Abstract
The ability to isolate multipotential neuroepithelial precursor cells from the mammalian nervous system provides exciting perspectives for the in vitro analysis of early nervous system development and the generation of donor cells for neural repair. New models are needed to study the properties of these cells in vivo. Neural chimeras have revealed a remarkable degree of plasticity in the developmental potential of neuroepithelial precursor cells. Following transplantation into the cerebral ventricle of embryonic hosts, precursors derived from various brain regions and developmental stages participate in host brain development and undergo region‐specific differentiation into neurons and glia. These findings indicate that in the developing nervous system, migration and differentiation of neural precursors cells are regulated to a large extent by extrinsic signals. Neural chimeras composed of genetically modified cells will permit the study of the molecular mechanisms underlying these guidance cues, which may eventually be exploited for cell replacement strategies in the adult brain. A key problem in neural transplantation is the availability of suitable donor tissue. Neural chimeras composed of embryonic stem (ES) cell‐derived neurons and glia depict ES cells as a versatile and virtually unlimited donor source for neural repair. Generation of interspecies neural chimeras composed of human and rodent cells facilitates the translation of these advances into clinical strategies for human nervous system repair.
Full Text
The Full Text of this article is available as a PDF (283.0 KB).
References
- 1. Altman, J (1969) Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb. J Comp Neurol 137: 433–458. [DOI] [PubMed] [Google Scholar]
- 2. Altman, J , Bayer, SA (1995) Atlas of Prenatal Rat Brain Development, CRC Press: Boca Raton . [Google Scholar]
- 3. Altman, J. D. DG (1965) Autoradiographic evidence of postnatal hippocampal neurogenesis in rats. J Comp Neurol 124: 319–336. [DOI] [PubMed] [Google Scholar]
- 4. Alvarado‐Mallart, RM , Martinez, S , Lance‐Jones, CC (1990) Pluripotentiality of the 2‐day‐old avian germinative neuroepithelium. Dev Biol 139: 75–88. [DOI] [PubMed] [Google Scholar]
- 5. Baimbridge, KG , Miller, JJ (1982) Immunohistochemical localization of calcium‐binding protein in the cerebellum, hippocampal formation and olfactory bulb of the rat. Brain Res 245: 223–229. [DOI] [PubMed] [Google Scholar]
- 6. Bain, G , Kitchens, D , Yao, M , Huettner, JE , Gottlieb, DI (1995) Embryonic stem cells express neuronal properties in vitro. Dev Biol 168: 342–357. [DOI] [PubMed] [Google Scholar]
- 7. Barbe, MF , Levitt, P (1991) The early commitment of fetal neurons to the limbic cortex. J Neurosci 11: 519–533. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Bregman, BS , Kunkel‐Bagden, E , Schnell, L , Dai, HN , Gao, D , Schwab, ME (1995) Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378: 498–501. [DOI] [PubMed] [Google Scholar]
- 9. Brinster, RL (1993) Stem cells and transgenic mice in the study of development. Int J Dev Biol 37: 89–99. [PubMed] [Google Scholar]
- 10. Brüstle, O , Choudhary, K , Karram, K , Hüttner, A , Murray, K , Dubois‐Dalcq, M , McKay, RDG (1998) Chimeric brains generated by intraventricular transplantation of fetal human brain cells into embryonic rats. Nature Biotechnol 16: 1040–1044. [DOI] [PubMed] [Google Scholar]
- 11. Brüstle, O , Cunningham, M , Tabar, V , Studer, L (1997) Experimental transplantation in the embryonic, neonatal, and adult mammalian brain In: Current Protocols in Neuroscience, Crawley, J , Gerfen, C , McKay, RDG , Rogawski, M , Sibley, D , Skolnick, P (eds.), pp. 3.10.11–13.10.28, John Wiley: New York . [Google Scholar]
- 12. Brüstle, O , Maskos, U , McKay, RDG (1995) Host‐guided migration allows targeted introduction of neurons into the embryonic brain. Neuron 15: 1275–1285. [DOI] [PubMed] [Google Scholar]
- 13. Brüstle, O , McKay, RDG (1996) Neuronal progenitors as tools for cell replacement in the nervous system. Curr Opinion Neurobiol 6: 688–695. [DOI] [PubMed] [Google Scholar]
