Skip to main content
Log in

Actions of neurotrophic factors and their signaling pathways in neuronal survival and axonal regeneration

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Adult axons in the mammalian central nervous system do not elicit spontaneous regeneration after injury, although many affected neurons have survived the neurotrauma. However, axonal regeneration does occur under certain conditions. These conditions include: (a) modification of regrowth environment, such as supply of peripheral nerve bridges and transplantation of Schwann cells or olfactory ensheathing glia to the injury site; (b) application of neurotrophic factors at the cell soma and axon tips; (c) blockade of growth-inhibitory molecules such as Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein; (d) prevention of chondroitin-sulfate-proteoglycans-related scar tissue formation at the injury site using chondroitinase ABC; and (e) elevation of intrinsic growth potential of injured neurons via increasing intra-cellular cyclic adenosine monophosphate level. A large body of evidence suggests that these conditions achieve enhanced neuronal survival and axonal regeneration through sometimes over-lapping and sometimes distinct signal transduction mechanisms, depending on the targeted neuronal populations and intervention circumstances. This article reviews the available information on signal transduction pathways underlying neurotrophic-factor-mediated neuronal survival and neurite outgrowth/axonal regeneration. Better understanding of signaling transduction is important in helping us develop practical therapeutic approaches for encouraging neuronal survival and axonal regeneration after traumatic injury in clinical context.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Jones L. L., Oudega M., Bunge M. B., and Tuszynski M. H. (2001) Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J. Physiol. 533, 83–89.

    PubMed  CAS  Google Scholar 

  2. Cheng L., Sapieha P., Kittlerova P., Hauswirth W. W., and Di Polo A. (2002) TrkB gene transfer protects retinal ganglion cells from axotomy-induced death in vivo. J. Neurosci. 22, 3977–3986.

    PubMed  CAS  Google Scholar 

  3. Schwab M. E. and Bartholdi D. (1996) Degeneration and regeneration of axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370.

    PubMed  CAS  Google Scholar 

  4. Carulli D., Laabs T., Geller H. M., and Fawcett J. W. (2005) Chondroitin sulfate proteoglycans in neural development and regeneration. Curr. Opin. Neurobiol. 15, 116–120.

    PubMed  Google Scholar 

  5. Mansour-Robaey S., Clarke D. B., Wang Y. C., Bray G. M., and Aguayo A. J. (1994) Effects of ocular injury and administration of BDNF on survival and regrowth of axotomized retinal ganglion cells. Proc. Natl. Acad. Sci. USA 91, 1632–1636.

    PubMed  CAS  Google Scholar 

  6. Peinado-Ramon P., Salvador M., Villegas-Perez M. P., and Vidal-Sanz M. (1996) Effects of axotomy and intraocular administration of NT-4, NT-3, and BDNF on the survival of adult rat retinal ganglion cells. A quantitative in vivo study. Invest. Ophthalmol. Vis. Sci. 37, 489–500.

    PubMed  CAS  Google Scholar 

  7. Boer G. J., Esseveldt K. E., Dijkhuizen P. A., et al. (2001) Adenoviral vector-mediated expression of NT-3 increases neuronal survival in suprachiasmatic nucleus grafts. Exp. Neurol. 169, 364–375.

    PubMed  CAS  Google Scholar 

  8. Blits B., Carlstedt T. P., Ruitenberg M. J., et al. (2004) Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal AAV-mediated expression of GDNF or BDNF. Exp. Neurol. 189, 303–316.

    PubMed  CAS  Google Scholar 

  9. Koeberle P. D., Gauldie J., and Ball A. K. (2004) Effects of adenoviral-mediated gene transfer of IL-10, IL-4, and TGF-β on the survival of axotomized retinal ganglion cells. Neuroscience 125, 903–920.

    PubMed  CAS  Google Scholar 

  10. Cui Q., Lu Q., So K. F., and Yip H. K. (1999) CNTF, not other trophic factors, promotes axonal regeneration of axotomized retinal ganglion cells in adult hamsters. Invest. Ophthalmol. Vis. Sci. 40, 760–766.

    PubMed  CAS  Google Scholar 

  11. Sawai H., Clarke D. B., Kittlerova P., Bray G. M., and Aguayo A. J. (1996) BDNF and NT-4/5 stimulate growth of axonal branches from regenerating retinal ganglion cells. J. Neurosci. 16, 3887–3894.

    PubMed  CAS  Google Scholar 

  12. Segal R. A. and Greenberg M. E. (1996) Intracellular signaling pathways activated by neurotrophic factors. Annu. Rev. Neurosci. 19, 463–489.

    PubMed  CAS  Google Scholar 

  13. Huang E. J. and Reichardt L. F. (2001) Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736.

    PubMed  CAS  Google Scholar 

  14. Bregman B. S., Broude E., McAtee M., and Kelley M. S. (1998) Transplants and neutrophic factors prevent atrophy of mature CNS neurons after spinal cord injury. Exp. Neurol. 149, 13–27.

    PubMed  CAS  Google Scholar 

  15. Jin Y., Fischer I., Tessler A., and Houle J. D. (2002) Transplants of fibroblasts genetically modified to express BDNF promote axonal regeneration from supraspinal neurons following chronic spinal cord injury. Exp. Neurol. 177, 265–275.

    PubMed  CAS  Google Scholar 

  16. Blits B., Oudega M., Boer G. J., Bunge M. B., and Verhaagen J. (2003) AAV-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function. Neuroscience 118, 271–281.

    PubMed  CAS  Google Scholar 

  17. Segal R. A. (2003) Selectivity in neurotrophin signaling: theme and variations. Annu. Rev. Neurosci. 26, 299–330.

    PubMed  CAS  Google Scholar 

  18. Shumsky J. S., Tobias C. A., Tumolo M., Long W. D., Giszter S. F., and Murray M. (2003) Delayed transplantation of fibroblasts genetically modified to secrete BDNF and NT-3 into a spinal cord injury site is associated with limited recovery of function. Exp. Neurol. 184, 114–130.

    PubMed  CAS  Google Scholar 

  19. Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., and Parada L. F. (1991) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252, 554–558.

    PubMed  CAS  Google Scholar 

  20. Kaplan D. R., Martin-Zanca D., and Parada L. F. (1991) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGP. Nature 350, 158–160.

    PubMed  CAS  Google Scholar 

  21. Klein R., Jing S. Q., Nanduri V., O'Rourke E., and Barbacid M. (1991) The trk proto-oncogene encodes a receptor for nerve growth factor. Cell 65, 189–197.

    PubMed  CAS  Google Scholar 

  22. Klein R., Nanduri V., Jing S. A., et al. (1991) The trkB tyrosine protein kinase is a receptor for BDNF and NT-3. Cell 66, 395–403.

    PubMed  CAS  Google Scholar 

  23. Klein R., Lamballe F., Bryant S., and Barbacid M. (1992) The trkB tyrosine protein kinase is a receptor for NT-4. Neuron 8, 947–956.

    PubMed  CAS  Google Scholar 

  24. Lamballe F., Klein R., and Barbacid M. (1991) trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for NT-3. Cell 66, 967–979.

    PubMed  CAS  Google Scholar 

  25. Dechant G. (2001) Molecular interactions between neurotrophin receptors. Cell Tissue Res. 305, 229–238.

    PubMed  CAS  Google Scholar 

  26. Yacoubian T. A. and Lo D. C. (2000) Truncated and full-length TrkB receptors regulate distinct modes of dendritic growth. Nat. Neurosci. 3, 342–349.

    PubMed  CAS  Google Scholar 

  27. Harrington A. W., Leiner B., Blechschimitt C., et al. (2004) Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury. Proc. Natl. Acad. Sci. USA 101, 6226–6230.

    PubMed  CAS  Google Scholar 

  28. Teng H. K., Teng K. K., Lee R., et al. (2005) ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J. Neurosci. 25, 5455–5463.

    PubMed  CAS  Google Scholar 

  29. Cui Q. and Harvey A. R. (1995) At least two mechanisms are involved in the death of retinal ganglion cells following target ablation in neonatal rats. J. Neurosci. 15, 8143–8155.

