Molecular Neurobiology

, Volume 27, Issue 3, pp 277–323 | Cite as

Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury

  • J. Gordon Boyd
  • Tessa Gordon


Over a half a century of research has confirmed that neurotrophic factors promote the survival and process outgrowth of isolated neurons in vitro. The mechanisms by which neurotrophic factors mediate these survival-promoting effects have also been well characterized. In vivo, peripheral neurons are critically dependent on limited amounts of neurotrophic factors during development. After peripheral nerve injury, the adult mammalian peripheral nervous system responds by making neurotrophic factors once again available, either by autocrine or paracrine sources. Three families of neurotrophic factors were compared, the neurotrophins, the GDNF family of neurotrophic factors, and the neuropoetic cytokines. Following a general overview of the mechanisms by which these neurotrophic factors mediate their effects, we reviewed the temporal pattern of expression of the neurotrophic factors and their receptors by axotomized motoneurons as well as in the distal nerve stump after peripheral nerve injury. We discussed recent experiments from our lab and others which have examined the role of neurotrophic factors in peripheral nerve injury. Although our understanding of the mechanisms by which neurotrophic factors mediate their effects in vivo are poorly understood, evidence is beginning to emerge that similar phenomena observed in vitro also apply to nerve regeneration in vivo.

Index Entries

NGF BDNF GDNF CNTF axon regeneration functional recovery Schwann cells motoneuron 


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  1. 1.
    Davies A. M. (1994) Intrinsic programmes of growth and survival in developing vertebrate neurons. TINS 17, 195–199.PubMedGoogle Scholar
  2. 2.
    Snider W. D. (1994) Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638.PubMedGoogle Scholar
  3. 3.
    Lindsay R. M. (1996) Role of neurotrophins and trk receptors in the development and maintenance of sensory neurons: an overview. Phil. Trans. Royal Soc. Lond. 351, 365–373.Google Scholar
  4. 4.
    Conover J. C. and Yancopoulos G. D. (1997) Neurotrophin regulation of the developing nervous system: analyses of knockout mice. Rev. Neurosci. 8, 13–27.PubMedGoogle Scholar
  5. 5.
    Chen W. P., Chang Y. C., and Hsieh S. T. (1999) Trophic interactions between sensory nerves and their targets. J. Biomed. Sci. 6, 79–85.PubMedGoogle Scholar
  6. 6.
    Rask C. A. (1999) Biological actions of nerve growth factor in the peripheral nervous system. Eur. Neurol. Suppl. 1, 14–19.Google Scholar
  7. 7.
    Thoenen H. (1995) Neurotrophins and neuronal plasticity. Science 270, 593–598.PubMedGoogle Scholar
  8. 8.
    Thoenen H (2000) Neurotrophins and activity-dependent plasticity. Prog. Brain. Res. 128, 183–191.PubMedGoogle Scholar
  9. 9.
    Snider W. D. and Silos-Santiago I. (1996) Dorsal root ganglion neurons require functional neurotrophin receptors for survival during development. Phil. Trans. Royal Soc. Lond. 351, 395–403.Google Scholar
  10. 10.
    Knipper M. and Rylett R. J. (1997) A new twist in an old story: the role for crosstalk of neuronal and trophic activity. Neurochem. Int. 31, 659–676.PubMedGoogle Scholar
  11. 11.
    Lu B. and Figurov A. (1997) Role of neurotrophins in synapse development and plasticity. Rev. Neurosci. 8, 1–12.PubMedGoogle Scholar
  12. 12.
    Marty S., Berzaghi M., da P., and Berninger B. (1997) Neurotrophins and activity-dependent plasticity of cortical interneurons. Trends Neurosci. 20, 198–202.PubMedGoogle Scholar
  13. 13.
    Shieh P. B. and Ghosh A. (1997) Neurotrophins: new roles for a seasoned cast. Curr Biol. 7, R627–630.PubMedGoogle Scholar
  14. 14.
    Frade J. M. and Barde Y.-A. (1998) Nerve growth factor: two receptors, multiple functions. Bioessays, 20, 137–145.PubMedGoogle Scholar
  15. 15.
    Lessmann V. (1998) Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol. 31, 667–674.PubMedGoogle Scholar
  16. 16.
