been developed that allow the introduction of recombinant DNA molecules into the cells of the nervous system. These methods include DNA uptake (transfection), microinjection of DNA, and infection with viral vectors. Gene transfer can be used for two general purposes: (1) To evaluate the regulation and function of a cloned gene following its modification and introduction into different cell types. Such studies include the definition of the regulatory elements that control levels of gene expression, alternate modes of RNA splicing, post-translational processing of peptides, sorting of proteins to their appropriate cellular locations, and biological activities of proteins. (2) To modify cells of the nervous system in culture and in vivo.

Index Entries

Gene transfer retrovirus herpes transgenic mice viral vectors nervous system 


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  1. Alema S., Casalbore P., Agostini E., and Tato F. (1985) Differentiation of PC12 phaeochromocytoma cells induced by v-src oncogene. Nature 316, 557–559.PubMedGoogle Scholar
  2. Baltimore D. (1971) Expression of animal virus genomes. Bacteriol. Rev. 35, 235–241.PubMedGoogle Scholar
  3. Basi G. S., Jacobson R. D., Virag I., Schilling J., and Skene J. H. K. (1987) Primary structure and transcriptional regulation of GAP-43, a protein associated with nerve growth. Cell 49, 785–791.PubMedGoogle Scholar
  4. Birnberg N. C., Lissitzky J.-C., Hinman M., and Herbert E. (1983) Glucocorticoids regulate proopiomelanocortin gene expression in vivo at the levels of transcription and secretion. Proc. Natl. Acad. Sci. USA 80, 6982–6986.PubMedGoogle Scholar
  5. Bernard H. U., Krammer G., and Rowekamp W. G. (1985) Construction of a fusion gene that confers resistance against hygromycin B to mammalian cells in culture. Exp. Cell Res. 158, 237–243.PubMedGoogle Scholar
  6. Black I. B., Adler J. E., Dreyfus C. F., Friedman W. F., LaGamma E. F., and Roach A. H. (1987) Biochemistry of information storage in the nervous system. Science 236, 1263–1268.PubMedGoogle Scholar
  7. Bloom F. E., Battenberg E. L. F., Milner R. J., and Sutcliffe J. G. (1985) Immuncytochemical mapping of IB236: A brain specific neuronal Polypeptide deduced from the sequence of a cloned mRNA. J. Neurosci. 5, 1781–1802.PubMedGoogle Scholar
  8. Brady R. O. (1983) Genetic errors and enzyme replacement strategies, Genetics of Neurological and Psychiatric Disorders (Kety, S. S., Rowland L. P., Sidman R. L., Matthysee S. W., eds), pp. 181–193. Raven Press, New York.Google Scholar
  9. Breakefield X. O. and Stern D. F. (1986) Oncogenes in neural tumors. TINS 9, 150–155.Google Scholar
  10. Brown Jr. R. H., Johnson D., Ogonowski M., and Weiner H. L. (1987) Type 1 human poliovirus binds to human synaptosomes. Ann. Neurol. 21, 64–70.PubMedGoogle Scholar
  11. Bucher P. and Trifonov E. N. (1986) Compilation and analysis of eucaryotic Pol II promoter sequences. Nuc. Acids. Res. 14, 10,009–10,026.Google Scholar
  12. Calof A. L. and Jessell T. M. (1986) Use of retroviral vector to transfer and express a foreign gene in murine neurons and neural ectoderm. Soc. Neurosci. Abst. 12, 183.Google Scholar
  13. Chamorro M., Aubert C., and Brahic M. (1986) Demyelinating lesions due to Theilers virus are associated with ongoing central nervous system infection. J. Virol. 57, 992–997.PubMedGoogle Scholar
  14. Chikaraishi D. M. (1986) The ID, brain identifier, model of neuronal gene expression: a reevaluation. TINS 9, 543–546.Google Scholar
  15. Chao M., Bothwell M., Ross A., Koprowski H., Lanahan A., Buck G, and Sehgal A. (1986) Gene transfer and molecular cloning of the human NGF receptor. Science 232, 518–521.PubMedGoogle Scholar
  16. Choo K. H., Filby R. G., Jennings I. G., Peterson G., and Fowler K. (1986) Vectors for expression and amplification of cDNA in mammaliam cells: Expression of rat Phenylalanine hydroxylase. DNA 5, 529–537.PubMedGoogle Scholar
  17. Co M. S., Gaulton G. N., Tominaga A., Homey G J., Fields B. N., and Greene M. I. (1985) Structural similarities between the mammalian beta-adrenergic and reovirus type 3 receptors. Proc. Natl. Acad. Sci. USA 82, 5315–5318.PubMedGoogle Scholar
  18. Colbere-Grapin F., Horodniceanu F., Kourilsky P., and Garapin A. G (1981) A new dominant hybrid selective marker for higher eukaryotic cell. J. Molec. Biol. 150, 1–14.Google Scholar
  19. Comb M., Liston D., Martin M., Rosen H., and Herbert E. (1985) Expression of the human proenkephalin gene in mouse pituitary cells: Accurate and efficient mRNA production and proteolytic processing. EMBO J. 4, 3115–3122.PubMedGoogle Scholar
  20. Cone R. D. and Mulligan R. G (1984) High efficiency gene transfer into mammalian cells: generation of helper-free recombination retrovirus with broad mammalian host range. Proc. Natl Acad. Sci. USA 81, 6349–6353.PubMedGoogle Scholar
  21. Cook M. L., Bastone V. B., and Stevens J. G. (1974) Evidence that neurons harbor latent herpes simplex virus. Infection and Immunity 9, 946–951.PubMedGoogle Scholar