    PubMed  CAS  Google Scholar 

  30. Boyd J. G., and Gordon T. (2003) GDNF and BDNF sustain the axonal regeneration of chronically axotomized motoneurons in vivo. Exp. Neurol. 183, 610–619.

    PubMed  CAS  Google Scholar 

  31. Curtis R., Tonra J. R., Stark J. L., et al. (1998) Neuronal injury increases retrograde axonal transport of the neurotrophins to spinal sensory neurons and motor neurons via multiple receptor mechanisms. Mol. Cell. Neurosci. 12, 105–118.

    PubMed  CAS  Google Scholar 

  32. Spalding K. L., Cui Q., and Harvey A. R. (1998) The effects of central administration of neurotrophins or transplants of fetal tectal tissue on retinal ganglion cell survival following removal of the superior colliculus in neonatal rats. Brain Res. Dev. Brain Res. 107, 133–142.

    PubMed  CAS  Google Scholar 

  33. Reynolds A. J., Bartlett S. E., and Hendry I. A. (2000) Molecular mechanisms regulating the retrograde axonal transport of neurotrophins. Brain Res. Brain Res. Rev. 33, 169–178.

    PubMed  CAS  Google Scholar 

  34. von Bartheld C. S., Wang X., and Butowt R. (2001) Anterograde axonal transport, transcytosis, and recycling of neurotrophic factors: the concept of trophic currencies in neural networks. Mol. Neurobiol. 24, 1–28.

    Google Scholar 

  35. Hetman M., Kanning K., Cavanaugh J. E., and Xia Z. (1999) Neuroprotection by BDNF is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 22,569–22,580.

    CAS  Google Scholar 

  36. Atwal J. K., Massie B., Miller F. D., and Kaplan D. R. (2000) The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron 27, 265–277.

    PubMed  CAS  Google Scholar 

  37. Klocker N., Kermer P., Weishaupt J. H., Labes M., Ankerhold R., and Bähr M. (2000) BDNF-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on PI-3K/protein kinase B signaling. J. Neurosci. 20, 6962–6967.

    PubMed  CAS  Google Scholar 

  38. Brunet A., Datta S. R., and Greenberg M. E. (2001) Transcription-dependent and-independent control of neuronal survival by the PI-3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11, 297–305.

    PubMed  CAS  Google Scholar 

  39. Watson F. L., Heerssen H. M., Bhattacharyya A., Klesse L., Lin M. Z., and Segal R. A. (2001) Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat. Neurosci. 4, 981–988.

    PubMed  CAS  Google Scholar 

  40. Nakazawa T., Tamai M., and Mori N. (2002) BDNF prevents axotomized retinal ganglion cell death through MAPK and PI-3K signalling pathways. Invest. Ophthalmol. Vis. Sci. 43, 3319–3326.

    PubMed  Google Scholar 

  41. Gao Y., Nikulina E., Mellado W., and Filbin M. T. (2003) Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. J. Neurosci. 23, 11,770–11,777.

    CAS  Google Scholar 

  42. Shalizi A., Lehtinen M., Gaudilliere B., et al. (2003) Characterization of a neurotrophin signaling mechanism that mediates neuron survival in a temporally specific pattern. J. Neurosci. 23, 7326–7336.

    PubMed  CAS  Google Scholar 

  43. Datta S. R., Dudet H., Tao X., et al. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241.

    PubMed  CAS  Google Scholar 

  44. Cardone M. H., Roy N., Slennicke H. R., et al. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 318–321.

    Google Scholar 

  45. Hanson M. G. Jr., Shen S., Wiemelt A. P., McMorris F. A., and Barres B. A. (1998) Cyclic AMP elevation is sufficient to promote the survival of spinal motor neurons in vitro. J. Neurosci. 18, 7361–7371.

    PubMed  CAS  Google Scholar 

  46. Williams E. J., and Doherty P. (1999) Evidence for and against a pivotal role of PI 3-kinase in a neuronal cell survival pathway. Mol. Cell Neurosci. 13, 272–280.

    PubMed  CAS  Google Scholar 

  47. Perron J. C. and Bixby J. L. (1999) Distinct neurite outgrowth signaling pathways converge on ERK activation. Mol. Cell. Neurosci. 13, 362–378.

    PubMed  CAS  Google Scholar 

  48. Pearse D. D., Pereira F. C., Marcillo A. E., et al. (2004) cAMP and Schwann cells promote axon growth and functional recovery after spinal cord injury. Nat. Med. 10, 610–616.

    PubMed  CAS  Google Scholar 

  49. Purves D., Snider W. D., and Voyvodic J. T. (1988) Trophic regulation of nerve cell morphology and innervation in the autonomic nervous system. Nature 336, 123–128.

    PubMed  CAS  Google Scholar 

  50. Levi-Montalcini R. (1987) The nerve growth factor 35 years later. Science 237, 1154–1162

    PubMed  CAS  Google Scholar 

  51. Acheson A., Conover J. C., Fandl J. P., et al. (1995) A BDNF autocrine loop in adult sensory neurons prevents cell death. Nature 374, 450–453.

    PubMed  CAS  Google Scholar 

  52. Robinson M., Buj-Bello A., and Davies A. M. (1996) Paracrine interactions of BDNF involving NGF-dependent embryonic sensory neurons. Mol. Cell. Neurosci. 7, 143–151.

    PubMed  CAS  Google Scholar 

  53. Yin Y., Cui Q., Li Y., et al. (2003) Macrophage-derived factors stimulate optic nerve regeneration. J. Neurosci. 23, 2284–2293.

    PubMed  CAS  Google Scholar 

  54. Yao R. and Cooper G. M. (1995) Requirement for PI-3K in the prevention of apoptosis by nerve growth factor. Science 267, 2003–2006.

    PubMed  CAS  Google Scholar 

  55. Kaplan D. R. and Miller F. D. (2000) Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391.

    PubMed  CAS  Google Scholar 

  56. Jones D. M., Tucker B. A., Rahimtula M., and Mearow K. M. (2003) The synergistic effects of NGF and IGF-1 on neurite growth in adult sensory neurons: convergence on the PI 3-kinase signaling pathway. J. Neurochem. 86, 1116–1128.

    PubMed  CAS  Google Scholar 

  57. Goold R. G. and Gordon-Weeks P. R. (2005) The MAP kinase pathway is upstream of the activation of GSK3beta that enables it to phosphorylate MAP1B and contributes to the stimulation of axon growth. Mol. Cell. Neurosci. 28, 524–534

    PubMed  CAS  Google Scholar 

  58. Xing J., Ginty D. D., and Greenberg M. E. (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963.

    PubMed  CAS  Google Scholar 

  59. Vaillant A. R., Mazzoni I., Tudan C., Boudreau M., Kaplan D. R., and Miller F. D. (1999) Depolarization and neurotrophins converge on the PI-3K-Akt pathway to synergistically regulate neuronal survival. J. Cell Biol. 146, 955–966.

    PubMed  CAS  Google Scholar 

  60. Datta S. R., Brunet A., and Greenberg M. E. (1999) Cellular survival: a play in three Akts. Genes Dev. 13, 2905–2927.

    PubMed  CAS  Google Scholar 

  61. Grewal S. S., York R. D., and Stork P. J. (1999) Extracellular-signal-regulated kinase signalling in neurons. Curr. Opin. Neurobiol. 9, 544–553.

    PubMed  CAS  Google Scholar 

  62. Riccio A., Ahn S., Davenport C. M., Blendy J. A., and Ginty D. D. (1999) Mediation by a CREB family transcription factor of NGF-dependent survival of sympathetic neurons. Science 286, 2358–2361.

    PubMed  CAS  Google Scholar 

  63. Cenni M. C., Bonfanti L., Martinou J. C., Ratto G. M., Strettoi E., and Maffei L. (1996) Longterm survival of retinal ganglion cells following optic nerve section in adult bcl-2 transgenic mice. Eur. J. Neurosci. 8, 1735–1745.

    PubMed  CAS  Google Scholar 

  64. Merry D. E. and Korsmeyer S. J. (1997) Bcl-2 gene family in the nervous system. Annu. Rev. Neurosci. 20, 245–267.

    PubMed  CAS  Google Scholar 

  65. Qiu D., Mao L., Kikuchi S., and Tomita M. (2004) Sustained MAPK activation is dependent on continual NGF receptor regeneration. Dev. Growth Differ. 46, 393–403.