    Takei N. and Nawa H. (1998) Roles of neurotrophins on synaptic development and functions in the central nervous system. Hum. Cell. 11, 157–165.PubMedGoogle Scholar
  17. 17.
    Berardi N. and Maffei L. (1999) From visual experience to visual function: roles of neurotrophins. J. Neurobiol. 41, 119–126.PubMedGoogle Scholar
  18. 18.
    Schuman E. M. (1999) Neurotrophin regulation of synaptic transmission. Curr. Opin. Neurobiol. 9, 105–109.PubMedGoogle Scholar
  19. 19.
    Schinder A. F. and Poo M. (2000) The neurotrophin hypothesis for synaptic plasticity. Trends Neurosci. 23, 639–645.PubMedGoogle Scholar
  20. 20.
    Lu B. and Gottschalk W. (2000) Modulation of hippocampal synaptic transmission and plasticity by neurotrophins. Prog. Brain Res. 128, 231–241.PubMedGoogle Scholar
  21. 21.
    Berardi N., Pizzorusso T., and Maffei L. (2000) Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145.PubMedGoogle Scholar
  22. 22.
    Verge V.M.K., Gratto K. A., Karchewski L. A., and Richardson P. M. (1996) Neurotrophins and nerve injury in the adult. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 35, 423–430.Google Scholar
  23. 23.
    Ebadi M., Bashir R. M., Heidrick M. L., et al. (1997) Neurotrophins and their receptors in nerve injury and repair. Neurochem. Int. 30, 347–374.PubMedGoogle Scholar
  24. 24.
    Fu S. Y. and Gordon T. (1997) The cellular and molecular basis of peripheral nerve regeneration. Mol. Neurobiol. 14, 67–116.PubMedGoogle Scholar
  25. 25.
    Muller H. W. and Stoll G. (1998) Nerve injury and regeneration: basic insights and therapeutic interventions. Curr. Opin. Neurol. 11, 557–562.PubMedGoogle Scholar
  26. 26.
    Yin Q., Kemp G. J., and Frostick S. P. (1998) Neurotrophins, neurones, and peripheral nerve regeneration. J. Hand. Surg. (British & European) 23B, 433–437.Google Scholar
  27. 27.
    Terenghi G. (1999) Peripheral nerve regeneration and neurotrophic factors. J. Anat. 194, 1–14.PubMedGoogle Scholar
  28. 28.
    Segal R. and Greenberg M. (1996) Intracellular pathways activated by neurotrophic factors. Ann. Rev. Neurosci. 19, 463–469.PubMedGoogle Scholar
  29. 29.
    Bredesen D. E. and Rabizadeh S. (1997) p75NTR and apoptosis: trk-dependent and trk-independent effects. TINS 20, 287–290.PubMedGoogle Scholar
  30. 30.
    Kaplan D. R. and Miller F. D. (1997) Signal transduction by the neurotrophin receptors. Curr. Opin. Cell Biol. 9, 213–221.PubMedGoogle Scholar
  31. 31.
    Kaplan D. R. and Miller F. D. (2000) Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391.PubMedGoogle Scholar
  32. 32.
    Barker P. A. (1998) p75NTR: a study in contrasts. Cell Death Differ. 5, 346–356.PubMedGoogle Scholar
  33. 33.
    Casaccia-Bonnefil P., Kong H., and Chao M. V. (1998) Neurotrophins: the biological paradox of survival factors eliciting apoptosis. Cell Death Diff. 5, 357–364.Google Scholar
  34. 34.
    Casaccia-Bonnefil P., Gu C., and Chao M. V. (1999a) Neurotrophins in cell survival/death decisions, in The functional roles of glial cells in health and disease. (Matsas and Tsacopoulos, eds.) Kluwer Academic/Plenum Publishers, New York, USA.Google Scholar
  35. 35.
    Casaccia-Bonnefil P., Gu C. H., Khursigara G., and Chao M. V. (1999b) p75 neurotrophin receptor as a modulator of survival and death decisions. Microsc. Res. Tech. 45, 217–224.PubMedGoogle Scholar
  36. 36.
    Chao M. V., Casaccia-Bonnefil P., Carter B., Chittka A., Kong H., and Yoon S. O. (1998) Neurotrophin receptors: mediators of life and death. Brain Res. Rev. 26, 295–301.PubMedGoogle Scholar
  37. 37.