- 14. Brüstle, O , Spiro, CA , Karram, K , Choudhary, K , Okabe, S , McKay, RDG (1997) In vitro‐generated neural precursors participate in mammalian brain development. Proc Natl Acad Sci USA 94: 14809–14814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Buc‐Caron, MH (1995) Neuroepithelial progenitor cells explanted from human fetal brain proliferate and differentiate in vitro. Neurobiol Dis 2: 37–47. [DOI] [PubMed] [Google Scholar]
- 16. Cajal, SR (1995) Histology of the nervous system of man and vertebrates [First English translation], Oxford University Press: New York . [Google Scholar]
- 17. Campbell, K , Olsson, M , Björklund, A (1995) Regional incorporation and site‐specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 15: 1259–1273. [DOI] [PubMed] [Google Scholar]
- 18. Campbell, KHS , McWhir, J , Ritchie, WA , Wilmut, I (1996) Sheep cloned by nuclear transfer from a cultured cell line. Nature 380: 64–66. [DOI] [PubMed] [Google Scholar]
- 19. Cattaneo, E , McKay, RDG (1990) Proliferation and differentiation of neuronal stem cells regulated by nerve growth factor. Nature 347: 762–765. [DOI] [PubMed] [Google Scholar]
- 20. Cepko, C (1988) Immortalization of neural cells via oncogene transduction. Trends Neurosci 11: 6–8. [DOI] [PubMed] [Google Scholar]
- 21. Cohen‐Tannoudji, M , Babinet, C , Wassef, M (1994) Early determination of a mouse somatosensory marker. Nature 368: 460–463. [DOI] [PubMed] [Google Scholar]
- 22. Damjanov, I (1993) Teratocarcinoma: neoplastic lessons about normal embryogenesis. Int J Dev Biol 37: 39–46. [PubMed] [Google Scholar]
- 23. Davies, SJ , Fitch, MT , Memberg, SP , Hall, AK , Raisman, G , Silver, J (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390: 680–683. [DOI] [PubMed] [Google Scholar]
- 24. Davies, SJA , Field, PM , Raisman, G (1994) Long inter‐fascicular axon growth from embryonic neurons transplanted into adult myelinated tracts. J Neurosci 14: 1596–1612. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Davis, AA , Temple, S (1994) A self‐renewing multipotential stem cell in embryonic rat cerebral cortex. Nature 372: 263–266. [DOI] [PubMed] [Google Scholar]
- 26. Deacon, T , Dinsmore, J , Costantini, LC , Ratliff, J , Isacson, O (1998) Blastula‐stage stem cells can differentiate into dopaminergic and serotonergic neurons after transplantation. Exp Neurol 149: 28–41. 9454612 [Google Scholar]
- 27. Dinsmore, J , Ratliff, J , Deacon, T , Pakzaban, P , Jacoby, D , Galpern, W , Isacson, O (1996) Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation. Cell Transplant 5: 131–143. [DOI] [PubMed] [Google Scholar]
- 28. Doetschman, T , Williams, P , Maeda, N (1988) Establishment of hamster blastocyst‐derived embryonic stem (ES) cells. Dev Biol 127: 224–227. [DOI] [PubMed] [Google Scholar]
- 29. Duncan, ID (1995) Inherited disorders of myelination of the central nervous system In: Neuroglial Cells, Ransom, BR , Kettenmann, HR (eds.), Oxford University Press: New York . [Google Scholar]
- 30. Duncan, ID , Grever, WE , Zhang, SC (1997) Repair of myelin disease: strategies and progress in animal models. Mol Med Today 3: 554–561. [DOI] [PubMed] [Google Scholar]
- 31. Ericson, J , Muhr, J , Placzek, M , Lints, T , Jessell, TM , Edlund, T (1995) Sonic hedgehog induces the differentiation of ventral forebrain neurons: a common signal for ventral patterning within the neural tube. Cell 81: 747–756. [DOI] [PubMed] [Google Scholar]
- 32. Eriksson, PS , Perfilieva, E , Bjork‐Eriksson, T , Alborn, AM , Nordborg, C , Peterson, DA , Gage, FH (1998) Neurogenesis in the adult human hippocampus. Nat Med 4: 1313–1317. [DOI] [PubMed] [Google Scholar]
- 33. Evans, MJ , Kaufman, MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292: 154–156. [DOI] [PubMed] [Google Scholar]
- 34. Finley, MFA , Kulkarni, N , Huettner, JE (1996) Synapse formation and establishment of neuronal polarity by P19 embryonic carcinoma cells and embryonic stem cells. J Neurosci 16: 1056–1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. First, NL , Sims, MM , Park, SP , Kent‐First, MJ (1994) Systems for production of calves from cultured bovine embryonic cells. Reprod Fertil Dev 6: 553–562. [DOI] [PubMed] [Google Scholar]