    PubMed  CAS  Google Scholar 

  66. Trivedi N., Marsh P., Goold R. G., Wood-Kaczmar A., and Gordon-Weeks P. R. (2005) Glycogen synthase kinase-3beta phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J. Cell Sci. 118, 993–1005.

    PubMed  CAS  Google Scholar 

  67. Bonni A., Brunet A., West A. E., Datta S. R., Takasu M. A., and Greenberg M. E. (1999) Cell survival promoted by the Ras-MAPK signalling pathway by transcription-dependent and-independent mechanism. Science 286, 1358–1362.

    PubMed  CAS  Google Scholar 

  68. Goldberg J. L. and Barres B. A. (2000) The relationship between neuronal survival and regeneration. Annu. Rev. Neurosci. 23, 579–612.

    PubMed  CAS  Google Scholar 

  69. Grill R. J., Blesch A., and Tuszynski M. H. (1997) Robust growth of chronically injured spinal cord axons induced by grafts of genetically modified NGF-secreting cells. Exp. Neurol. 148, 444–452.

    PubMed  CAS  Google Scholar 

  70. Bloch J., Fine E. G., Bouche N., Zurn A. D., and Aebischer P. (2001) NGF- and NT-3-releasing guidance channels promote regeneration of the transected rat dorsal root. Exp. Neurol. 172, 425–432.

    PubMed  CAS  Google Scholar 

  71. Romero M. I., Rangappa N., Garry M. G., and Smith G. M. (2001) Functional regeneration of chronically injured sensory afferents into adult spinal cord after neurotrophin gene therapy. J. Neurosci. 21, 8408–8416.

    PubMed  CAS  Google Scholar 

  72. Hagg T., Vahlsing H. L., Manthorpe M., and Varon S. (1990) NGF infusion into the denervated adult rat hippocampal formation promotes its cholinergic reinnervation. J. Neurosci. 10, 3087–3092.

    PubMed  CAS  Google Scholar 

  73. Ramirez J. J., Caldwell J. L., Majure M., et al. (2003) AAV expressing NGF enhances cholinergic axonal sprouting after cortical injury in rats. J. Neurosci. 23, 2797–2803.

    PubMed  CAS  Google Scholar 

  74. Yamashita T., Tucker K. L., and Barde Y. A. (1999) neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron 24, 585–593.

    PubMed  CAS  Google Scholar 

  75. Kimpinski K. and Mearow K. (2001) Neurite growth promotion by NGF and IGF-1 in cultured adult sensory neurons: role of PI-3K and MAPK. J. Neurosci. Res. 63, 486–499.

    PubMed  CAS  Google Scholar 

  76. Markus A., Zhong J., and Snider W. D. (2002) Raf and Akt mediate distinct aspects of sensory axon growth. Neuron 35, 65–76.

    PubMed  CAS  Google Scholar 

  77. Hofer M. M. and Barde Y. A. (1988) BDNF prevents neuronal death in vivo. Nature 331, 261–262.

    PubMed  CAS  Google Scholar 

  78. Alderson R. F., Alterman A. L., Barde Y. A., and Lindsay R. M. (1990) BDNF increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron 5, 297–306.

    PubMed  CAS  Google Scholar 

  79. Hyman C., Hofer M., Barde Y. A., et al. (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia, nigra. Nature 350, 230–232.

    PubMed  CAS  Google Scholar 

  80. Kobayashi N. R., Fan D. P., Giehl K. M., Bedard A. M., Wiegand S. J., and Tetzlaff W. (1997) BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talphal-tubulin mRNA expression, and promote axonal regeneration. J. Neurosci. 17, 9583–9595.

    PubMed  CAS  Google Scholar 

  81. Cui Q., Yip H. K., Zhao R. C., So K. F., and Harvey A. R. (2003) Intraocular elevation of cyclic AMP potentiates CNTF-induced regeneration of adult rat retinal ganglion cell axons. Mol. Cell. Neurosci. 22, 49–61.

    PubMed  CAS  Google Scholar 

  82. Ruitenberg M. J., Plant G. W., Hamers F. P., et al. (2003) Ex vivo adenoviral vector-mediated neurotrophin gene transfer to olfactory ensheathing glia: effects on rubrospinal tract regeneration, lesion size, and functional recovery after implantation in the injured rat spinal cord. J. Neurosci. 23, 7045–7058.

    PubMed  CAS  Google Scholar 

  83. Skaper S. D., Floreani M., Negro A., Facci L., and Giusti P. (1998) Neurotrophins rescue cerebellar granule neurons from oxidative stress-mediated apoptotic death: selective involvement of PI-3K and MAPK pathway. J. Neurochem. 70, 1859–1868.

    PubMed  CAS  Google Scholar 

  84. Dolcet X., Egea J., Soler R. M., Martin-Zanca D., and Comella J. X. (1999) Activation of PI-3K, but not ERK, is necessary to mediate BDNF-induced motoneuron survival. J. Neurochem. 73, 521–531.

    PubMed  CAS  Google Scholar 

  85. Yuen E. C. and Mobley W. C. (1999) Early BDNF, NT-3, and NT-4 signaling events. Exp. Neurol. 159, 297–308.

    PubMed  CAS  Google Scholar 

  86. Kashiwagi F., Kashiwagi K., Iizuka Y., and Tsukahara S. (2000) Effects of BDNF and NT-4 on isolated cultured retinal ganglion cells: evaluation by flow cytometry. Invest. Ophthalmol. Vis. Sci. 41, 2373–2377.

    PubMed  CAS  Google Scholar 

  87. Bosco A. and Linden R. (1999) BDNF and NT-4 differentially modulate neurite outgrowth in developing retinal ganglion cells. J. Neurosci. Res. 57, 759–769.

    PubMed  CAS  Google Scholar 

  88. Zhi Y., Lu Q., Zhang C. W., Yip H. K., So K. F., and Cui Q. (2005) Different optic nerve injury sites result in differential cellular responses of retinal ganglion cell to BDNF but not NT-4/5. Brain Res., 1047, 224–232.

    PubMed  CAS  Google Scholar 

  89. Fan G., Egles C., Sun Y., et al. (2000) Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities. Nat. Neurosci. 3, 350–357.

    PubMed  CAS  Google Scholar 

  90. Williams G., Williams E. J., Maison P., Pangalos M. N., Walsh F. S., and Doherty P. (2005) Overcoming the inhibitors of myelin with a novel neurotrophin strategy. J. Biol. Chem. 280, 5862–5869.

    PubMed  CAS  Google Scholar 

  91. Gao Y., Deng K., Hou J., et al. (2004) Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621.

    PubMed  CAS  Google Scholar 

  92. Klocker N., Jung M., Stuermer C. A., and Bähr M. (2001) BDNF increases the number of axotomized rat retinal ganglion cells expressing GAP-43, L1, and TAG-1 mRNA—a supportive role for nitric oxide?. Neurobiol. Dis. 8, 103–113.

    PubMed  CAS  Google Scholar 

  93. Aigner L., Arber S., Hapfhammer J. P., et al. (1995) Overexpression of the neural growthassociated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell 83, 269–278.

    PubMed  CAS  Google Scholar 

  94. Meiri K. F., Saffell J. L., Walsh F. S., and Doherty P. (1998) Neurite outgrowth stimulated by neural cell adhesion molecules requires growth-associated protein-43 (GAP-43) function and is associated with GAP-43 phosphorylation in growth cones. J. Neurosci. 18, 10,429–10,437.

    CAS  Google Scholar 

  95. Gianola S. and Rossi F. (2004) GAP-43 overexpression in adult mouse Purkinje cells overrides myelin-derived inhibition of neurite growth. Eur. J. Neurosci. 19, 819–830.

    PubMed  Google Scholar 

  96. Liot G., Gabriel C., Cacquevel M., et al. (2004) Neurotrophin-3-induced PI-3 kinase/Akt signaling rescues cortical neurons from apoptosis. Exp. Neurol. 187, 38–46.