  22. Costantini F., Chada K., and Magram J. (1986) Correction of murine beta-thalassemia by gene transfer into germ line. Science 233, 1192–1194.PubMedGoogle Scholar
  23. DesGroseillers L., Rassart R., Robitaille Y., and Jolicoeur P. (1985) Retrovirus-induced spongiform encephalopathy: The 3′-end long terminal repeat-containing viral sequences influence the incidence of the disease and the specificity of the neurological syndrome. Proc. Natl. Acad. Sci. USA 82, 8818–8822.PubMedGoogle Scholar
  24. Dick J. E., Magli M. C., Huszar D., Phillips R. A., and Bernstein A. (1985) Introduction of a selectable gene into primitive stem cells capable of long-term reconstitution of the hemopoietic System of W/Wvmice. Cell 42, 71–79.PubMedGoogle Scholar
  25. DiMaio D. (1984) Eukaryotic cloning vectors based on bovine papilloma viruses. Bio. Essays 1, 23–26.Google Scholar
  26. Dixon R. A. F., Kobilka B. K., Strader D. J., Benovic J. L., Dohlman H. G., Frielle T., Bolanowski M. A., Bennett C. D., Rands E., Diehl R. E., Mumford R. A., Slater E. E., Sigal I. S., Caron M. G., Lefkowitz R. J., and Strader C. D. (1986) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79.PubMedGoogle Scholar
  27. Doehmer J., Barinaga M., Vale W., Rosenfield M., Verma I., and Evans R. (1982) Introduction of rat growth hormone gene into mouse fibroblasts via a retroviral DNA vector: Expression and regulation. Proc. Natl Acad. Sci. USA 79, 2268–2272.PubMedGoogle Scholar
  28. Dubensky T. W., Campbell B. A., and Villarreal L. P. (1984) Direct transfection of viral and plasmid DNA into the liver or spleen of mice. Proc. Natl Acad. Sci. USA 81, 7529–7533.PubMedGoogle Scholar
  29. Edelstein S. B. and Breakefield X. O. (1986) Monoamine oxidases A and B are differentially regulated by glucocorticoids and “aging” in human skin fibroblasts. Cell, and Molec. Neurobiol 6, 121–150.Google Scholar
  30. Edwards R. H., Selby M. J., and Rutter W. J. (1986) Differential RNA splicing predicts two distinct nerve growth factor precursors. Nature 319, 784–787.PubMedGoogle Scholar
  31. Evans G. A., Ingraham H. A., Lewis K., Cunningham K., Seki T., Moriuchi T., Chang H. C., Silver J., and Hyman R. (1984) Expression of the Thy-1 glycoprotein gene by DNA-mediated gene transfer. Proc. Natl Acad. Sci. USA 81, 5532–5536.PubMedGoogle Scholar
  32. Forss-Petter S., Danielson P., and Sutcliffe J. G. (1986) Neuron-specific enolase: Complete structure of rat mRNA, multiple transcriptional start sites and evidence suggesting post-transcriptional control. J. Neurosci. Res. 16, 141–156.PubMedGoogle Scholar
  33. Frenkel N., Locker H., and Vlazny D. A. (1980) Studies of defective herpes simplex viruses. Annals NY Acad. Sci. 354, 347–370.Google Scholar
  34. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., and Dryja T. P. (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643–646.PubMedGoogle Scholar
  35. Gage F. H., Wolf F. J. A., Rosenberg M. B., Xu L., Yee J.-K., Shults G, and Friedmann T. Grafting genetically modified cells to the brain. Neuroscience, in press.Google Scholar
  36. Gajdusek D. G (1985) Unconventional viruses causing subacute spongiformencephalopathies, Virology (Fields B. N., Knipe D., Chanock R., Melnick J., Roizman B., and Shope R., eds), pp. 1519–1557. Raven Press, New York.Google Scholar
  37. Gibbs R. A. and Caskey G T. (1987) Identification and localization of mutations at the Lesch-Nyhan locus by ribonuclease A cleavage. Science 236, 303–305.PubMedGoogle Scholar
  38. Gilboa E., Eglitis M. A., Kantoff P. W., and Anderson, W. F. (1986) Transfer and expression of cloned genes using retroviral vectors. Biotech. 4, 504–512.Google Scholar
  39. Gnahn H., Hefti F., Heumann R., Schwab M. E., and Thoenen H. (1983) NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal forebrain: evidence for a physiological role of NGF in the brain? Brain Res. 285, 45–52.PubMedGoogle Scholar
  40. Goldgaber D., Lerman M. I., McBride O. W., Saffiotti U., and Gajdusek D. G (1986) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235, 877–880.Google Scholar
  41. Gordon J. W. and Ruddle F. H. (1985) DNA-mediated genetic transformation of mouse embryos and bone marrow—a review. Gene. 33, 121–136.PubMedGoogle Scholar
  42. Goring D. R., Rossant J., Clapoff S., Breitman L., and Tsui L.-C. (1987) In situ detection of beta-galactosidase in lenses of transgenic mice with a γ-crystallin/lacZ gene. Science 235, 456–458.PubMedGoogle Scholar
  43. Graf Jr., L. H., Urlaub G., and Chasin L. (1979) Transformation of the gene for hypoxanthine phosphoribosyltransferase. Somat. Cell Genet. 6, 1031–1044.Google Scholar
  44. Greene L. A. and Shooter E. M. (1980) The nerve growth factor: biochemistry, synthesis and mechanism of action. Annu. Rev. Neurosci. 3, 353–402.PubMedGoogle Scholar
  45. Grenningloh G., Rienitz A., Schmitt B., Methfessel G, Zensen M., Beyreuther K., Gundelfinger E. D., and Betz H. (1987) The strychnine-binding sub-unit of the glycine receptor shows homology with nicotinic acetylcholine receptors. Nature 328, 215–220.PubMedGoogle Scholar