- 36. Fishell, G (1995) Striatal precursors adopt cortical identities in response to local cues. Development 121: 803–812. [DOI] [PubMed] [Google Scholar]
- 37. Flax, JD , Aurora, S , Yang, C , Simonin, C , Wills, AM , Billinghurst, LL , Jendoubi, M , Sidman, RL , Wolfe, JH , Kim, SU , Snyder, EY (1998) Engraftable human neural stem cells respond to development cues, replace neurons, and express foreign genes. Nature Biotechnol 16: 1033–1039. [DOI] [PubMed] [Google Scholar]
- 38. Fraichard, A , Chassande, O , Bilbaut, G , Dehay, C , Savatier, P , Samarut, J (1995) In vitro differentiation of embryonic stem cells into glial cells and functional neurons. J Cell Sci 108: 3181–3188. [DOI] [PubMed] [Google Scholar]
- 39. Franklin, RJM , Blakemore, WF (1997) Transplanting oligodendrocyte progenitors into the adult CNS. J Anat 190: 23–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Frederiksen, K , Jat, JS , Valtz, N , Levy, D , McKay, RDG (1988) Immortalization of precursor cells from the mammalian CNS. Neuron 1: 439–448. [DOI] [PubMed] [Google Scholar]
- 41. Frederiksen, K , McKay, RDG (1988) Proliferation and differentiation of rat neuroepithelial precursor cells in vivo. J Neurosci 8: 1144–1151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Friedrich, G , Soriano, P (1991) Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes & Dev 5: 1513–1523. [DOI] [PubMed] [Google Scholar]
- 43. Frisén, J , Johansson, CB , Török, C , Risling, M , Lendahl, U (1995) Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury. J Cell Biol 131: 453–464. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44. Gage, FH , Coates, PW , Palmer, TD , Kuhn, TD , Fisher, LJ , Suhonen, JO , Peterson, DA , Suhr, ST , Ray, J (1995) Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci USA 92: 11879–11883. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Gosh, A , Greenberg, ME (1995) Distinct roles for bFGF and NT‐3 in the regulation of cortical neurogenesis. Neuron 15: 89–103. [DOI] [PubMed] [Google Scholar]
- 46. Gritti, A , Parati, EA , Cova, L , Frolichsthal, P , Galli, R , Wanke, E , Faravelli, L , Morassutti, DJ , Roisen, F , Nickel, DD , Vescovi, AL (1996) Multipotential stem cells from the adult mouse brain proliferate and self‐renew in response to basic fibroblast growth factor. J Neurosci 16: 1091–1100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Groves, AK , Barnett, SC , Franklin, RJM , Crang, AJ , Mayer, M , Blakemore, WF , Noble, M (1993) Repair of demyelinated lesions by transplantation of purified O‐2A progenitor cells. Nature 362: 453–455. [DOI] [PubMed] [Google Scholar]
- 48. Hockfield, S , McKay, RDG (1985) Identification of major cell classes in the developing mammalian nervous system. J Neurosci 5: 3310–3328. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Hodes, ME , Pratt, VM , Dlouhy, SR (1993) Genetics of Pelizaeus‐Merzbacher disease. Dev Neurosci 15: 383–394. [DOI] [PubMed] [Google Scholar]
- 50. Holmin, S , Almqvist, P , Lendahl, U , Mathiesen, T (1997) Adult nestin‐expressing subependymal cells differentiate to astrocytes in response to brain injury. Eur J Neurosci 9: 65–75. [DOI] [PubMed] [Google Scholar]
- 51. Hörz, W , Altenburger, W (1981) Nucleotide sequence of mouse satellite DNA. Nucl Acids Res 9: 683–696. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 52. Hu, H , Tomasiewicz, H , Magnuson, T , Rutishauser, U (1996) The role of polysialic acid in migration of olfactory bulb interneuron precursors in the subventricular zone. Neuron 16: 735–743. [DOI] [PubMed] [Google Scholar]
- 53. Hynes, M , Porter, JA , Chiang, C , Chang, D , Tessier‐Lavigne, M , Beachy, PA , Rosenthal, A (1995) Induction of midbrain dopaminergic neurons by Sonic hedgehog. Neuron 15: 35–44. [DOI] [PubMed] [Google Scholar]
- 54. Isacson, O , Deacon, T (1997) Neural transplantation studies reveal the brain's capacity for continuous reconstruction. Trends Neurosci 20: 477–482. [DOI] [PubMed] [Google Scholar]
- 55. Isacson, O , Deacon, TW (1996) Specific axon guidance factors persist in the adult brain as demonstrated by pig neuroblasts transplanted to the rat. Neuroscience 75: 827–837. [DOI] [PubMed] [Google Scholar]