    PubMed  CAS  Google Scholar 

  97. Ventimiglia R., Mather P. E., Jones B. E., and Lindsay R. M. (1995) The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur. J. Neurosci. 7, 213–222.

    PubMed  CAS  Google Scholar 

  98. Giehl K. M. and Tetzlaff W. (1996) BDNF and NT-3, but not NGF, prevent axotomy-induced death of rat corticospinal neurons in vivo. Eur. J. Neurosci. 8, 1167–1175.

    PubMed  CAS  Google Scholar 

  99. Novikova L. N., Novikov L. N., and Kellerth J. O. (2000) Survival effects of BDNF and NT-3 on axotomized rubrospinal neurons depend on the temporal pattern of neurotrophin administration. Eur. J. Neurosci. 12, 776–780.

    PubMed  CAS  Google Scholar 

  100. Novikova L. N., Novikov L. N., and Kellerth J. O. (2000) BDNF abolishes the survival effect of NT-3 in axotomized Clarke neurons of adult rats. J. Comp. Neurol. 428, 671–680.

    PubMed  CAS  Google Scholar 

  101. Giehl K. M., Rohrig S., Bonate H., et al. (2001) Endogenous BDNF and NT-3 antagonistically regulate survival of axotomized corticospinal neurons in vivo. J. Neurosci. 21, 3492–3502.

    PubMed  CAS  Google Scholar 

  102. Aletsee C., Beros A., Mullen L., et al. (2001) Ras/MEK but not p38 signaling mediates NT-3-induced neurite extension from spiral ganglion neurons. J. Assoc. Res. Otolaryngol. 2, 377–387.

    PubMed  CAS  Google Scholar 

  103. Wiklund P., Ekstrom P. A., and Edstrom A. (2002) MAPK inhibition reveals differences in signalling pathways activated by NT-3 and other growth-stimulating conditions of adult mouse dorsal root ganglia neurons. J. Neurosci. Res. 67, 62–68.

    PubMed  CAS  Google Scholar 

  104. Hermann D. M., Kilic E., Kugler S., Isenmann S., and Bähr M. (2001) Adenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol. Dis. 8, 655–666.

    PubMed  CAS  Google Scholar 

  105. van Adel B. A., Kostic C., Deglon N., Ball A. K., and Arsenijevic Y. (2003) Delivery of CNTF via lentiviral-mediated transfer protects axotomized retinal ganglion cells for an extended period of time. Hum. Gene. Ther. 14, 103–115.

    PubMed  Google Scholar 

  106. Ji J. Z., Elyaman W., Yip H. K., et al. (2004) CNTF promotes survival of retinal ganglion cells after induction of ocular hypertension in rats: the possible involvement of STAT3 pathway. Eur. J. Neurosci. 19, 265–272.

    PubMed  Google Scholar 

  107. Jo S. A., Wang E., and Benowitz L. I. (1999) CNTF is an axogenesis factor for retinal ganglion cells. Neuroscience 80, 579–591.

    Google Scholar 

  108. Park K., Luo J. M., Hisheh S., Harvey A. R., and Cui Q. (2004) Cellular mechanisms associated with spontaneous and CNTF-cAMP-induced survival and axonal regeneration of adult retinal ganglion cells. J. Neurosci. 24, 10,806–10,815.

    CAS  Google Scholar 

  109. Hu Y., Leaver S. G., Plant G. W., et al. (2005) Peripheral nerve constructs genetically engineered to express CNTF enhance the regeneration of adult CNS axons. Mol. Ther. 11, 906–915.

    PubMed  CAS  Google Scholar 

  110. Ip NY and Yancopoulos G. D. (1992) CNTF and its receptor complex. Prog. Growth Factor Res. 4, 139–155.

    PubMed  CAS  Google Scholar 

  111. Davis S., Aldrich T. H., Stahl N., et al. (1993) LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260, 1805–1808.

    PubMed  CAS  Google Scholar 

  112. Ip NY, McClain J., Barrezueta N. X., et al. (1993) The alpha component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 10, 89–102.

    PubMed  CAS  Google Scholar 

  113. Ip NY and Yancopoulos G. D. (1996) The neurotrophins and CNTF: two families of collaborative neurotrophic factors. Annu. Rev. Neurosci. 19, 491–515.

    PubMed  CAS  Google Scholar 

  114. MacLennan A. J., Neitzel K. L., Devlin B. K., et al. (2000) In vivo localization and characterization of functional CNTFs which utilize JAK-STAT signaling. Neuroscience 99, 761–772.

    PubMed  CAS  Google Scholar 

  115. Peterson W. M., Wang Q., Tzekova R., and Wiegand S. J. (2000). CNTF and stress activate the Jak-STAT pathway in retinal neurons and glia. J. Neurosci. 20, 4081–4090.

    PubMed  CAS  Google Scholar 

  116. Alonzi T., Middleton G., Wyatt S., et al. (2001) Role of STAT3 and PI3-kinase/Akt in mediating the survival actions of cytokines on sensory neurons. Mol. Cell. Neurosci. 18, 270–282.

    PubMed  CAS  Google Scholar 

  117. Dolcet X., Soler R. M., Gould T. W., Egea J., Oppenheim R. W., and Comella J. X. (2001) Cytokines promote motoneuron survival through the Janus kinase-dependent activation of the PI-3K pathway. Mol. Cell. Neurosci. 18, 619–631.

    PubMed  CAS  Google Scholar 

  118. Goldberg J. L., Espinosa J. S., Xu Y., Davidson N., Kovasc G. T., and Barres B. A. (2002) Retinal ganglion cells do not extend axons by default: promotion by neurotrophic signalling and electrical activity. Neuron 33, 689–702.

    PubMed  CAS  Google Scholar 

  119. Boucher M. J., Morisset J., Vachon P. H., Reed J. C., Laine J., and Rivard N. (2000) MEK/ERK signalling pathway regulates the expression of Bcl-2. Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J. Cell. Biochem. 79, 355–369.

    PubMed  CAS  Google Scholar 

  120. Jin K., Mao X. O., Zhu Y., and Greenberg D. A. (2002) MEK and ERK protect hypoxia cortical neurons via phosphorylation of Bad. J. Neurochem. 80, 119–125.

    PubMed  CAS  Google Scholar 

  121. Darnell J. E. Jr., Kerr I. M., and Stark G. R. (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415–1421.

    PubMed  CAS  Google Scholar 

  122. Lutticken C., Negenka U. M., Yuan J., et al. (1994) Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science 263, 89–92.

    PubMed  CAS  Google Scholar 

  123. Stahl N., Boulton T. G., Farruggalla T., et al. (1994) Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components. Science 263, 92–95.

    PubMed  CAS  Google Scholar 

  124. Ihle J. N. (1996) STATs: signal transducers and activators of transcription. Cell 84, 331–334.

    PubMed  CAS  Google Scholar 

  125. Vignais M. L., Sadowski H. B., Watling D., Rogers N. C., and Gilman M. (1996) Plateletderived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins. Mol. Cell Biol. 16, 1759–1769.

    PubMed  CAS  Google Scholar 

  126. Schweizer U., Gunnersen J., Karch C., et al. (2002) Conditional gene ablation of Stat3 reveals differential, signaling requirements for survival of motoneurons during development and after nerve injury in the adult. J. Cell Biol. 156, 287–297.

    PubMed  CAS  Google Scholar 

  127. Boyd Z. S., Kriatchko A., Yang J., Agarwal N., Wax M. B., and Patil R. V. (2003) IL-10 receptor signaling through STAT-3 regulates the apoptosis of retinal ganglion cells in response to stress. Invest. Ophthalmol. Vis. Sci. 44, 5206–5211.

    PubMed  Google Scholar 

  128. Fuhrmann S., Kirsch M., Heller S., Rohrer H., and Hofmann H. D. (1998) Differential regulation of ciliary, neurotrophic factor receptor-alpha expression in all major neuronal cell classes during development of the chick retina. J. Comp. Neurol. 400 244–254.

    PubMed  CAS  Google Scholar 

  129. Cowley S., Paterson H., Kemp P., and Marshall C. J. (1994) Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell 77, 841–852.

    PubMed  CAS  Google Scholar 

  130. Miura T., Tanaka S., Seichi A., et al. (2000) Partial functional recovery of paraplegic rat by adenovirus-mediated gene delivery of constitutively active MEK1. Exp. Neurol. 166, 115–126.