  46. Gurney M. E., Heinrich S. P., Lee M. R., and Yin H. S. (1986) Molecular cloning and expression of neuroleukin, a neurotrophic factor for spinal and sensory neurons. Science 234, 566–574.PubMedGoogle Scholar
  47. Gusella J., Keys C., Varsanyi-Breiner A., Kao F.-T., Jones G, Puck T., and Housman D. (1980) Isolation and localization of DNA segments from specific human chromosomes. Proc. Natl. Acad. Sci. USA 77, 2829–2833.PubMedGoogle Scholar
  48. Hamer D. H. and Leder P. (1979) Expression of the chromosomal mouse beta maj-globin gene cloned in SV40. Nature 281, 35–40.PubMedGoogle Scholar
  49. Hamer D. H. and Leder P. (1979) SV40 recombinants carrying a functional RNA splice junction and polyadenylation site from the chromosomal mouse beta-globin gene. Cell 17, 737–747.PubMedGoogle Scholar
  50. Harrington C. A., Lewis E. J., Krzemien D., and Chikaraishi D. M. (1987) Identification and cell-type specificity of the tyrosine hydroxylase gene promoter. Nucleic Acids Res. 15, 2363–2384.PubMedGoogle Scholar
  51. Hellerman J. G., Cone R. C., Potts Jr., J. T., Rich A., Mulligan R. C., and Kronenberg H. M. (1984) Secretion of human parathyroid hormone from rat pituitary cells infected with a recombinant retro-virus encoding preproparathyroid hormone. Proc. Natl Acad. Sci. USA 81, 5340–5344.PubMedGoogle Scholar
  52. Hemperly J. J., Murray B. A., Edelman G. M., and Cunningham B. A (1986) Sequence of a cDNA clone ending the polysialic acid-rich and cytoplasmic domains of the neural cell adhesion molecule N-CAM. Proc. Natl Acad. Sci. USA 83, 3037–3041.PubMedGoogle Scholar
  53. Hinrichs S. H., Nerenberg M., Reynolds R. K., Khoury G., and Jay G. (1987) A transgenic mouse model for human neurofibromatosis. Science 237, 1340–1343PubMedGoogle Scholar
  54. Hock R. A. and Miller A. D. (1986) Retrovirus-mediated transfer and expression of dmp resistance genes in human haematopoietic progenitor cells. Nature 320, 275–277.PubMedGoogle Scholar
  55. Hooper M., Hardy K., Handyside A., Hunter S., and Monk M. (1987) HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells. Nature 326, 292–298.PubMedGoogle Scholar
  56. Hsu Y.-P. P., Powell J., Chen S., Weyler W., Ozelius L., Bruns G., Utterback M., Mallet J., Gusella J. F., and Breakefield X. O. Molecular genetic studies of MAO genes in Sixth International Catecholamine Symposium, Raven Press, NY, in press.Google Scholar
  57. Hudson L. D., Berndt J. A., Puckett C., Kozak C. A., and Lazzarini R. A. (1987) Aberrant splicing of proteolipid protein mRNA in the dysmyelinating jimpy mutant mouse. Proc. Natl. Acad. Sci. USA 84, 1454–1458.PubMedGoogle Scholar
  58. Igarashi T., Okazaki T., Potter H., Gaz R., and Kronenberg H. M. (1986) Cell-specific expression of the human parathyroid hormone gene in rat pituitary cells. Mol. Cell. Biol. 6, 1830–1833.PubMedGoogle Scholar
  59. Ingraham H. A. and Evans G. A. (1986) Characterization of two atypical promoters and alternate mRNA processing in the mouse Thy-1.2 glycoproteingene. Mol. Cell. Biol. 6, 2923–2931.PubMedGoogle Scholar
  60. Itoh N., Obata K., Yanaihara N., and Okamoto H. (1983) Human preprovasoactive intestinal Polypeptide contains a novel PHI-27 like peptide, PHM-27. Nature 304, 547–549.PubMedGoogle Scholar
  61. Julien J. P., Grosveld F., Yazdanbaksh K., Flavell D., and Mushynski W. (1987) The structure of a human neurofilament gene (NF-L): a unique exonintron organization in the intermediate filament gene family. Biochim. Biophys. Acta. 909, 10–20.PubMedGoogle Scholar
  62. Kantoff P. W., Kohn D. B., Mitsuya H., Armentano D., Sieberg M., Zweibel J. A., Eglitis M. A., McLachlin J. R., Wiginton D. A., Hutton J. J., Horowitz S. D., Gilboa E., Blaese R. M., and Anderson W. F. (1986) Correction of adenosine deaminase deficiency in human T and B cells using retrovi-ral-mediated gene transfer. Proc. Natl Acad. Sci. USA 83, 6563–6567.PubMedGoogle Scholar
  63. Karlsson S., Van Doren K., Schweiger S. G., Nienhuis A. W., and Gluzman Y. (1986) Stable gene transfer and tissue-specific expression of a human globin gene using adenoviral vectors EMBO J. 5, 2377–2385.PubMedGoogle Scholar
  64. Karns L. R., Ng S. C., Freeman J. A., and Fishman M. C. (1987) Cloning of complementary DNA for GAP-43, a neuronal growth related protein. Science 236, 597–600.PubMedGoogle Scholar
  65. Kaufman D. L., McGinnis J. F., Krieger N. R., Tobin A. J. (1986) Brain glutamate decarboxylase cloned in lambda gt-11: fusion protein produces gamma-aminobutyric acid. Science 232, 1138–1140.PubMedGoogle Scholar
  66. Keller G., Paige C., Gilboa E., and Wagner E. F. (1985) Expression of a foreign gene in myeloid and lymphoid cells derived from multipotent haematopoietic precursors. Nature 318, 149–154.PubMedGoogle Scholar
  67. Kelley K. A. and Herrup K. (1987) Unexpected CNS tumor cytologyin wild type and mutant SV-40 T-antigen transgenic mice. Soc. Neurosci. Abst. 154.6.Google Scholar
  68. Kelly R. B. (1985) Pathways of protein secretion in eukaryotes. Science 230, 25–31.PubMedGoogle Scholar
  69. Kcnney S., Natarajan V., Strike D., Khoury G., and Salzman N. (1984) JC virus enhancer-promoter active in human brain cells. Science 266, 1337–1339.Google Scholar