- 56. Isacson, O , Deacon, TW , Pakzaban, P , Galpern, WR , Dinsmore, J , Burns, LH (1995) Transplanted xenogeneic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibers. Nature Med 1: 1189–1194. [DOI] [PubMed] [Google Scholar]
- 57. Jat, PS , Sharp, PA (1989) Cell lines established by a temperature‐sensitive simian virus 40 large‐T‐antigen gene are growth restricted at the nonpermissive temperature. Mol Cell Biol 9: 1672–1681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Johe, KK , Hazel, TG , Müller, T , Dugich‐Djordjevic, MM , McKay, RDG (1996) Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes & Dev 10: 3129–3140. [DOI] [PubMed] [Google Scholar]
- 59. Kilpatrick, TJ , Bartlett, PF (1993) Cloning and growth of multipotential neural precursors: requirements for proliferation and differentiation. Neuron 10: 255–265. [DOI] [PubMed] [Google Scholar]
- 60. Kordower, JH , Freeman, TB , Snow, BJ , Vingerhoets, FJ , Mufson, EJ , Sanberg, PR , Hauser, RA , Smith, DA , Nauert, GM , Perl, DP , Olanow, CW (1995) Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N Engl J Med 332: 1118–1124. [DOI] [PubMed] [Google Scholar]
- 61. Lachapelle, F (1995) Glial transplants: an in vivo analysis of extrinsic and intrinsic determinants of dysmyelination in genetic variants. Brain Pathol 5: 289–299. [DOI] [PubMed] [Google Scholar]
- 62. Lachapelle, F , Duhamel‐Clerin, E , Gansmüller, A , Baron‐Van Evercooren, A , Villarroya, H , Gumpel, M (1994) Transplanted transgenically marked oligodendrocytes survive, migrate and myelinate in the normal mouse brain as they do in the shiverer mouse brain. Eur J Neurosci 6: 814–824. [DOI] [PubMed] [Google Scholar]
- 63. Lacorazza, HD , Flax, JD , Snyder, EY , Jendoubi, M (1996) Expression of human beta‐hexosaminidase alpha‐subunit gene (the gene defect of Tay‐Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat Med 2: 424–429. [DOI] [PubMed] [Google Scholar]
- 64. Lagenaur, C , Schachner, M (1981) Monoclonal antibody (M2) to glial and neuronal cell surfaces. J Supramol Struct Cell Biochem 15: 335–346. [DOI] [PubMed] [Google Scholar]
- 65. Lee, JJ , von Kessler, DP , Parks, S , Beachy, PA (1992) Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. Cell 71: 33–50. [DOI] [PubMed] [Google Scholar]
- 66. Lendahl, U , McKay, RDG (1990) The use of cell lines in neurobiology. Trends Neurosci 13: 132–137. [DOI] [PubMed] [Google Scholar]
- 67. Lendahl, U , Zimmermann, LB , McKay, RDG (1990) CNS stem cells express a new class of intermediate filament protein. Cell 60: 585–595. [DOI] [PubMed] [Google Scholar]
- 68. Levitt, P (1984) A monoclonal antibody to limbic system neurons. Science 223: 299–301. [DOI] [PubMed] [Google Scholar]
- 69. Levitt, P , Ferri, RT , Barbe, MF (1993) Progressive acquisition of cortical phenotypes as a mechanism for specifying the developing cerebral cortex. Perspect Dev Neurobiol 1: 65–74. [PubMed] [Google Scholar]
- 70. Li, M , Pevny, L , Lovell‐Badge, R , Smith, A (1998) Generation of purified neural precursors from embryonic stem cells by lineage selection. Curr Biol 8: 971–974. [DOI] [PubMed] [Google Scholar]
- 71. Lim, DA , Fishell, GJ , Alvarez‐Buylla, A (1997) Postnatal mouse subventricular zone neuronal precursors can migrate and differentiate within multiple levels of the developing neuraxis. Proc Natl Acad Sci USA 94: 14832–14836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 72. Lin, RCS , Matesic, DF , Marvin, M , McKay, RDG , Brüstle, O (1995) Reexpression of the intermediate filament nestin in reactive astrocytes. Neurobiol Disease 2: 79–85. [DOI] [PubMed] [Google Scholar]
- 73. Lois, C , García‐Verdugo, JM , Alvarez‐Buylla, A (1996) Chain migration of neuronal precursors. Science 271: 978–981. [DOI] [PubMed] [Google Scholar]
- 74. Ludlow, JW (1993) Interactions between SV40 large‐tumor antigen and the growth suppressor proteins pRB and p53. FASEBJ 7: 866–871. [DOI] [PubMed] [Google Scholar]
- 75. Lumsden, A , Krumlauf, R (1996) Patterning the vertebrate neuraxis. Science 214: 1109–1015. [DOI] [PubMed] [Google Scholar]