    PubMed  CAS  Google Scholar 

  131. Namikawa K., Honma M., Abe K., et al. (2000) Akt/protein kinase B prevents injury-induced motoneuron death and accelerates axonal regeneration. J. Neurosci. 20, 2875–2886.

    PubMed  CAS  Google Scholar 

  132. Desbarats J., Birge R. B., Mimouni-Rongy M., Weinstein D. E., Palerme J. S., and Newell M. K. (2003) Fas engagement induces neurite growth through ERK activation and p35 upregulation. Nat. Cell Biol. 5, 118–125.

    PubMed  CAS  Google Scholar 

  133. Mazzoni I.E., Said F. A., Aloyz R., Miller F. D., and Kaplan D. (1999) Ras regulates sympathetic neuron survival by suppressing the p53-mediated cell death pathway. J. Neurosci. 19, 9716–9727.

    PubMed  CAS  Google Scholar 

  134. Alessandrini A., Namura S., Moskowitz M. A., and Bonventre J. V. (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc. Natl. Acad. Sci. USA 96, 12,866–12,869.

    CAS  Google Scholar 

  135. Lin L. F., Doherty D. H., Lile J. D., Bektesh S., and Collins F. (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132.

    PubMed  CAS  Google Scholar 

  136. Airaksinen M. S. and Saarma M. (2002) the GDNF family: signalling, biological functions and therapeutic value. Nat. Rev. Neurosci. 3, 383–394.

    PubMed  CAS  Google Scholar 

  137. Arenas E., Trupp M., Akerud P., and Ibanes C. F. (1995) GDNF prevents degeneration and promotes the phenotype of brain noradrenergic neurons in vivo. Neuron 15, 1465–1473.

    PubMed  CAS  Google Scholar 

  138. Schmeer C., Straten G., Kugler S., Gravel C., Bähr M., and Isenmann S. (2002) Dose-dependent rescue of axotomized rat retinal ganglion cells by adenovirus-mediated expression of GDNF in vivo. Eur. J. Neurosci. 15, 637–643.

    PubMed  Google Scholar 

  139. Cheng C., Huang S. S., Lin S. M., et al. (2003) The neuroprotective effect of glial cell line-derived neurotrophic factor in fibrin glue against chronic focal cerebral ischemia in conscious rats. Brain Res. 1033, 28–33.

    Google Scholar 

  140. Iannotti C., Li H., Yan P., Lu X., Wirthlin L., and Xu X. M. (2003) GDNF-enriched bridging transplants promote propriospinal axonal regeneration and enhance myelination after spinal cord injury. Exp. Neurol. 183, 379–393.

    PubMed  CAS  Google Scholar 

  141. Jin G., Omori N., Li F., et al. (2003) Protection against ischemic brain damage by GDNF affecting cell survival and death signals. Neurol. Res. 25, 249–253.

    PubMed  CAS  Google Scholar 

  142. Ishikawa K., Takano M., Matsumoto N., et al. (2005) Effect of GDNF gene transfer into axotomized retinal ganglion cells using in vivo electroporation with a contact lens-type electrode. Gene Ther. 12, 289–298.

    PubMed  CAS  Google Scholar 

  143. Lindqvist N., Peinado-Ramónn P., Vidal-Sanz M., and Hallböök F. (2004) GDNF, Ret, GFRα1 and 2 in the adult rat retino-tectal system after optic nerve transection. Exp. Neurol. 187, 487–499.

    PubMed  CAS  Google Scholar 

  144. Henderson C. E., Phillips H. S., Pollock R. P., et al. (1994) GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266, 1062–1064.

    PubMed  CAS  Google Scholar 

  145. Bohn M. C. (2004) Motoneurons crave GDNF. Exp. Neurol. 190, 263–275.

    PubMed  CAS  Google Scholar 

  146. Sariola H. and Saarma M. (2003). Novel functions and signalling pathways for GDNF. J. Cell Sci. 116, 3855–3862.

    PubMed  CAS  Google Scholar 

  147. Paratcha G., Ledda F., and Ibanes C. F. (2003). The neural cell adhesion molecule NCAM is an alternative signalling receptor for GDNF family ligands. Cell 113, 867–879.

    PubMed  CAS  Google Scholar 

  148. Soler R. M., dolcet X., Encinas M., Egea J., Bayascas J. R., and Comella J. X. (1999) Receptors of the GDNF family of neurotrophic factors signal cell survival through the PI-3K pathway in spinal cord motoneurons. J. Neurosci. 19, 9160–9169.

    PubMed  CAS  Google Scholar 

  149. Trupp M., Scott R., Whittemore S. R., and Ibanez C. F. (1999) Ret-dependent and-independent mechanisms of GDNF signalling in neuronal cells. J. Biol. Chem. 274, 20,885–20,894.

    CAS  Google Scholar 

  150. Hayashi H., Ichihara M., Iwashita T., et al. (2000) Characterization of intracellular signals via tyrosine 1062 in RET activated by GDNF. Oncogene 19, 4469–4475.

    PubMed  CAS  Google Scholar 

  151. Mograbi B., Bocciardi R., Bourget I., et al. (2001) GDNF-stimulated PI-3K and Akt activities exert opposing effects on the ERK pathway: importance for the rescue of neuroectodermic cells. J. Biol. Chem. 276, 45,307–45,319.

    CAS  Google Scholar 

  152. Storer P. D., Dolbeare D., and Houle J. D. (2003) Treatment of chronically injured spinal cord with neurotrophic factors stimulates betaII-tubulin and GAP-43 expression in rubrospinal tract neurons. J. Neurosci. Res. 74, 502–511.

    PubMed  CAS  Google Scholar 

  153. Mark R.J., Fuson K. S., Keane-Lazar K., and May P. C. (1999) FGF-8 protects cultured rat hippocampal neurons from oxidative insult. Brain Res. 830, 88–93.

    PubMed  CAS  Google Scholar 

  154. Alzheimer C. and Werner S. (2002) Fibroblast growth factors and neuroprotection. Adv. Exp. Med. Biol. 513, 335–351.

    PubMed  CAS  Google Scholar 

  155. Walicke P., Cowan W. M., Ueno N., Baird A., and Guillemin R. (1986) FGF promotes survival of dissociated hippocampal neurons and enhances neurite extension. Proc. Natl. Acad. Sci. USA 83, 3012–3016.

    PubMed  CAS  Google Scholar 

  156. Anderson K. J., Dam D., Lee S., and Cotman C. W. (1988) Basic FGF prevents death of lesioned cholinergic neurons in vivo. Nature 332, 360,361.

    Google Scholar 

  157. Williams E. J., Furness J., Walsh F. S., and Doherty P. (1994) Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron 13, 583–594.

    PubMed  CAS  Google Scholar 

  158. Lin H. Y., Xu J., Ornitz D. M., Halegoua S., and Hayman M. J. (1996) The FGF receptor-1 is necessary for the induction of neurite outgrowth in PC12 cells by aFGF. J. Neurosci. 16, 4579–4587.

    PubMed  CAS  Google Scholar 

  159. Fontaine V., Kinkl N., Sahel J., Dreyfus H., and Hicks D. (1998) Survival of purified rat photoreceptors in vitro is stimulated directly by FGF-2. J. Neurosci. 18, 9662–9672.

    PubMed  CAS  Google Scholar 

  160. Kuzis K., Coffin J. D., and Eckenstein F. P. (1999) Time course and age dependence of motor neuron death following facial nerve crush injury: role of fibroblast growth factor. Exp. Neurol. 157, 77–87.

    PubMed  CAS  Google Scholar 

  161. Lau D., McGee L. H., Zhou S., et al. (2000) Retinal degeneration is slowed in transgenic rats by AAV-mediated delivery of FGF-2. Invest. Ophthalmol. Vis. Sci. 41, 3622–3633.

    PubMed  CAS  Google Scholar 

  162. Sapieha P. S., Peltier M., Rendahl K. G., Manning W. C., and Di Polo A. (2003) FGF-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury. Mol. Cell. Neurosci. 24, 656–672.