    Dobrowsky R. T. and Carter B. D. (1998) Coupling of the p75 neurotrophin receptor to sphingolipid signaling. Ann. NY Acad. Sci. 19, 32–45.Google Scholar
  38. 38.
    Miller F. D. and Kaplan D. R. (1998) Life and death decisions: a biological role for the p75 neurotrophin receptor. Cell Death Diff. 5, 343–345.Google Scholar
  39. 39.
    Friedman W. J. and Greene L. A. (1999) Neurotrophin signaling via trks and p75. Exp. Cell Res. 253, 131–142.PubMedGoogle Scholar
  40. 40.
    Klesse L. J. and Parada L. F. (1999) Trks: signal transduction and intracellular pathways. Microsc. Res. Tech. 45, 210–216.PubMedGoogle Scholar
  41. 41.
    Barrett G. L. (2000) The p75 receptor and neuronal apoptosis. Prog. Neurobiol. 61, 205–229.PubMedGoogle Scholar
  42. 42.
    Yano H. and Chao M. (2000) Neurotrophin receptor structure and interactions. Pharm. Acta. Helv. 74, 253–260.PubMedGoogle Scholar
  43. 43.
    Levi-Montalcini R. and Hamburger V. (1953) A diffusible agent of mouse sarcoma, producing hyperplasia of sympathetic ganglia and hyperneurotization of viscera in the chick embryo. J. Exp. Zool. 123, 233–288.Google Scholar
  44. 44.
    Barde Y.-A., Edgar D., and Thoenen H. (1982) Purification of a new neurotrophic factor from mammalian brain. EMBO J. 1, 549–553.PubMedGoogle Scholar
  45. 45.
    Gotz R., Koster R., Winkler C., Raulf F., Lottspeich F., Schartl M., and Thoenen H. (1994) Neurotropin-6 is a new member of the neurotrophin family. Nature 372, 266–269.PubMedGoogle Scholar
  46. 46.
    Lai K. O., Fu W. Y., Ip F. C., and Ip N. Y. (1998) Cloning and expression of a novel neurotrophin, NT-7, from carp. Mol. Cell. Neurosci. 11, 64–76.PubMedGoogle Scholar
  47. 47.
    McDonald N. Q. and Chao M. V. (1995) Structural determinants of neurotrophin action. J. Biol. Chem. 270, 19,669–19,672.Google Scholar
  48. 48.
    McDonald N. Q. and Blundell T. L. (1991) Crystallization and characterization of the high molecular weight form of nerve growth factor (7 S NGF) J. Mol. Biol. 219, 595–601.PubMedGoogle Scholar
  49. 49.
    Rodriguez-Tebar A., Dechant G., Gotz R., and Barde Y.-A. (1992) Binding of neurotrophin-3 to its neuronal receptors and interactions with nerve growth factor and brain-derived neurotrophic factor. EMBO J. 11, 917–922.PubMedGoogle Scholar
  50. 50.
    Barbacid M. (1994) The trk family of neurotrophin receptors. J. Neurobiol. 25, 1386–1403.PubMedGoogle Scholar
  51. 51.
    Eide F. F., Vining E. R., Eide B. L., Zang K., Wang X. Y., and Reichardt L. F. (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci. 16, 3123–3129.PubMedGoogle Scholar
  52. 52.
    Fryer R. H., Kaplan D. R., and Kromer L. F. (1997) Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro. Exp Neurol. 148, 616–627.PubMedGoogle Scholar
  53. 53.
    Chao M. V. (1992) Growth factor signaling: where is the specificity? Cell 68, 995–997.PubMedGoogle Scholar
  54. 54.
    Schneider R. and Schweiger M. (1991) A novel modular mosaic of cell adhesion motifs in the extracellular domains of the neurogenic trk and trkB tyrosine kinase receptors. Oncogene 6, 1807–1811.PubMedGoogle Scholar
  55. 55.
    Perez P., Coll P. M., Hempstead B. L., Martin-Zanca D., and Chao M. V. (1995) NGF binding to the trk tyrosine kinase receptor requires the extracellular immunoglobulin-like domains. Mol. Cell. Neurosci. 6, 97–105.PubMedGoogle Scholar
  56. 56.