- 76. Lundberg, C , Winkler, C , Whittemore, SR , Björklund, A (1996) Conditionally immortalized neural progenitor cells grafted to the striatum exhibit site‐specific neuronal differentiation and establish connections with the host globus pallidus. Neurobiol Dis 3: 33–50. [DOI] [PubMed] [Google Scholar]
- 77. Macklis, JD (1993) Transplanted neocortical neurons migrate selectively into regions of neuronal degeneration produced by chromophore‐targeted laser photolysis. J Neurosci 13: 3848–3863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Magrassi, L , Ehrlich, ME , Butti, G , Pezzotta, S , Govoni, S , Cattaneo, E (1998) Basal ganglia precursors found in aggregates following embryonic transplantation adopt a striatal phenotype in heterotopic locations. Development 125: 2847–2855. [DOI] [PubMed] [Google Scholar]
- 79. Martin, GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78: 7634–7638. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Martinez, S , Wassef, M , Alvarado‐Mallart, RM (1991) Induction of a mesencephalic phenotype in the 2‐day‐old chick prosencephalon is preceded by the early expression of the homeobox gene en. Neuron 6: 971–981. [DOI] [PubMed] [Google Scholar]
- 81. Martínez‐Serrano, A , Björklund, A (1996) Protection of the neostriatum against excitotoxic damage by neurotrophin‐producing, genetically modified neural stem cells. J Neurosci 16: 4604–4616. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Martínez‐Serrano, A , Fischer, W , 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. [DOI] [PubMed] [Google Scholar]
- 83. Martínez‐Serrano, A , Hantzopoulos, PA , Björklund, A (1996) Ex vivo gene transfer of brain‐derived neurotrophic factor to the intact rat forebrain: neurotrophic effects on cholinergic neurons. Eur J Neurosci 8: 727–735. [DOI] [PubMed] [Google Scholar]
- 84. Martínez‐Serrano, A , Lundberg, C , Horellou, P , Fischer, W , Bentlage, C , Campbell, K , McKay, RDG , Mallet, J , Björklund, A (1995) CNS‐derived neural progenitor cells for gene transfer of nerve growth factor to the adult rat brain: Complete rescue of axotomized cholinergic neurons after transplantation into the septum. J Neurosci 15: 5668–5680. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Martínez‐Serrano, A , Olsson, M , Gates, MA , Bjorklund, A (1998) In utero gene transfer reveals survival effects of nerve growth factor on rat brain cholinergic neurones during development. Eur J Neurosci 10: 263–271. [DOI] [PubMed] [Google Scholar]
- 86. Mayer, E , Fawcett, JW , Dunnett, SB (1993) Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons‐II. Effects on nigral transplants in vivo. Neuroscience 56: 389–398. [DOI] [PubMed] [Google Scholar]
- 87. McConnell, SK (1988) Fates of visual cortical neurons in the ferret after isochronic and heterochronic transplantation. J Neurosci 8: 945–974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88. McKay, RDG (1997) Stem cells in the central nervous system. Science 276: 66–71. [DOI] [PubMed] [Google Scholar]
- 89. Miyazono, M , Lee, VMY , Trojanowski, JQ (1995) Proliferation, cell death, and neuronal differentiation in transplanted human embryonal carcinoma (NTera2) cells depend on the graft site in nude and severe combined immunodeficient mice. Lab Invest 73: 273–283. [PubMed] [Google Scholar]
- 90. Murray, K , Dubois‐Dalcq, M (1997) Emergence of oligodendrocytes from human neural spheres. J Neurosci Res 50: 146–156. [DOI] [PubMed] [Google Scholar]
- 91. Na, E , McCarthy, M , Neyt, C , Lai, E , Fishell, G (1998) Telencephalic progenitors maintain anteroposterior identities cell autonomously. Curr Biol 8: 987–990. [DOI] [PubMed] [Google Scholar]
- 92. Nakagawa, Y , Kaneko, T , Ogura, T , Suzuki, T , Torii, M , Kaibuchi, K , Arai, K , Nakamura, S , Nakafuku, M (1996) Roles of cell‐autonomous mechanisms for differential expression of region‐specific transcription factors in neuroepithelial cells. Development 122: 2449–2464. [DOI] [PubMed] [Google Scholar]
- 93. Nakao, N , Frodl, EM , Duan, WM , Widner, H , Brundin, P (1994) Lazaroids improve the survival of grafted rat embryonic dopamine neurons. Proc Natl Acad Sci USA 91: 12408–12412. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 94. Nakao, N , Frodl, EM , Widner, H , Carlson, E , Eggerding, FA , Epstein, CJ , Brundin, P (1995) Overexpressing Cu/Zn superoxide dismutase enhances survival of transplanted neurons in a rat model of Parkinson's disease. Nat Med 1: 226–231. [DOI] [PubMed] [Google Scholar]