    PubMed  CAS  Google Scholar 

  163. Tanabe K., Bonilla I., Winkles J. A., and Strittmatter S. M. (2003) Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth. J. Neurosci. 23, 9675–9686.

    PubMed  CAS  Google Scholar 

  164. Williams E. J., Furness J., Walsh F. S., and Doherty P. (1994) Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF. Development 120, 1685–1693.

    PubMed  CAS  Google Scholar 

  165. Creuzet C., Loeb J., and Barbin G. (1995) FGFs stimulate protein tyrosine phosphorylation and MAPK activity in primary cultures of hippocampal neurons. J. Neurochem. 64, 1541–1547.

    PubMed  CAS  Google Scholar 

  166. Desire L., Courtois Y., and Jeanny J. C. (2000) Endogenous and exogenous FGF 2 support survival of chick retinal neurons by control of neuronal neuronal bcl-x(L) and bcl-2 expression through a FGF receptor 1- and ERK-dependent pathway. J. Neurochem. 75, 151–163.

    PubMed  CAS  Google Scholar 

  167. Miho Y., Kouroku Y., Fujita E., et al. (1999) bFGF inhibits the activation of caspase-3 and apoptosis of P19 embryonal carcinoma cells during neuronal differentiation. Cell Death Differ. 6, 463–470.

    PubMed  CAS  Google Scholar 

  168. Renaud F., Desset S., Oliver L., et al. (1996) The neurotrophic activity of fibroblast growth factor 1 (FGF1) depends on endogenous FGF1 expression and is independent of the MAPK cascade pathway. J. Biol. Chem. 271, 2801–2811.

    PubMed  CAS  Google Scholar 

  169. Saffell J. L., Williams E. J., Mason I. J., Walsh F. S., and Doherty P. (1997) Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. Neuron 18, 231–242.

    PubMed  CAS  Google Scholar 

  170. Viollet C. and Doherty P. (1997) CAMs and the FGF receptor: an interacting role in axonal growth. Cell Tissue Res. 290, 451–455.

    PubMed  CAS  Google Scholar 

  171. Williams E. J., Walsh F. S., and Doherty P. (2003) The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response. J. Cell Biol. 160, 481–486.

    PubMed  CAS  Google Scholar 

  172. Rydel R. E. and Greene L. A. (1988). cAMP analogues promote survival and neurite outgrowth in cultures of rat sympathetic and sensory neurons independently of nerve growth factor. Proc. Natl. Acad. Sci. USA 85, 1257–1261.

    PubMed  CAS  Google Scholar 

  173. Song H. J. and Poo M. M. (1999). Signal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363.

    PubMed  CAS  Google Scholar 

  174. Ming G., Song H. J., Berninger B., Holt C. E., Tessier-Lavigne M., and Poo M. M. (1997) cAMP-dependent growth cone guidance by netrin-1. Neuron 19, 1225–1235.

    PubMed  CAS  Google Scholar 

  175. Nishiyama M., Hoshino A., Tsai L., et al. (2003) Cyclic AMP/GMP-dependent modulation of Ca channels sets the polarity of nerve growthcone turning. Nature 423, 990–995.

    PubMed  CAS  Google Scholar 

  176. Kao H. T., Song H. J., Porton B., et al. (2002) A protein kinase A-dependent molecular switch in synapsins regulates neurite outgrowth. Nat. Neurosci. 5, 431–437.

    PubMed  CAS  Google Scholar 

  177. Song H., Ming G. L., and Poo M. M. (1997) cAMP-induced switch in turning direction of nerve growth cones. Nature 388, 275–279.

    PubMed  CAS  Google Scholar 

  178. Cai D., Shen Y., De Bellard M., Tang S., and Filbin M. T. (1999) Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism. Neuron 22, 89–101.

    PubMed  CAS  Google Scholar 

  179. Cai D., Deng K., Mellado W., Lee J., Ratan R. R., and Filbin M. T. (2002) Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro. Neuron 35, 711–719.

    PubMed  CAS  Google Scholar 

  180. Meyer-Franke A., Kaplan M. R., Pfrieger F. W., and Barres B. A. (1995) Characterization of the signalling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15, 805–819.

    PubMed  CAS  Google Scholar 

  181. Meyer-Franke A., Wilkinson G. A., Kruttgen A., et al. (1998) Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron 21, 681–693.

    PubMed  CAS  Google Scholar 

  182. Shen S., Wiemelt A. P., McMorris F. A., and Barres B. A. (1999) Retinal ganglion cells lose trophic responsiveness after axotomy. Neuron 23, 285–295.

    PubMed  CAS  Google Scholar 

  183. Finkbeiner S. and Greenberg M. E. (1998) Calcium channel regulated neuronal gene expression. J. Neurobiol. 37, 171–189.

    PubMed  CAS  Google Scholar 

  184. Tao X., Finkbeiner S., Arnold D. B., Shaywitz A. J., and Greenberg M. E. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726.

    PubMed  CAS  Google Scholar 

  185. Finkbeiner S. (2000) Calcium regulation of the BDNF gene. Cell Mol. Life Sci. 57, 394–401.

    PubMed  CAS  Google Scholar 

  186. Deogracias R., Espliguero G., Iglesias T., and Rodriguez-Pena A. (2004) Expression of the neurotrophin receptor trkB is regulated by the cAMP/CREB pathway in neurons. Mol. Cell. Neurosci. 26, 470–480.

    PubMed  CAS  Google Scholar 

  187. Poser S., Impey S., Xia Z., and Storm D. R. (2003) BDNF protection of cortical neurons from serum withdrawal-induced apoptosis is inhibited by cAMP. J. Neurosci. 23, 4420–4427.

    PubMed  CAS  Google Scholar 

  188. Hansen M. R., Zha X. M., Bok J., and Green S. H. (2001) Multiple distinct signal pathways, including an autocrine neurotrophic mechanism, contribute to the survival-promoting effect of depolarization on spiral ganglion neurons in vitro. J. Neurosci. 21, 2256–2267.

    PubMed  CAS  Google Scholar 

  189. Gallo G., Ernst A. F., McLoon S. C., and Letourneau P. C. (2002) Transient PKA activity is required for initiation but not maintenance of BDNF-mediated protection from nitric oxide-induced growth-cone collapse. J. Neurosci. 22, 5016–5023.

    PubMed  CAS  Google Scholar 

  190. Watanabe M., Tokita Y., Kato M., and Fukuda Y. (2003) Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized β ganglion cells in cat retina. Neuroscience 116, 733–742.

    PubMed  CAS  Google Scholar 

  191. Cai D., Qiu J., Cao Z., McAtee M., Bregman B. S., and Filbin M. T. (2001) Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J. Neurosci. 21, 4731–4739.

    PubMed  CAS  Google Scholar 

  192. Neumann S., Bradke F., Tessier-Lavigne M., and Basbaum A. I. (2002) Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885–893.

    PubMed  CAS  Google Scholar 

  193. Qiu J., Cai D., Dai H., et al. (2002) Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903.

    PubMed  CAS  Google Scholar 

  194. Nikulina E., Tidwell J. L., Dai H. N., Bregman B. S. and Filbin M. T. (2004) The phosphodiesterase inhibitor rolipram delivered after a spinal cord lesion promotes axonal regeneration and functional recovery. Proc. Natl. Acad. Sci. USA 101, 8786–8790.

    PubMed  CAS  Google Scholar 

  195. Monsul N. T., Geisendorfer A. R., Han P. J., et al. (2004) Intraocular injection of dibutyryl cyclic AMP promotes axon regeneration in rat optic nerve. Exp. Neurol. 186, 124–133.

    PubMed  CAS  Google Scholar 

  196. Lu P., Yang H., Jones L. L., Filbin M. T., and Tuszynski M. H. (2004) Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury. J. Neurosci. 24, 6402–6409.

    PubMed  CAS  Google Scholar 

  197. Li M., Wang X., Meintzer M. K., Laessig T., Birnbaum M. J., and Heidenreich K. A. (2000) Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol. Cell Biol. 20, 9356–9363.

    PubMed  CAS  Google Scholar 

  198. Esch F., Lin K. I., Hills A., et al. (1998) Purification of a multipotent antideath activity from bovine liver and its identification as arginase: nitric oxide-independent inhibition of neuronal apoptosis. J. Neurosci. 18, 4083–4095.