  70. Khoury G. and Gruss P. (1983) Enhancer elements. Cell 33, 313–314.PubMedGoogle Scholar
  71. Kinzler K. W., Bigner S. H., Bigner D. D., Trent J. M., Law M. L., O’Brien S. J., Wong A. J., and Vogelstein B. (1987) Identification of an amplified highly expessed gene in a human glioma. Science 236, 70–73.PubMedGoogle Scholar
  72. Klobutcher L. A. and Ruddle F. H. (1981) Chromosome-mediated gene transfer. Ann. Rev. Biochem. 50, 533–554.PubMedGoogle Scholar
  73. Kollias G., Spanopoulou E., Grosveld F., Ritter M., Beech J., and Morris R. (1987) Differential regulation of a Thy-1 gene in transgenic mice. Proc. Natl Acad. Sci. USA 84, 1492–1496.PubMedGoogle Scholar
  74. Koprowski H. (1978) Possible role of herpes virus in chronic CNS disease, in Persistent Viruses (Stevens F. G., eds.), pp. 691–699, Academic, NY.Google Scholar
  75. Korneluk R. G., Mahuran D. J., Neote K., O’Dowd B. F., Tropak M., Willard H. F., Anderson M. J., Lowden J. A., and Gravel R. A. (1986) Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase. J. Biol. Chem. 261, 8407–8413.PubMedGoogle Scholar
  76. Kraus M. H., Popescu N. C., Amsbaugh C., and King C. R. (1987) Overexpression of the EGF receptor-related proto-oncogene erb-2 in human mammary tumor cell lines by different molecular mechanisms. EMBO J. 6, 605–610.PubMedGoogle Scholar
  77. Kubo T., Fukuda K., Mikami A., Maeda A., Takahashi H., Mishina M., Haga T., Haga K., Ichiyama A., Kangawa K., Kojima M., Matsuo H., Hirose T., and Numa S. (1986) Cloning, sequencing and expression of complementary DNA encoding the muscarinic acetylcholine receptor. Nature 323, 411–416.PubMedGoogle Scholar
  78. Kuehn M. R., Bradley A., Robertson E. J., and Evans M. J. (1987) A potential animal model for the human Lesch-Nyhan syndrome through introduction of HPRT mutations into mice. Nature 326, 295–298.PubMedGoogle Scholar
  79. Kuwano R., Usui H., Maeda T., Fukui T., Yamanari N., Ohtsuka E., Ikehara M., and Takahashi Y. (1984) Molecular cloning and the complete nucleotide sequence of cDNA to mRNA for S-100 protein of rat brain. Nuc. Acids Res. 12, 7455–7465.Google Scholar
  80. Kwong A. D. and Frenkel N. (1984) Herpes simplex virus amplicon: Effect of size on replication of constructed defective genomes containing eucaryotic DNA sequences. J. Virol 51, 595–603.PubMedGoogle Scholar
  81. Larhammar D., Ericsson A., and Persson H. (1987) Structure and expression of the rat neuropeptide Y gene. Proc. Natl Acad. Sci. USA 84, 2068–2072.PubMedGoogle Scholar
  82. Larsen P. R., Harney J. W., and Moore D. D. (1986) Repression mediates cell-type specific expression of the rat growth hormone gene. Proc. Natl. Acad. Sci. USA 83, 8283–8287.PubMedGoogle Scholar
  83. Ledley F., Grennet H., McGinnis-Shelnutt M., and Woo S. (1986) Retroviral-mediated gene transfer of human Phenylalanine hydroxylase into NIH 3T3 and heptoma cells. Proc. Natl Acad. Sci. USA 83, 409–413.PubMedGoogle Scholar
  84. Lee W.-H., Bookstein R., Hong F., Young L.-J., Shew J.-Y., and Lee E. Y.-H.P. (1987) Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235, 1394–1399.PubMedGoogle Scholar
  85. Leff S. E., Evans R. M., and Rosenfeld M. G. (1987) Splice commitment dictates neurospecific alternative RNA processing in calcitonin/CGRP gene expression. Cell 48, 517–524.PubMedGoogle Scholar
  86. LeMeur M., Gerlinging P., Benoist G, and Mathis D. (1985) Correcting an immune-response deficiency by creating E alpha gene transgenic mice. Nature 316, 38–42.Google Scholar
  87. Lentz T. Z., Benson R. J., Klimowicz D., Wilson P. T., and Hawrot E. (1986) Binding of rabies virus to purified Torpedo acetylcholine receptor. Brain Res. 387, 211–219.Google Scholar
  88. Lewis S. A., Balcarek J. M., Krek V., Shelanski M., and Cowan N. J. (1984) Sequence of a cDNA clone encoding mouse glial fibrillary acidic protein: structural conservation of intermediate filaments. Proc. Natl Acad. Sci. USA 81, 2743–2746.PubMedGoogle Scholar
  89. Lewis S. A. and Cowan N. J. (1985) Genetics, evolution, and expression of the 68,000-mol-wt neurofilament protein: isolation of a cloned cDNA probe. J. Cell Biol. 100, 843–850.PubMedGoogle Scholar
  90. Lewis E. J., Harrington G A., and Chikaraishi D. M. (1987) Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP. Proc. Natl Acad. Sci. USA 84, 3550–3554.PubMedGoogle Scholar
  91. Libermann T. A., Nusbaum H. R., Razon N., Kris R., Lax L, Soreq H., Whittle N., Waterfield M. D., Ullrich A., and Schessinger J. (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumors of glial origin. Nature 313, 144–147.PubMedGoogle Scholar
  92. Luthman H. and Magnusson G. (1983) High efficiency polyoma DNA transfection of chloroquine treated cells. Nuc. Acids Res. 11, 1295–1308.Google Scholar
  93. Mackett M. and Smith, G. L. (1986) Vaccinia virus expression vectors. J. Gen. Virol 67, 2067–2082.PubMedGoogle Scholar
  94. Mandl C., Walker D. L., and Frisque R. J. (1987) Derivation and characterization of POJ cells, transformed human fetal glial cells that retain their permissivity for JC virus. J. Virol. 61, 755–763.PubMedGoogle Scholar