- 95. Nusslein‐Volhard, C , Wieschaus, E (1980) Mutations affecting segment number and polarity in Drosophila. Nature 287: 795–801. [DOI] [PubMed] [Google Scholar]
- 96. O'Rourke, NA , Dailey, ME , Smith, SJ , McConnell, SK (1992) Diverse migratory pathways in the developing cerebral cortex. Science 258: 299–302. [DOI] [PubMed] [Google Scholar]
- 97. Okabe, S , Forsberg‐Nilsson, K , Spiro, AC , Segal, M , McKay, RDG (1996) Development of neuronal precursor cells and functional postmitotic neurons from embryonic stem cells in vitro. Mech Dev 59: 89–102. [DOI] [PubMed] [Google Scholar]
- 98. Olsson, M , Bjerregaard, K , Winkler, C , Gates, M , Björklund, A , Campbell, K (1998) Incorporation of mouse neural progenitors transplanted into the rat embryonic forebrain is developmentally regulated and dependent on regional and adhesive properties. Eur J Neurosci 10: 71–85. [DOI] [PubMed] [Google Scholar]
- 99. Olsson, M , Campbell, K , Turnbull, DH (1997) Specification of mouse telencephalic and mid‐hindbrain progenitors following heterotopic ultrasound‐guided embryonic transplantation. Neuron 19: 761–772. [DOI] [PubMed] [Google Scholar]
- 100. Ono, K , Yasui, Y , Rutishauser, U , Miller, RH (1997) Focal ventricular origin and migration of oligodendrocyte precursors into the chick optic nerve. Neuron 19: 283–292. [DOI] [PubMed] [Google Scholar]
- 101. Pain, B , Clark, ME , Shen, M , Nakazawa, H , Sakurai, M , Samarut, M , Etches, RJ (1996) Long‐term in vitro culture and characterisation of avian embryonic stem cells with multiple morphogenetic potentialities. Development 122: 2339–2348. [DOI] [PubMed] [Google Scholar]
- 102. Rakic, P (1988) Specification of cerebral cortical areas. Science 241: 170–176. [DOI] [PubMed] [Google Scholar]
- 103. Ray, J , Gage, FH (1994) Spinal cord neuroblasts proliferate in response to basic fibroblast growth factor. J Neurosci 14: 3548–3564. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104. Ray, J , Peterson, DA , Schinstine, M , Gage, FH (1993) Proliferation, differentiation, and long‐term culture of primary hippocampal neurons. Proc Natl Acad Sci USA 90: 3602–3606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105. Renfranz, PJ , Cunningham, MG , McKay, RDG (1991) Region‐specific differentiation of the hippocampal stem cell line HiB5 upon implantation into the developing mammalian brain. Cell 66: 713–729. [DOI] [PubMed] [Google Scholar]
- 106. Reynolds, BA , Tetzlaff, W , Weiss, S (1992) A multipotent EGF‐responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 12: 4565–4574. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107. Reynolds, BA , Weiss, S (1992) Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 255: 1707–1710. [DOI] [PubMed] [Google Scholar]
- 108. Richards, LJ , Kilpatrick, TJ , Bartlett, PF (1992) De novo generation of neuronal cells from the adult mouse brain. Proc Natl Acad Sci USA 89: 8591–8595. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109. Roelink, H , Augsburger, A , Heemskerk, J , Korzh, V , Norlin, S , Rui Zi Altaba, A , Tanabe, Y , Placzek, M , Edlund, T , Jessell, TM , Dodd, J (1994) Floor plate and motor neuron induction by vhh‐1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76: 761–775. [DOI] [PubMed] [Google Scholar]
- 110. Rosenblad, C , Martinez‐Serrano, A , Bjorklund, A (1996) Glial cell line‐derived neurotrophic factor increases survival, growth and function of intrastriatal fetal nigral dopaminergic grafts. Neuroscience 75: 979–985. [DOI] [PubMed] [Google Scholar]
- 111. Rosenblad, C , Martinez‐Serrano, A , Bjorklund, A (1998) Intrastriatal glial cell line‐derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson's disease. Neuroscience 82: 129–137. [DOI] [PubMed] [Google Scholar]
- 112. Sabaté, O , Horellou, P , Vigne, E , Colin, P , Perricaudet, M , Buc‐Caron, MH , Mallet, J (1995) Transplantation to the rat brain of human neural progenitors that were genetically modified using adenoviruses. Nature Genet 9: 256–260. [DOI] [PubMed] [Google Scholar]
