Delivery of Nerve Growth Factor Within the Rat Brain Using Genetically Modified Cells

  • M. D. Kawaja
  • F. H. Gage
Conference paper
Part of the Research and Perspectives in Neurosciences book series (NEUROSCIENCE)


enetic modification of primary skin fibroblasts followed by grafting is a new approach to deliver nerve growth factor within the adult central nervous system. Intracerebral grafts of nerve growth factor-producing fibroblasts have been used to assess the regenerative capacities of select neuronal populations within the damaged adult rat brain. Our data reveal that this trophic factor is a necessary requirement to sustain neurons following axotomy. As importantly, nerve growth factor is needed to induce and promote the regeneration of lesioned axons. Regardless of the cellular or extracellular substrates used by these regrowing axons, the availability of nerve growth factor is a minimum requirement for successful regeneration of adult perturbed axons.


Nerve Growth Factor Cholinergic Neuron Basal Forebrain Medial Septum Nerve Growth Factor Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barde Y-A (1989) Trophic factors and neuronal survival. Neuron 2:1525–1534PubMedCrossRefGoogle Scholar
  2. Benfry M, Aguayo A (1982) Extensive elongation of axons from rat brain into peripheral nerve grafts. Nature 296:150–152CrossRefGoogle Scholar
  3. Caramia F, Angeletti PU, Levi-Montalcini R (1962) Experimental analysis of the mouse submaxillary salivary gland in relationship to its nerve growth factor content. Endocrinology 70:915–922PubMedCrossRefGoogle Scholar
  4. Cohen R, Levi-Montalcini R, Hamburger V (1954) A nerve growth-stimulating factor isolated from sarcomas 37 and 180. Proc Natl Acad Sci USA 40:1014–1018PubMedCrossRefGoogle Scholar
  5. Cunningham LA, Short MP, Vielkind U, Breakefield XO, Bohn MC (1991) Survival and differentiation within the adult mouse striatum of grafted rat pheochromocytoma (PC12) genetically modified to express recombinant β-NGF. Exp Neurol 112:174–182PubMedCrossRefGoogle Scholar
  6. David S, Aguayo A (1981) Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214:931–933PubMedCrossRefGoogle Scholar
  7. Ernfors P, Ebendal T, Olson L, Mouton P, Strömberg I, Persson A (1989) A cell line producing recombinant nerve growth factor evokes growth responses in intrinsic and grafted central cholinergic neurons. Proc Natl Acad Sci USA 86:4756–4760PubMedCrossRefGoogle Scholar
  8. Fischer W, Björklund A (1991) Loss of AChE-and NGFr-labelling precedes neuronal death of axotomized septal-diagonal band neurons: Reversal by intraventricular NGF infusion. Exp Neurol 113:93–108PubMedCrossRefGoogle Scholar
  9. Fischer W, Wictorin K, Björklund A, Williams LR, Varon S, Gage FH (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329:65–68PubMedCrossRefGoogle Scholar
  10. Gage FH, Wolff JA, Rosenberg MB, Xu L, Yee JL, Shults C, Friedmann T (1987) Grafting genetically modified cells to the brain: possibilities for the future. Neuroscience 23:795–807PubMedCrossRefGoogle Scholar
  11. Gage FH, Batchelor P, Chen KS, Chin D, Higgins GA, Koh S, Deputy S, Rosenberg MB, Fischer W, Björklund A (1989) NGF-receptor re-expression and NGF-mediated cholinergic neuronal hypertrophy in the damaged adult neostriatum. Neuron 2:1177–1184PubMedCrossRefGoogle Scholar
  12. Gage FH, Tuszynski MH, Chen KS, Fagan A, Higgins GA (1991) Nerve growth factor in the central nervous system. In: Bothwell M (ed) Trophic factors in the central nervous system. Springer-Verlag Berlin, pp 71–93Google Scholar