  95. Mann R., Mulligan R. C., and Baltimore D. (1983) Construction of retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell 33, 153–159.PubMedGoogle Scholar
  96. McBride O. W. and Peterson J. L. (1980) Chromosome-mediated gene transfer in mammalian cells. Ann. Rev. Genet. 14, 321–345.PubMedGoogle Scholar
  97. McKinnon R. D., Shinnick T. M., and Sutcliffe J. G. (1986) The neuronal identifier element is a as-acting positive regulator of gene expression. Proc. Natl Acad. Sci. USA 83, 3751–3755.PubMedGoogle Scholar
  98. Mellman I., Fuchs R., and Helenius A. (1986) Acidification of the endocytic and exocytic pathways. Annu. Rev. Biochem. 55, 663–700.PubMedGoogle Scholar
  99. 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, 461–463.PubMedGoogle Scholar
  100. Meulen V. T. and Hall W. W. (1978) Slow virus infections of the nervous system: Virological, immunological, and pathogenetic considerations. J. Gen. Virol. 41, 1–25.PubMedGoogle Scholar
  101. Miller A. D., Eckner R. J., Jolly D. J., Friedmann T., and Verma I. M. (1984) Expression of a retrovirus encoding human HPRT in mice. Science 225, 630–631.PubMedGoogle Scholar
  102. Miller A. D., Jolly D. J. Friedmann T., and Verma I. (1983) A transmissable retrovirus expressing human hypoxanthine phosphoribosyl transferase (HPRT): gene transfer into cells obtained from humans deficient in HPRT. Proc. Natl Acad. Sci. USA 80, 4709–4713.PubMedGoogle Scholar
  103. Miller A. D., Law M.-F., and Verma, I. M. (1985) Generation of helper-free amphotropic retroviruses that transduce a dominant-acting, methotrexate-resistant dihydrofolate reductase gene. Mol. Cell Biol. 5, 431–437.PubMedGoogle Scholar
  104. Milner R. J., Lai C., Nave K.-A., Lenoir D., Ogata J., and Sutcliffe J. G. (1985) Nucleotide sequences of two mRNAs for rat brain myelin proteolipid protein. Cell 42, 931–939.PubMedGoogle Scholar
  105. Minth C. M., Bloom S. R., Polak J. M., and Dixon J. E. (1984) Cloning, characterization and DNA sequence of a human cDNA encoding neuropeptide tyrosine. Proc. Natl Acad. Sci. 81, 4577–4581.Google Scholar
  106. Molineaux S. M., Engh H., de Ferra F., Hudson L., and Lazzarini R. A. (1986) Recombination within the myelin basic protein gene created the dys-myelinating shiverer mouse mutation. Proc. Natl. Acad. Sci. USA 83, 7542–7546.PubMedGoogle Scholar
  107. Monaco A. P., Neve R. L., Colletti-Feener C., Bertelson C. J., Kurnit D. M., and Kunkel L. M. (1986) Isolation of candidate cDNAs for portions of the Duchenne muscular dystrophy gene. Nature 323, 646–650.PubMedGoogle Scholar
  108. Montminy M. R., Sevarino K. A., Wagner J. A., and Mandell G. (1986) Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc. Natl Acad. Sci. USA 83, 6682–6686.PubMedGoogle Scholar
  109. Moore H. and Kelly R. (1986) Re-routing of a secretory protein by fusion with human growth hormone sequences. Nature 321, 443–462.PubMedGoogle Scholar
  110. Moore H. P., Walker M. D., Lee F., and Kelly R. B (1983) Expressing a human proinsulin cDNA in a mouse ACTH-secreting cell. Intracellular storage, proteolytic processing, and secretion on stimulation. Cell 35, 531–538.PubMedGoogle Scholar
  111. Mulligan R. C., Howard B. H., and Berg P. (1979) Synthesis of rabbit beta-globin in cultured monkey kidney cells following transfection with a SV40 beta-globin recombinant genome. Nature 277, 108–144.PubMedGoogle Scholar
  112. Mulligan R. C. and Berg P. (1981) Selection for animal cells that express the Escherichia coli gene coding for xanthine-guanine phosphoribosyl transferase. Proc. Natl Acad. Sci. USA 78, 2072–2076.PubMedGoogle Scholar
  113. Mulligan R. C. (1982) Development of new mammalian transducing vectors, Eukaryotic Viral Vectors (Gluzman, Y., ed.), pp. 133–137. Cold Spring Harbor Lab, NY.Google Scholar
  114. Myerowitz R., Piekarz R., Neufeld E. F., Shows T. B., and Suzuki K. (1985) Human beta-hexosaminidase alpha-chain: coding sequence and homology with the beta-chain. Proc. Natl Acad. Sci. USA 82, 7830–7834.PubMedGoogle Scholar
  115. Narayan O. and Coile L. C. (1985) Lentiviral diseases of sheep and goats: chronic pneumonia, leukoencephalomyelitis, and arteritis. Rev. Infect. Dis. 1, 89–98.Google Scholar
  116. Nave K.-A., Lai C., Bloom F. E., and Milner R. J. (1986) Jimpy mutant mouse: a 74-base deletion in the mRNA for myelin proteolipid protein and evidence for a primary defect in RNA splicing. Proc. Natl Acad. Sci. USA 83, 9264–9268.PubMedGoogle Scholar
  117. Ornitz D. M., Palmiter R. D., Hammer R. E., Brinster R. L., Swift G. H., and MacDonald R. J. (1985) Specific expression of an elastase-human growth hormone fusion gene. Nature 313, 600–602.PubMedGoogle Scholar
  118. Palmer T. D., Hock R. A., Osborne W. R. A., and Miller A. D. (1987) Efficient retrovirus-mediated transfer and expression of a human adenosine deaminase gene in diploid skin fibroblasts from an adenosine deaminase-deficient human. Proc. Natl Acad. Sci. USA 84, 1055–1059.PubMedGoogle Scholar