- 113. Schierle, GS , Hansson, O , Leist, M , Nicotera, P , Widner, H , Brundin, P (1999) Caspase inhibition reduces apoptosis and increases survival of nigral transplants. Nat Med 5: 97–100. [DOI] [PubMed] [Google Scholar]
- 114. Schnell, L , Schneider, R , Kolbeck, R , Barde, YA , Schwab, ME (1994) Neurotrophin‐3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367: 170–173. [DOI] [PubMed] [Google Scholar]
- 115. Shamblott, MJ , Axelman, J , Wang, S , Bugg, EM , Littlefield, JW , Donovan, PJ , Blumenthal, PD , Huggins, GR , Gearhart, JD (1998) Derivation of pluripotent stem cells from cultured human primordial germ cells. Proc Natl Acad Sci USA 95: 13726–13731. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 116. Sheen, VL , Macklis, JD (1995) Targeted neocortical cell death in adult mice guides migration and differentiation of transplanted embryonic neurons. J Neurosci 15: 8378–8392. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 117. Shihabuddin, LS , Hertz, JA , Holets, VR , Whittemore, SR (1995) The adult CNS retains the potential to direct region‐specific differentiation of a transplanted neuronal precursor cell line. J Neurosci 15: 6666–6678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118. Sinclair, SR , Svendsen, CN , Torres, EM , Martin, D , Fawcett, JW , Dunnett, SB (1996) GDNF enhances dopaminergic cell survival and fibre outgrowth in embryonic nigral grafts. Neuroreport 7: 2547–2552. [DOI] [PubMed] [Google Scholar]
- 119. Smith, A (1998) Cell therapy: in search of pluripotency. Curr Biol 8: R802–R804. [DOI] [PubMed] [Google Scholar]
- 120. Smith, AG , Heath, JK , Donaldson, DD , Wong, GG , Moreau, J , Stahl, M , Rogers, D (1988) Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336: 688–690. [DOI] [PubMed] [Google Scholar]
- 121. Snyder, EY , Deitcher, DL , Walsh, C , Arnold‐Aldea, S , Hartwieg, EA , Cepko, CL (1992) Multipotent neural cell lines can engraft and participate in development of mouse cerebellum. Cell 68: 33–51. [DOI] [PubMed] [Google Scholar]
- 122. Snyder, EY , Senut, MC (1997) The use of nonneuronal cells for gene delivery. Neurobiol Dis 4: 69–102. [DOI] [PubMed] [Google Scholar]
- 123. Snyder, EY , Taylor, RM , Wolfe, JH (1995) Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374: 367–370. [DOI] [PubMed] [Google Scholar]
- 124. Snyder, EY , Yoon, C , Flax, JD , Macklis, JD (1997) Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc Natl Acad Sci USA 94: 11663–11668. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125. Strübing, C , Ahnert‐Hilger, G , Shan, J , Wiedenmann, B , Hescheler, J , Wobus, AM (1995) Differentiation of pluripotent embryonic stem cells into the neuronal lineage in vitro gives rise to mature inhibitory and excitatory neurons. Mech Dev 53: 275–287. [DOI] [PubMed] [Google Scholar]
- 126. Studer, L , Tabar, V , McKay, RDG (1998) Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nature Neurosci 1: 290–295. [DOI] [PubMed] [Google Scholar]
- 127. Suhonen, JO , Peterson, DA , Ray, J , Gage, FH (1996) Differentiation of adult hippocampus‐derived progenitors into olfactory neurons in vivo. Nature 383: 624–627. [DOI] [PubMed] [Google Scholar]
- 128. Sun, L , Bradford, CS , Ghosh, C , Collodi, P , Barnes, DW (1995) ES‐like cell cultures derived from early zebrafish embryos. Mol Mar Biol Biotechnol 4: 193–199. [PubMed] [Google Scholar]
- 129. Svendsen, CN , Caldwell, MA , Shen, J , ter Borg, MG , Rosser, AE , Tyers, P , Karmiol, S , Dunnett, SB (1997) Long‐term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp Neurol 148: 135–146. [DOI] [PubMed] [Google Scholar]
- 130. Takayama, H , Ray, J , Raymon, HK , Baird, A , Hogg, J , Fisher, LJ , Gage, FH (1995) Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson's disease. Nature Med 1: 53–58. [DOI] [PubMed] [Google Scholar]
- 131. Tan, SS , Breen, S (1993) Radial mosaicism and tangential cell dispersion both contribute to mouse neocortical development. Nature 362: 638–640. [DOI] [PubMed] [Google Scholar]
- 132. Temple, S (1989) Division and differentiation of isolated CNS blast cells in microculture. Nature 340: 471–473. [DOI] [PubMed] [Google Scholar]