  13. Hagg T, Fass-Holmes B, Vahling HL, Manthorpe M, Conner JM, Varon S (1989) Nerve growth factor (NGF) reverses axotomy-induced decreases in choline acetyltransferase, NGF receptor and size of medial septum cholinergic neurons. Brain Res 505:29–38PubMedCrossRefGoogle Scholar
  14. Hagg T, Vahlsing HL, Manthorpe M, Varon S (1990) Septohippocampal cholinergic axonal regeneration through peripheral nerve bridges: Quantification and temporal development. Exp. Neurol 109:153–163PubMedCrossRefGoogle Scholar
  15. Hefti F (1986) Nerve growth factor promotes survival of septal cholinergic neurons after fimbrial transections. J Neurosci 8:21155–2162Google Scholar
  16. Hendry IA, Stöckel K, Thoenen H, Iversen LL (1974) The retrograde axonal transport for nerve growth factor. Brain Res 68:103–121PubMedCrossRefGoogle Scholar
  17. Higgins GA, Koh S, Chen KG, Gage FJ (1989) NGF induction of NGF receptor gene expression and cholinergic neuronal hypertrophy within the basal forebrain of the adult rat. Neuron 3:247–256PubMedCrossRefGoogle Scholar
  18. Hoffman D, Wahlberg L, Aebischer P (1990) NGF released from a polymer matrix prevents loss of ChAT expression in basal forebrain neurons following a fimbria-fornix lesion. Exp Neurol 110:39–44PubMedCrossRefGoogle Scholar
  19. Horellou P, Brundin P, Kalén P, Mallet J, Björklund A (1990) In vivo release of DOPA and dopamine from genetically engineered cells grafted to the denervated rat striatum. Neuron 5:393–402PubMedCrossRefGoogle Scholar
  20. Johnson EM, Andres RY, Bradshaw RA (1978) Characterization of the retrograde transport of nerve growth factor (NGF) using high specific activity [125]NGF. Brain Res 150:319–331PubMedCrossRefGoogle Scholar
  21. Kawaja MD, Gage FH (1992) Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J Comp Neurol 317:102–116PubMedCrossRefGoogle Scholar
  22. Kawaja MD, Gage FH (1991) Reactive astrocytes are substrates for the growth of adult CNS axons in the presence of elevated levels of nerve growth factor. Neuron 7:1019–1030PubMedCrossRefGoogle Scholar
  23. Kawaja MD, Fagan AM, Firestein BL, Gage FH (1991) Intracerebral grafting of cultured autologous skin fibroblasts into the rat striatum: An assessment of graft size and ultrastructure. J Comp Neurol 307:695–706PubMedCrossRefGoogle Scholar
  24. Kawaja MD, Rosenberg MB, Yoshida K, Gage FH (1992) Somatic gene transfer of nerve growth factor promotes the survival of axotomized septal neurons and the regeneration of their axons in adult rats. J Neurosci 12:2849–2864PubMedGoogle Scholar
  25. Koliatsos VE, Nauta HJW, Clatterbuck RE, Holtzmann DM, Mobley WC, Price DL (1990) Mouse nerve growth factor prevents degeneration of axotomized basal forebrain cholinergic neurons in the monkey. J Neurosci 10:3801–3813PubMedGoogle Scholar
  26. Kromer LF (1987) Nerve growth factor treatment after brain injury prevents neuronal dealth. Science 235:214–216PubMedCrossRefGoogle Scholar
  27. Levi-Montalcini R, Angeletti PU (1968) Nerve growth factor. Physiol Rev 8:534–569Google Scholar
  28. Levi-Montalcini R, Cohen S (1960) Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann NY Acad Sci 85:324–341PubMedGoogle Scholar
  29. Levi-Montalcini R, Meyer H, Hamburger V (1954) In vitro experiments on the effects of mouse sarcomas 180 and 37 on the spinal and sympathetic ganglia of the chick embryo. Cancer Res 14:49–57PubMedGoogle Scholar