    Urfer R., Tsoulfas P., O’Connel L., Shelton D., Parada L. F., and Presta L. G. (1995) An immunoglobulin-like domain determines the specificity of neurotrophin receptors. EMBO J. 14, 2795–2805.PubMedGoogle Scholar
  57. 57.
    Zhou H., Welcher A. A., and Shooter E. M. (1997) BDNF/NT4–5 receptor TrkB and cadherin participate in cell-cell adhesion. J. Neurosci. Res. 49, 281–291.PubMedGoogle Scholar
  58. 58.
    smith C. A., Farra T., and Goodwin R. G. (1994) The TNF receptor superfamily of cellular and viral proteins. Cell 76, 959–962.PubMedGoogle Scholar
  59. 59.
    Baker S. J. and Reddy E. P. (1996) Transducer of life and death: TNF receptor superfamily and associated proteins. Oncogene 12, 1–9.PubMedGoogle Scholar
  60. 60.
    Rydén M., Murray-Rust J. G. D., Ilag L. L., et al. (1995) Functional analysis of mutant neurotrophins deficient in low affinity binding reveals a role for p75LNGFR in NT-4 signaling. EMBO J. 14, 1979–1990.PubMedGoogle Scholar
  61. 61.
    Mahadeo D., Kaplan L., Chao M. V., and Hempstead B. L. (1994) High affinity nerve growth factor binding displays a faster rate of association than p140(trk) binding: implications for multisubunit polypeptide receptors. J. Biol. Chem. 269, 6884–6891.PubMedGoogle Scholar
  62. 62.
    Barker P. A. and Shooter E. M. (1994) Disruption of NGF binding to the low-affinity neurotrophin receptor p75 reduces NGF binding to trkA on PC12 cells. Neuron 13, 203–215.PubMedGoogle Scholar
  63. 63.
    Saarma M. and Sariola H. (1999) Other neurotrophic factors: Glial cell line-derived neurotrophic factor (GDNF) Microsc. Res. Tech. 45, 292–302.PubMedGoogle Scholar
  64. 64.
    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.PubMedGoogle Scholar
  65. 65.
    Lin L.-F., Zhang T. J., Collins F., and Armes L. G., (1994) Purification and initial characterization of rat B49 glial cell line-derived neurotrophic factor. J. Neurochem. 63, 758–768.PubMedGoogle Scholar
  66. 66.
    Oppenheim R. W., Houenou L. J., Johnson J. E., et al. (1995) Developing motor neurons rescued from programmed and axotomy-induced cell death by GDNF. Nature 373, 344–346.PubMedGoogle Scholar
  67. 67.
    Yan Q., Matheson C., and Lopez O. T. (1995) In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature 360, 753–755.Google Scholar
  68. 68.
    Kotzbauer P. T., Lampe P. A., Heuckeroth R. O., et al. (1996) Neuturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384, 467–470.PubMedGoogle Scholar
  69. 69.
    Baloh R. H., Tansey M. G., Lampe P. A., et al. (1998) Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRα3-RET receptor complex. Neuron 21, 1291–1302.PubMedGoogle Scholar
  70. 70.
    Milbrandt J., de Sauvage F. J., Fahrner T. J., et al. (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20, 245–253.PubMedGoogle Scholar
  71. 71.
    Hui J. O., Woo G., Chow D. T., Katta V., Osslund T., and Haniu M. (1999) The intermolecular disulfide bridge of human glial cell line-derived neurotrophic factor: its selective reduction and biological activity of the modified protein. J. Prot. Chem. 18, 585–593.Google Scholar
  72. 72.
    Durbec P., Marcos-Gutierrez C. V., Kilkenny C., et al. (1996) GDNF signaling through the Ret receptor tyrosine kinase. Nature 381, 789–793.PubMedGoogle Scholar
  73. 73.
    Jing S., Wen D., Yu Y., et al. (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF. Cell 85, 1113–1124.PubMedGoogle Scholar
  74. 74.
    Treanor J. J., Goodman L., de Sauvage F., et al. (1996) Characterization of a multicomponent receptor for GDNF. Nature 382, 80–83.PubMedGoogle Scholar
  75. 75.
    Trupp M., Arena E., Fainzilber M., et al. (1996) Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785–788.PubMedGoogle Scholar
  76. 76.
    Vega Q. C., Worby C. A., Lechner M. S., Dixon J. E., and Dressler G. R. (1996) Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc. Nat. Acad. Sci. 93, 10,657–10,661.Google Scholar
  77. 77.