    PubMed  CAS  Google Scholar 

  199. Kaminska B., Kaczmarek L., and Grzelakowska-Sztabert B. (1992) Inhibitors of polyamine biosynthesis affect the expression of genes encoding cytoskeletal proteins. FEBS Lett. 304, 198–200.

    PubMed  CAS  Google Scholar 

  200. Williams K., Zappia A. M., Pritchett D. B., Shen Y. M., and Molinoff P. B. (1994) Sensitivity of the N-methyl-D-aspartate receptor to polyamines is controlled by NR2 subunits. Mol. Pharmacol. 45, 803–809.

    PubMed  CAS  Google Scholar 

  201. Kashiwagi K., Pahk A. J., Masuko T., Igarashi K., and Williams K. (1997) Block and modulation of N-methyl-D-aspartate receptors by polyamines and protons: role of amino acid residues in the transmembrane and poreforming regions of NR1 and NR2 subunits. Mol. Pharmacol. 52, 701–713.

    PubMed  CAS  Google Scholar 

  202. Williams K. (1997) Modulation and block of ion channels: a new biology of polyamines. Cell Signal 9, 1–13.

    PubMed  CAS  Google Scholar 

  203. Wang K. C., Kim J. A., Sivasankaran R., Segal R., and He Z. (2002) p75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature 420, 74–78.

    PubMed  CAS  Google Scholar 

  204. Wong S. T., Henley J. R., Kanning K. C., Huang K. H., Bothwell M., and Poo M. M. (2002) A p75(NTR) and Nogo receptor complex mediates repulsive signaling by MAG. Nat. Neurosci. 5, 1302–1308.

    PubMed  CAS  Google Scholar 

  205. Mi S., Lee X., Shao Z., et al. (2004) LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex. Nat. Neurosci. 7, 221–228.

    PubMed  CAS  Google Scholar 

  206. Luo L. (2000) Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1, 173–180.

    PubMed  CAS  Google Scholar 

  207. Niederost B., Oertle T., Fritsche J., McKinney R. A., and Bandtlow C. E. (2002) Nogo-A and MAG mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J. Neurosci. 22, 10,368–10,376.

    CAS  Google Scholar 

  208. Ahmed Z., Dent R. G., Suggate G. L. et al. (2005) Disinhibition of neurotrophin-induced dorsal root ganglion cell neurite outgrowth on CNS myelin by siRNA-mediated knockdown of NgR, p75NTR and Rho-A. Mol. Cell. Neurosci. 28, 509–523.

    PubMed  CAS  Google Scholar 

  209. Bryan B., Cai Y., Wrighton K., Wu G., Feng X. H., and Liu M. (2005) Ubiquitination of RhoA by Smurf1 promotes neurite outgrowth. FEBS Lett. 579, 1015–1019.

    PubMed  CAS  Google Scholar 

  210. Lehmann M., Fournier A. E., Selles-Navarro I., et al. (1999). Inactivation of Rho signaling pathway promotes CNS axon regeneration. J. Neurosci. 19, 7537–7547.

    PubMed  CAS  Google Scholar 

  211. Fournier A. E. and McKerracher L. (1997) Expression of specific tubulin isotypes increases during regeneration of injured CNS neurons, but not after the application of BDNF. J. Neurosci. 17, 4623–4632.

    PubMed  CAS  Google Scholar 

  212. Mason M. R., Campbell G., Caroni P., Anderson P. N., and Lieberman A. R. (2000) Overexpression of GAP-43 on thalamic projection neurons of transgenic mice does not enable them to regenerate axons-through peripheral nerve grafts. Exp. Neurol. 165, 143–152.

    PubMed  CAS  Google Scholar 

  213. Wewetzer K., Grothe C., and Claus P. (2001) In vitro expression and regulation of ciliary neurotrophic factor and its alpha receptor subunit in neonatal rat olfactory ensheathing cells. Neurosci. Lett. 306, 165–168.

    PubMed  CAS  Google Scholar 

  214. Caroni P. and Schwab M. E. (1988) Antibody against myelin-associated inhibitor of neurite growth neutralizes nonpermissive substrate properties of CNS white matter. Neuron 1, 85–96.

    PubMed  CAS  Google Scholar 

  215. McKerracher L., David S., Jackson D. L., Kottis V., Dunn R. J., and Braun P. E. (1994) Identification of MAG as a major myelin-derived inhibitor of neurite growth. Neuron 13, 805–811.

    PubMed  CAS  Google Scholar 

  216. Mukhopadhyay G., Doherty P., Walsh F. S., Crocker P. R., and Filbin M. T. (1994) A novel role for MAG as an inhibitor of axonal regeneration. Neuron 13, 757–767.

    PubMed  CAS  Google Scholar 

  217. Kottis V., Thibault P., Mikol D., et al. (2002) Oligodendrocyte-myelin glycoprotein (OMgp) is an inhibitor of neurite outgrowth. J. Neurochem. 82, 1566–1569.

    PubMed  CAS  Google Scholar 

  218. Bregman B. S., Kunkel-Bagden E., Schnell L., Dai H. N., Gao D., and Schwab M. E. (1995) Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors. Nature 378, 498–501.

    PubMed  CAS  Google Scholar 

  219. Z'Graggen W. J., Metz G. A., Kartje G. L., Thallmair M., and Schwab M. E. (1998) Functional recovery and enhanced corticofugal plasticity after unilateral pyramidal tract lesion and blockade of myelin-associated neurite growth inhibitors in adult rats. J. Neurosci. 18, 4744–4757.

    PubMed  Google Scholar 

  220. Hunt D., Mason M. R., Campbell G., Coffin R., and Anderson P. N. (2002) Nogo receptor mRNA expression in intact and regenerating CNS neurons. Mol. Cell. Neurosci. 20, 537–552.

    PubMed  CAS  Google Scholar 

  221. Bähr M. and Schwab M. E. (1996) Antibody that neutralizes myelin-associated inhibitors of axon growth does not interfere with recognition of target-specific guidance information by rat retinal axons. J. Neurobiol. 30, 281–292.

    PubMed  Google Scholar 

  222. Weibel D., Cadelli D., and Schwab M. E. (1994) Regeneration of lesioned rat optic nerve fibers is improved after neutralization of myelin-associated neurite growth inhibitors. Brain Res. 642, 259–266.

    PubMed  CAS  Google Scholar 

  223. Schnell L., Schneider R., Kolbeck R., Barde Y. A., and Schwab M. E. (1994) NT-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion. Nature 367, 170–173.

    PubMed  CAS  Google Scholar 

  224. Chen M. S., Huber A. B., van der Haar M. E., et al. (2000) Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1. Nature 403, 434–439.

    PubMed  CAS  Google Scholar 

  225. GrandPre T., Nakamura F., Vartanian T., and Strittmatter S. M. (2000) Identification of the Nogo inhibitor of axon regeneration as a Reticulon protein. Nature 403, 439–444.

    PubMed  CAS  Google Scholar 

  226. Fournier A. E., GrandPre T., and Strittmatter S. M. (2001) Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 409, 341–346.

    PubMed  CAS  Google Scholar 

  227. Prinjha R., Moore S. E., Vinson M., et al. (2000) Inhibitor of neurite outgrowth in humans. Nature 403, 383–384.

    PubMed  CAS  Google Scholar 

  228. Yamaguchi Y., Katoh H., Yasui H., Mori K., and Negishi M. (2001) RhoA inhibits the nerve growth factor-induced Rac1 activation through Rho-associated kinase-dependent pathway. J. Biol. Chem. 276, 18,977–18,983.

    CAS  Google Scholar 

  229. Domeniconi M., Cao Z., Spencer T., et al. (2002) Myelin-associated glycoprotein interacts with the Nogo66 receptor to inhibit neurite outgrowth. Neuron 35, 283–290.

    PubMed  CAS  Google Scholar 

  230. Liu B. P., Fournier A., GrandPre T., and Strittmatter S. M. (2002) MAG as a functional ligand for the Nogo-66 receptor. Science 297, 1190–1193.