  119. Palmiter R. D., Behringer R. R., Quiate C. J., Maxwell I. H.. and Brinster R. L. (1987) Cell lineage ablation in transgenic mice by cell-specific expression of a toxin gene. Cell 50, 435–443.PubMedGoogle Scholar
  120. Palmiter R. D., Norstedt G., Gelinas R. E., Hammer R. E., and Brinster R. L. (1983) Metallothionein-human GH fusion genes stimulate growth of mice. Science 222, 809–814.PubMedGoogle Scholar
  121. Palmiter R. D. and Brinster R. (1985) Transgenic Mice. Cell 41, 343–345.PubMedGoogle Scholar
  122. Palmiter R. D., Chen H. Y., Messing A., and Brinster R. L. (1985) SV40 enhancer and large-T antigen are instrumental indevelopment of choroid plexus tumors in transgenic mice. Nature 316, 457–460.PubMedGoogle Scholar
  123. Papazian D. M., Schwarz T. L., Tempel B. L., Jan Y. N., and Jan L. Y. (1987) Cloning of genomic and complementary DNA from shaker, a putative potassium channel gene from Drosophila. Science 237, 749–753.Google Scholar
  124. Parker B. A. and Stark G. R. (1979) Regulation of simian virus 40 transcription: Sensitive analysis of the RNA present early in infections by virus or virus DNA. J. Virol 31, 360–369.PubMedGoogle Scholar
  125. Popko B., Puckett C., Lai E., Shine H. D., Readhead C., Takahashi N., Hunt S. W., Sidman R. L., and Hood L. (1987) Myelin deficient mice: Expression of myeline basic protein and generation of mice with varying levels of myelin. Cell 48, 713–721.PubMedGoogle Scholar
  126. Potter H., Weir L., and Leder P. (1984) Enchancer-dependent expression of human k Immunoglobulin genes introduced into mouse pre-beta lymphocytes by electroporation. Proc. Natl. Acad. Sci. USA 81, 7161–7165.PubMedGoogle Scholar
  127. Price J., Turner D., and Cepko C. (1987) Lineage analysis in the vertebrate nervous system by retrovirus-mediated gene transfer. Proc. Natl. Acad. Sci. USA, 34, 156–160.Google Scholar
  128. Prody C. A., Zevin-Sonkin D., Gnatt A., Goldberg O., and Soreq H. (1987) Isolation and characterization of full-length cDNA clones coding for Cholinesterase from fetal human tissues. Proc. Natl. Acad. Sci. USA 84, 3555–3559.PubMedGoogle Scholar
  129. Radeke M. J., Misko T. P., Hsu C., Herzenberg L. A., and Shooter E. M. (1987) Gene transfer and molecular cloning of the rat nerve growth factor receptor. Nature 325, 593–597.PubMedGoogle Scholar
  130. Readhead C., Popko B., Takahashi N., Shine H. D., Saavedra R. A., Sidman R. L., and Hood L. (1987) Expression of a myelin basic protein gene in transgenic shiverer mice: correction of the dysmyelinating phenotype. Cell 48, 703–712.PubMedGoogle Scholar
  131. Roach A., Takahashi N., Pravtcheva D., Ruddle F., and Hood L. (1987) Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell 42, 149–155.Google Scholar
  132. Robinson P. A., Wion D., and Anderton B. H. (1986) Isolation of a cDNA for the rat heavy neurofilament Polypeptide (NF-H) Febs Lett 209, 203–205.PubMedGoogle Scholar
  133. Rosenberg M., Hansen G, and Breakefield X. O. (1985) Molecular genetic approaches to neurologic and psychiatric diseases. Progress in Neurobiology 24, 95–140.PubMedGoogle Scholar
  134. Sanes J. R., Rubenstein J. L. R., and Nicholas J.-F. (1987) Use of a recombinant retrovirus to study postimplantation cell lineage in mouse embryos. EMBO J. 5, 3133–3134.Google Scholar
  135. Sasaki H., Sasaki Y., Matsuo H., Goto I., Kuroiwa Y., Sahashi I., Takahashi A., Shinoda T., Isobe T., and Takagi Y. (1984) Diagnosis of familial amyloidotic polyneuropathy by recombinant DNA techniques. Biochem. Biophys. Res. Commun. 125, 636–642.PubMedGoogle Scholar
  136. Schechter A. L., Stern D. F., Vaidyanathan L., Decker S. J., Drebin J. A., Greene M. I., and Weinberg R. A. (1984) The neu oncogene: an erb-B-related gene encoding a 185, 000-Mr tumour antigen. Nature 312, 513–516.PubMedGoogle Scholar
  137. Schnieke A., Harbers K., and Jaenisch R. (1983) Embryonic lethal mutation in mice induced by retrovirus insertion into the alpha 1 (I) collagen gene. Nature 304, 315–320.PubMedGoogle Scholar
  138. Schwab M., Ellison J., Busch M., Rosenau W., Varmus H. E., and Bishop J. M. (1984) Enchanced expression of the human gene N-myc consequent to amplification of DNA may contribute to malignant progression of neuroblastoma. Proc. Natl. Acad. Sci. USA 81, 4940–4944.PubMedGoogle Scholar
  139. Schweitzer E. and Kelly R. (1985) Selective packaging of human growth hormone into synaptic vesicles in rat neuronal (PC12) cell line. J. Cell Biol. 101, 667–676.PubMedGoogle Scholar
  140. Seiden R. F., Skoskiewicz M. J., Howie K. B., Russell P. S., and Goodman H. M. (1987) Implantation of genetically engineered fibroblasts into mice: implications for gene therapy. Science 236, 714–718.Google Scholar
  141. Serfling E., Jasin M., and Schaffner W. (1985) Enhancers and eukaryotic gene transcription. Trends Genet. 1, 224–230.Google Scholar
  142. Sharpe A. H., Jaenisch R., and Cuprecht R. M. (1987) Retrovirus and mouse embryos: A rapid model for neurovirulence and transplancental antiviral therapy. Science 236, 1671–1674.PubMedGoogle Scholar