  30. Menesini-Chen MG, Chen JS, Levi-Montalcini R (1978) Sympathetic nerve fiber ingrowth in the central nervous system of neonatal rodent upon intracerebral NGF injections. Arch Ital Biol 116:53–84PubMedGoogle Scholar
  31. Montero CN, Hefti F (1988) Rescue of lesioned septal cholinergic neurons by nerve growth factor: Specificity and requirement for chronic treatment. J Neurosci 8:2986–2999PubMedGoogle Scholar
  32. Paravicini U, Stoeckel K, Thoenen H (1975) Biological importance of retrograde axonal transport of nerve growth factor in adrenal neurons. Brain Res 84:279–291PubMedCrossRefGoogle Scholar
  33. Purves D (1976) Functional and structural changes in mammalian sympathetic neurons following colchicine application to post-ganglionic nerves. J Physiol (Lond) 259:159–175Google Scholar
  34. Richardson PM, Ebendal T (1982) Nerve growth activities in rat peripheral nerve. Brain Res 246:57–64PubMedCrossRefGoogle Scholar
  35. Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M, Wolff JA, Breakefield XO, Gage FH (1988) Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 242:1575–1578PubMedCrossRefGoogle Scholar
  36. Schwab ME, Otten U, Thoenen H (1979) Nerve growth factor (NGF) in the rat CNS: Absence of specific retrograde axonal transport and tyrosine hydroxylase induction in locus coeruleus and substantia nigra. Brain Res 168:473–483PubMedCrossRefGoogle Scholar
  37. Sciler M, Schwab ME (1984) Specific retrograde transport of nerve growth factor (NGF) from neocortex to nucleus basalis in the rat. Brain Res 300:33–3CrossRefGoogle Scholar
  38. Stöckel K, Schwab ME, Thoenen H (1975) Specificity of retrograde transport of nerve growth factor (NGF) in sensory neurons: A biochemical and morphological study. Brain Res 89:1–14CrossRefGoogle Scholar
  39. Strömberg I, Wetmore CJ, Ebendal T, Ernfors P, Persson H, Olson L (1990) Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. J Neursoci Res 25:405–411CrossRefGoogle Scholar
  40. Tello F (1911) La influencia del neurotropismo en la regeneracion de las centros nerviosos. Trab Lab Biol Univ Madr 9:123–159Google Scholar
  41. Thoenen H, Barde Y-A (1980) Physiology of nerve growth factor. Physiol Rev 60:1284–1334PubMedGoogle Scholar
  42. Tuszynski MH, Buzsaki G, Gage FH (1990 a) Nerve growth factor infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septohippocampal formation. Neursocience 36:33–44CrossRefGoogle Scholar
  43. Tuszynski MH, U HS, Amaral DG, Gage FH (1990b) Nerve growth factor infusion in primate brain reduces lesion-induced cholinergic neuronal degeneration. J Neursoci 10:3604–3614Google Scholar
  44. van Horne CG, Strömberg I, Young D, Olson L, Hoffer B (1991) Functional enhancement of intrastriatal dopamine-containing grafts by the co-transplantation of sciatic nerve tissue in 6-hydroxydopamine-lesioned rats. Exp Neurol 113:143–154PubMedCrossRefGoogle Scholar
  45. Williams LR, Varon S, Peterson GM, Wictorin K, Fischer W, Björklund A, Gage FH (1986) Continuous infusion of nerve growth factor prevents basal forebrain neuronal death after fimbria-fornix transection. Proc Natl Acad Sci USA 83:9231–9235PubMedCrossRefGoogle Scholar
  46. Wolf D, Richter-Landsberg C, Short MP, Cepko C, Breakefield XO (1988) Retrovirus-mediated gene transfer of β-nerve growth factor into mouse pituitary line AtT-20. Mol Biol Med 5:43–59PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1992

Authors and Affiliations

  • M. D. Kawaja
  • F. H. Gage

There are no affiliations available

Personalised recommendations