    PubMed  CAS  Google Scholar 

  231. Wang K. C., Koprivica V., Kim J. A., et al. (2002) Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature 417, 941–944.

    PubMed  CAS  Google Scholar 

  232. Yamashita T., Higuchi H., and Tohyama M. (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J. Cell Biol. 157, 565–570.

    PubMed  CAS  Google Scholar 

  233. Fournier A. E., Takizawa B. T., and Strittmatter S. M. (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J. Neurosci. 23, 1416–1423.

    PubMed  CAS  Google Scholar 

  234. Woolf C. J. (2002) No Nogo: now where to go? Neuron 38, 153–156.

    Google Scholar 

  235. Dergham P., Ellezam B., Essagian C., Avedissian H., Lubell W. D., and McKerracher L. (2002) Rho signaling pathway targeted to promote spinal cord repair. J. Neurosci. 22, 6570–6577.

    PubMed  CAS  Google Scholar 

  236. Mizuno T., Yamashita T., and Tohyama M. (2004) Chimaerins act downstream from neurotrophins in overcoming the inhibition of neurite outgrowth produced by myelin-associated glycoprotein. J. Neurochem. 91, 395–403.

    PubMed  CAS  Google Scholar 

  237. Bareyre F. M., Haudenschild B., and Schwab M. E. (2002) Long-lasting sprouting and gene expression changes induced by the monoclonal antibody IN-1 in the adult spinal cord. J. Neurosci. 22, 7097–7110.

    PubMed  CAS  Google Scholar 

  238. Thallmair M., Metz G. A., Z'Graggen W. J., Raineteau O., Kartje G. L., and Schwab M. E. (1998) Neurite growth inhibitors restrict plasticity and functional recovery following corticospinal tract lesions. Nat. Neurosci. 1, 124–131.

    PubMed  CAS  Google Scholar 

  239. Merkler D., Metz G. A., Raineteau O., Dietz V., Schwab M. E., and Fouad K. (2001) Locomotor recovery in spinal cord-injured rats treated with an antibody neutralizing the myelin-associated neurite growth inhibitor Nogo-A. J. Neurosci. 21, 3665–3673.

    PubMed  CAS  Google Scholar 

  240. Oudega M., Rosano C., Sadi D., Wood P. M., Schwab M. E., and Hagg T. (2000) Neutralizin antibodies against neurite growth inhibitor NI-35/250 do not promote regeneration of sensory axons in the adult rat spinal cord. Neuroscience 100, 873–883.

    PubMed  CAS  Google Scholar 

  241. Kim J. E., Li S., GrandPré T., Qiu D., and Strittmatter S. M. (2003) Axon Regeneration in Young Adult Mice Lacking Nogo-A/B. Neuron 38, 187–199.

    PubMed  CAS  Google Scholar 

  242. Simonen M., Pedersen V., Weinmann O., et al. (2003) Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury. Neuron 38, 201–211.

    PubMed  CAS  Google Scholar 

  243. Zheng B., Ho C., Li S., Keirstead H., Steward O., and Tessier-Lavigne M. (2003) Lack of Enhanced Spinal Regeneration in Nogo-Dificient Mice. Neuron 38, 213–224.

    PubMed  CAS  Google Scholar 

  244. GrandPre T., Li S., and Strittmatter S. M. (2002) Nogo-66 receptor antagonist peptide promotes axonal regeneration. Nature 417, 547–551.

    PubMed  CAS  Google Scholar 

  245. Davies S. J., Fitch M. T., Memberg S. P., Hall A. K., Raisman G., and Silver J. (1997) Regeneration of adult axons in white matter tracts of the central nervous system. Nature 390, 680–683.

    PubMed  CAS  Google Scholar 

  246. Davies S. J., Goucher D. R., Doller C., and Silver J. (1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 5810–5822.

    PubMed  CAS  Google Scholar 

  247. Fawcett J. W. (1997) Astrocytic and neuronal factors affecting axon regeneration in the damaged central nervous system. Cell Tissue Res. 290, 371–377.

    PubMed  CAS  Google Scholar 

  248. David S. and Lacroix S. (2003) Molecular approaches to spinal cord repair. Annu. Rev. Neurosci. 26, 411–440.

    PubMed  CAS  Google Scholar 

  249. Moon L. D., Asher R. A., Rhodes K. E., and Fawcett J. W. (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat. Neurosci. 4, 465–466.

    PubMed  CAS  Google Scholar 

  250. Chao M. V. (1994) The p75 neurotrophin receptor. J. Neurobiol. 25, 1373–1385.

    PubMed  CAS  Google Scholar 

  251. Davies A. M., Lee K. F., and Jaenisch R. (1993) p75-deficient trigeminal sensory neurons have an altered response to NGF but not to other neurotrophins. Neuron 11, 565–574.

    PubMed  CAS  Google Scholar 

  252. Hantzopoulos P. A., Suri C., Glass D. J., Goldfarb M. P., and Yancopøulos G. D. (1994) The low affinity NGF receptor, p75, can collaborate with each of the Trks to potentiate functional responses to the neurotrophins. Neuron 13, 187–201.

    PubMed  CAS  Google Scholar 

  253. Bible M., Hoppe E., and Barde Y. A. (1999) Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR EMBO J. 186, 616–622.

    Google Scholar 

  254. Mischel P. S., Smith S. G., Vining E. R., Valletta J. S., Mobley W. C., and Reichardt L. F. (2001) The extracellular domain of p75NTR is necessary to inhibit NT-3 signaling through receptors trk. J. Biol. Chem. 276, 11,294–11,301.

    CAS  Google Scholar 

  255. Naumann T., Casademunt E., Hollerbach E., et al. (2002) Complete deletion of the neurotrophin receptor p75NTR leads to long-lasting increases in the number of basal forebrain cholinergic neurons. J. Neurosci. 22, 2409–2418.

    PubMed  CAS  Google Scholar 

  256. von Schack D., Casademunt E., Schweigreiter R., Meyer M., Bibel M., and Dechant G. (2001) Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat. Neurosci. 4, 977–978.

    Google Scholar 

  257. Schweigreiter R., Walmsley A. R., Neiderost B., et al. (2004) Versican V2 and the central inhibitory domain of Nogo-A inhibit neurite growth via p75NTR/NgR-independent pathways that converge at RhoA. Mol. Cell. Neurosci. 27, 163–174.

    PubMed  CAS  Google Scholar 

  258. Yamashita T. and Tohyama M. (2003) The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nat. Neurosci. 6, 461–467.

    PubMed  CAS  Google Scholar 

  259. Walsh G. S., Krol K. M., Crutcher K. A., and Kawaja M. D. (1999) Enhanced neurotrophin-induced axon growth in myelinated portions of the CNS in mice lacking the p75NTR. J. Neurosci. 19, 4155–4168.

    PubMed  CAS  Google Scholar 

  260. Hannila S. S. and Kawaja M. D. (2005) NGF-mediated collateral sprouting of central sensory axons into deafferentated regions of the dorsal horn is enhanced in the absence of the p75NTR. J. Comp. Neurol. 486, 331–343.

    PubMed  CAS  Google Scholar 

  261. Gschwendtner A., Liu Z., Hucho T., et al. (2003) Regulation, cellular localization, and function of the p75 neurotrophin receptor (p75NTR) during the regeneration of facial motoneurons. Mol. Cell. Neurosci. 24, 307–322.

    PubMed  CAS  Google Scholar 

  262. Hempstead B. L. (2002) The many faces of p75NTR. Curr. Opin. Neurobiol. 12, 260–267.

    PubMed  CAS  Google Scholar 

  263. Park J. B., Yiu G., Komeko S., et al. (2005) A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors Neuron 45, 345–351.

    PubMed  CAS  Google Scholar 

  264. Shao Z., Browning J. L., Lee X., et al. (2005) TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration. Neuron 45, 353–359.

    PubMed  CAS  Google Scholar 

  265. Li Y., Field P. M., and Raisman G. (1997) Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000–2002.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Qi Cui.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cui, Q. Actions of neurotrophic factors and their signaling pathways in neuronal survival and axonal regeneration. Mol Neurobiol 33, 155–179 (2006). https://doi.org/10.1385/MN:33:2:155

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:33:2:155

Index Entries

Navigation