  143. Shih M.-F., Arsenakis M., Tiollais P., and Roizman B. (1984) Expression of hepatitis B virus S gene by herpes simplex virus type I vectors carrying alpha- and beta-regulated gene chimeras. Proc. Natl Acad. Sci. USA 81, 5867–5870.PubMedGoogle Scholar
  144. Schofield P. R., Darlison M. G., Fujita N., Burt D. R., Stephenson F. A., Rodriquez H., Rhee L. M., Ramachandran J., Reale V., Glencorse T. A., Seeburg P. H., and Barnard E. A. (1987) Sequence and functional expression of the GABAA receptor shows a ligand-gated receptor super-family. Nature 328, 221–227.PubMedGoogle Scholar
  145. Slamon D. J., Clark G. M., Wong S. G., Levin W. J., Ullrich A., and McGuire W. L. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182.PubMedGoogle Scholar
  146. Sorge J., Gelbart T., West G, Westwood B., and Beutler E. (1985) Heterogeneity in type I Gaucher disease demonstrated by restriction mapping of the gene. Proc. Natl Acad. Sci. USA 82, 5442–5445.PubMedGoogle Scholar
  147. Sorge J., Kuhl W., West C., and Beutler E. (1987) Complete correction of the enzymatic defect of type I Gaucher disease fibroblasts by retroviral-mediated gene transfer. Proc. Natl. Acad. Sci. USA 84, 906–909.PubMedGoogle Scholar
  148. Soriano P., Cone R. D., Mulligan R. G, and Jaenisch R. (1986) Tissue-specific and ectopic expression of genes introduced into transgenic mice by retroviruses. Science 234, 1409–1413.PubMedGoogle Scholar
  149. Soriano P. and Jaenisch R. (1986) Retroviruses as probes for mammalian development: allocation of cells to the somatic and germ cell lineages. Cell 46, 19–29.PubMedGoogle Scholar
  150. Southern P. J. and Berg P. (1982) Transformation of mammalian cells to antibiotic resistance with bacterial gene under control of the SV40 early region promoter. J. Molec. and App. Gen. 1, 327–341.Google Scholar
  151. Spear P. G. and Roizman B. (1981) Herpes simplex virus, DNA Tumor Viruses (Tooze, J., ed.) pp. 615–746. Cold Spring Harbor Laboratory, NY.Google Scholar
  152. Spaete R. R. and Frenkel N. (1982) The herpes simplex virus amplicon: A new eucaryotic defective-virus cloning amplifying vector. Cell 30, 85–304.Google Scholar
  153. Spaete R. R., and Frenkel N. (1985) The herpes simplex virus amplicon: Analysis of as-acting replication functions. Proc. Natl Acad. Sci. USA 82, 694–698.PubMedGoogle Scholar
  154. Stevens J. G. (1975) Latent herpes simplex virus and the nervous system. Curr. Topics in Microbiol. and Immunol. 70, 31–50.Google Scholar
  155. Stewart T. A., Pattengale P. K., and Leder P. (1984) Spontaneous mammary adenocarcinomas in transgenic mice that carry and express MTV/myc fusion genes. Cell 38, 627–637.PubMedGoogle Scholar
  156. Stewart C. L., Schuetze S., Vanek M., and Wagner E. F. (1987) Expression of retroviral vectors in transgenic mice obtained by embryo infection. EMBO J. 6, 383–388.PubMedGoogle Scholar
  157. Stout J. T., Chen H. Y., Brennand J., Caskey C. T., and Brinster R. (1985) Expression of human HPRT in the central nervous system of transgenic mice. Nature 317, 250–252.PubMedGoogle Scholar
  158. Stout J. T. and Caskey C. T. Anti-sense RNA inhibition of endogenous genes. Methods Enzymol, in press.Google Scholar
  159. Stow N. D. and McGonagle E. C. (1982) Propagation of foreign DNA sequence linked to a herpes simplex virus origin of replication, Eucaryotic Viral Vectors (Gluzman Y., ed.), pp. 199–204. Cold Spring Harbor Laboratory, NY.Google Scholar
  160. Strader C. D., Sigal I. S., Blake A. D., Cheung A. H., Register R. B., Rands E., Zemcik B. A., Candelore M. R., and Dixon R. A. F. (1987) The carboxyl terminus of the hamster beta-adrenergic receptor expressed in mouse L cells is not required for receptor sequestration. Cell 49, 855–863.PubMedGoogle Scholar
  161. Subramani S., Mulligan R., and Berg P. (1981) Expression of the mouse dihydrofolate reductase complementary deoxyribonucleic acid in simian virus 40 vectors. Mol. and Cell Biol. 1, 854–864.Google Scholar
  162. Sutcliffe J. G., Milner R. J., Gottesfeld J. M., and Lerner R. A. (1984) Identifier sequences are transcribed specifically in brain. Nature 308, 237–241.PubMedGoogle Scholar
  163. Swanson L. W., Simmons D. M., Arriza J., Hammer R., Brinster R., Rosenfeld M. G., and Evans R. M. (1985) Novel developmental specificity in the nervous system of transgenic animals expressing growth hormone fusion genes. Nature 317, 363–366.PubMedGoogle Scholar
  164. Taniuchi M., Clark H. B., and Johnson E. M. Jr. (1986) Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc. Natl Acad. Sci. USA 83, 4094–4098.PubMedGoogle Scholar
  165. Tanzi R. E., Gusella J. F., Watkins P. C., Bruns G. A. P., St. George-Hyslop P., Van Keuren M. L., Patterson D., Pagan S., Kurnit D. M., and Neve R. L. (1987) Amyloid protein gene: cDNA, mRNA distribution, and genetic linkage near the Alzheimer locus. Science 235, 880–884.PubMedGoogle Scholar
  166. Taparowsky E., Shimizu K., Goldfarb M., and Wigler M. (1983) Structure and activation of the human N-ras gene. Cell 34, 581–586.PubMedGoogle Scholar
  167. Thoenen H. and Edgar D. (1985) Neurotrophic factors. Science 229, 238–242.PubMedGoogle Scholar