- 133. Thallmair, M , Metz, GAS , Z'Graggen, WJ , Raineteau, O , Kartje, GL , Schwab, ME (1998) Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nat Med 1: 124–131. [DOI] [PubMed] [Google Scholar]
- 134. Thomson, JA , Itskovitz‐Eldor, J , Shapiro, SS , Waknitz, MA , Swiergiel, JJ , Marshall, VS , Jones, JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282: 1145–1147. [DOI] [PubMed] [Google Scholar]
- 135. Thomson, JA , Kalishman, J , Golos, TG , Durning, M , Harris, CP , Becker, RA , Hearn, JP (1995) Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 92: 7844–7848. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 136. Tontsch, U , Archer, DR , Dubois‐Dalcq, M , Duncan, ID (1994) Transplantation of an oligodendrocyte cell line leading to extensive myelination. Proc Natl Acad Sci USA 91: 11616–11620. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 137. Vicario‐Abejón, C , Cunningham, MG , McKay, RDG (1995) Cerebellar precursors transplanted to the neonatal dentate gyrus express features characteristic of hippocampal neurons. J Neurosci 15: 6351–6363. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 138. Vicario‐Abejón, C , Johe, KK , Hazel, TG , Collazo, D , McKay, RDG (1995) Functions of basic fibroblast growth factor and neurotrophins in the differentiation of hippocampal neurons. Neuron 15: 105–114. [DOI] [PubMed] [Google Scholar]
- 139. Wakayama, T , Perry, AC , Zuccotti, M , Johnson, KR , Yanagimachi, R (1998) Full‐term development of mice from enucleated oocytes injected with cumulus cell nuclei. Nature 394: 369–374. [DOI] [PubMed] [Google Scholar]
- 140. Walsh, C , Cepko, CL (1992) Widespread dispersion of neuronal clones across functional regions of the cerebral cortex. Science 255: 434–440. [DOI] [PubMed] [Google Scholar]
- 141. Warrington, AE , Barbarese, E , Pfeiffer, SE (1993) Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J Neurosci Res 34: 1–13. [DOI] [PubMed] [Google Scholar]
- 142. Weiss, S , Dunne, C , Hewson, J , Wohl, C , Wheatley, M , Peterson, AC , Reynolds, BA (1996) Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuraxis. J Neurosci 16: 7599–7609. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 143. Weiss, S , Reynolds, BA , Vescovi, AL , Morshead, C , Craig, CG , van der Kooy, D (1996) Is there a neural stem cell in the mammalian forebrain Trends Neurosci 19: 387–393. [DOI] [PubMed] [Google Scholar]
- 144. Westerman, KA , Leboulch, P (1996) Reversible immortalization of mammalian cells mediated by retroviral transfer and site‐specific recombination. Proc Natl Acad Sci USA 93: 8971–8976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 145. Wheeler, MB (1994) Development and validation of swine embryonic stem cells: a review. Reprod Fertil Dev 6: 563–568. [DOI] [PubMed] [Google Scholar]
- 146. Wictorin, K , Brundin, P , Gustavii, B , Lindvall, O , Björklund, A (1990) Reformation of long axon pathways in adult rat central nervous system by human forebrain neuroblasts. Nature 347: 556–558. [DOI] [PubMed] [Google Scholar]
- 147. Wictorin, K , Brundin, P , Sauer, H , Lindvall, O , Björklund, A (1992) Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6‐hydroxydopamine lesioned adult rats. J Comp Neurol 323: 475–494. [DOI] [PubMed] [Google Scholar]
- 148. Wilmut, I , Schnieke, AE , McWhir, J , Kind, AJ , Campbell, KHS (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385: 810–813. [DOI] [PubMed] [Google Scholar]
- 149. Ye, W , Shimamura, K , Rubenstein, JL , Hynes, MA , Rosenthal, A (1998) FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93: 755–766. [DOI] [PubMed] [Google Scholar]
- 150. Yurek, DM , Lu, W , Hipkens, S , Wiegand, SJ (1996) BDNF enhances the functional reinnervation of the striatum by grafted fetal dopamine neurons. Exp Neurol 137: 105–118. [DOI] [PubMed] [Google Scholar]
- 151. Zhou, HF , Lee, LHC , Lund, RD (1990) Timing and patterns of astrocyte migration from xenogeneic transplants of the cortex and corpus callosum. J Comp Neurol 292: 320–330. [DOI] [PubMed] [Google Scholar]
- 152. Zimmer, A (1992) Manipulating the genome by homologous recombination in embryonic stem cells. Ann Rev Neurosci 15: 115–137. [DOI] [PubMed] [Google Scholar]