  168. Thomas G., Herbert E., and Hruby D. E. (1986) Expression and cell type-specific processing of human preproenkephalin with a vaccinia recombinant. Science 232, 1641–1643.PubMedGoogle Scholar
  169. Thomas K. R. and Capecchi M. R. (1986) Introduction of homologous DNA sequences into mammalian cells induces mutations in the cognate gene. Nature 324, 34.PubMedGoogle Scholar
  170. Townes T. M., Lingrel J. B., Chen H. Y., Brinster R. L., and Palmiter, R. D. (1985) Erythroid-specific expression of human beta-globin genes in transgenic mice. EMBO J. 4, 1715–1723.PubMedGoogle Scholar
  171. Tsuji S., Choudary P. V., Martin B. M., Stubblefield B. K., Mayor J. A., Barranger J. A., and Ginns E. I., (1987) A mutation in the human glucocerebrosi-dase gene in neuronopathic Gaucher’s disease. N. Engl J.Med. 316, 570–575.PubMedGoogle Scholar
  172. Tsukada T., Fink J. S., Mandel G., and Goodman R. H. (1987) Identification of a region in the human vasoactive intestinal Polypeptide gene responsible for regulation by cyclic AMP. J. Biol. Chem. 262, 8743–8747.PubMedGoogle Scholar
  173. Tsukada T., Horovitch S. J., Montminy M. R., Mandel G., and Goodman R. H. (1985) Structure of the human vasoactive intestinal Polypeptide gene. DNA 4, 293–300PubMedGoogle Scholar
  174. Turner D. L and Cepko C. (1987) Cell lineage in the rat retina: a common progenitor for neurons and glia persists late in development. Nature, in press.Google Scholar
  175. Warren T. and Sheilds, D. (1984) Expression of preprosomatostatin in heterologous cells: Biosynthesis, postranslational processing, and secretion of mature somatostatin. Cell 39, 547–555.PubMedGoogle Scholar
  176. Waterman M., Murdoch G. H., Evans R. M., and Rosenfeld M. G. (1985) Cylic AMP regulation of eukaryotic gene transcription by two discrete molecular mechanisms. Science 229, 267–269.PubMedGoogle Scholar
  177. Weiss R., Tsnich N., Varmus H., and Coffin J. (1985) RNA tumor viruses. Cold Spring Harbor Labs, NYGoogle Scholar
  178. Wigdahl B., Smith C. A., Iraglia A. M., and Rapp F. (1984) Herpes simplex virus latency in isolated human neurons. Proc. Natl Acad. Sci. USA 81, 6217–6221.PubMedGoogle Scholar
  179. Wigler M., Silverstein S., Lee L. S., Pellicer A., Cheng Y. C., and Axel R. (1977) Transfer of purified herpes virus thymidine kinase gene to cultures mouse cells Cell 11, 223–232.PubMedGoogle Scholar
  180. Wigler M., Pellicer A., Silverstein S., Axel R., Urlaub G., and Chasin L. (1979a) DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc. Natl. Acad. Sci. USA 76, 13731–13736.Google Scholar
  181. Wigler M., Sweet R., Sim G. K., Wold B., Pellicer A., Lacy E., Maniatis T., Silverstein S., and Axel R. (1979b) Transformation of mammalian cells with genes from procaryotes and eucaryotes. Cell 16, 777–785.PubMedGoogle Scholar
  182. Wiley C. A., Shrier R. D., Nelson J. A., Lampert P. W., and Oldstone B. A. (1986) Cellular localization of human immunodeficiency virus infection within the brains of acquired immune deficiency syndrome patients. Proc. Natl. Acad. Sci. USA 83, 7089–7093.PubMedGoogle Scholar
  183. Williams D. A., Lemishchka I. R., Nathan D. G., and Mulligan R. C. (1984) Introduction of new genetic material into pluripotent haematopoietic stem cells of the mouse. Nature 310, 476–480.PubMedGoogle Scholar
  184. Williams D., Orkin S., and Mulligan R. (1986a) Retrovirus-mediated transfer of human adenosine deaminase gene sequences into cells in culture and into murine hematopoietic cells in vivo. Proc. Natl Acad. Sci. USA 83, 2566–2570.PubMedGoogle Scholar
  185. Williams L. R., Varon S., Peterson G. M., Wictorin K., Fischer W., Bjorklund A., and Gage F. H. (1986b) Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria fornix transection. Proc. Natl Acad. Sci. USA 83, 9231–9235.PubMedGoogle Scholar
  186. Willis R. C., Jolly D. J., Miller A. D., Plent M. M., Esty A. G, Anderson P. J., Chang H.-C., Jones O. W., Seegmiller J. E., and Friedmann T. (1984) Partial phenotypic correction of human Lesch-Nyhan (hypoxanthine-guanine phosphoribosyl-transferase-deficient) lymphoblasts with a transmissable retroviral vector. J. Biol. Chem. 259, 7842–7849.PubMedGoogle Scholar
  187. Wolf D., Richter-Landsberg C., Short M. P., Cepko C., and Breakefield X. O. Retrovirus-mediated gene transfer of nerve growth factor into mouse pituitary line AtT-20. Manuscript submitted.Google Scholar
  188. Yamamoto K. R. (1985) Steroid receptor regulated transcription of specific genes and gene networks. Ann. Reo. Genet. 19, 209–252.Google Scholar
  189. Yates J. L., Warren N., and Sugden B. (1985) Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313, 812–815.PubMedGoogle Scholar

Copyright information

© The Humana Press Inc. 1988

Authors and Affiliations

  • Xandra O. Breakefield
    • 1
    • 2
    • 3
  • Alfred I. Geller
    • 1
    • 2
    • 3
  1. 1.Molecular NeurogeneticsEunice Kennedy Shriver CenterWalthamUSA
  2. 2.Laboratory of NeurogeneticsMassachusetts General HospitalBostonUSA
  3. 3.Neuroscience Program (Neurology)Harvard Medical SchoolBostonUSA

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