    Takahashi M., Ritz J., and Cooper G. M. (1985) Activation of a novel human transforming gene, ret, by DNA rearrangements. Cell 42, 581–588.PubMedGoogle Scholar
  78. 78.
    Kuma K., Iwabe N., and Miyata T. (1993) Motifs of cadherin-and fibronectin type III-related sequences and evolution of the receptor-type-protein tyrosine kinases: sequence similarity between proto-oncogene ret and cadherin family. Mol. Biol. Evol. 10, 539–551.PubMedGoogle Scholar
  79. 79.
    Oppenheim J. J. and Saklatvala J. (1993) Cytokines and their receptors, In Clinical Applications of Cytokinase: Role in Pathogenesis, Diagnosis, and Therapy. (Oppenheim J. J., Rossio J. L., and Gearing A.J.H., eds) Oxford University Press, Oxford, UK.Google Scholar
  80. 80.
    Heinrich P. C., Behrmann I., Muller-Newen G., Schaper F., and Graeve L. (1998) Interleukin-6-type cytokine signaling through the gp130/Jak/STAT pathway. Biochem. J. 234, 297–314.Google Scholar
  81. 81.
    Senaldi G., Varnum B. C., Sarmiento U., et al. (1999) Novel neurotrophin-1/B cell-stimulating factor-3: a cytokine of the IL-6 family. Proc. Natl. Acad. Sci. USA 96, 11,458–11,463.Google Scholar
  82. 82.
    Landis S. C. (1980) Developmental changes in the neurotransmitter properties of dissociated sympathetic neurons: a cytochemical study of the effects of the medium. Dev. Biol. 77, 349–361.PubMedGoogle Scholar
  83. 83.
    Yamamori T., Fukada K., Aebersold R., Korshing S., Fann M. J., and Patterson P. H. (1989) The cholinergic neuronal differentiation factor from hair cells is identical to leukemia inhibitory factor. Science 246, 1412–1416.PubMedGoogle Scholar
  84. 84.
    Nicola N. A. (1994) Guidebook to cytokines and their receptors. Oxford University Press, Oxford, UK, pp. 1–7.Google Scholar
  85. 85.
    Stockli K. A., Lottspeich F., Sendtner M., et al. (1989) Molecular cloning, expression, and regional expression of rat ciliary neurtrophic factor. Nature 342, 920–923.PubMedGoogle Scholar
  86. 86.
    Simpson R. J., Hammacher A., Smith D. K., Matthews J. M., and Ward L. D. (1997) Interleukin-6: structure-function relationships. Prot. Sci. 6, 929–955.Google Scholar
  87. 87.
    Bravo J. and Heath J. K. (2000) Receptor recognition by gp130 cytokines. EMBO 19, 2399–2411.Google Scholar
  88. 88.
    Yawata H., Yasukawa K., Natsuka S., et al. (1993) Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6-binding and for IL-6 signal transduction through gp130. EMBO J. 12, 1705–1712.PubMedGoogle Scholar
  89. 89.
    Tischler A. S. and Greene L. A. (1975) Nerve growth factor-induced process formation by cultured rat pheochromocytoma cells. Nature 258, 341–342.PubMedGoogle Scholar
  90. 90.
    Greene L. A. and Tischler A. S. (1976) Establishmentof a noradrenergic clonal line of rat adreanl pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad Sci. USA 73, 2424–2428.PubMedGoogle Scholar
  91. 91.
    Cunningham M. E. and Greene L. A. (1998) A function-structure model for NGF-activated TRK. EMBO J. 17, 7282–7293.PubMedGoogle Scholar
  92. 92.
    McCarty J. H. and Feinstein S. C. (1998) Activation loop tyrosines contribute varying roles to TrkB autophosphorylation and signal transduction. Oncogene 16, 1691–1700.PubMedGoogle Scholar
  93. 93.
    Grob P. M., Ross A. H., Koprowski H., and Bothwall M. (1985) Characterization of the human melanoma nerve growth factor receptor. J. Biol. Chem. 260, 8044–8049.PubMedGoogle Scholar
  94. 94.
    Kaplan D. R., Hempstead B. L., Martin-Zanca D., Chao M. V., and Parada L. F. (1991a) The trk proto-oncogene product: a signal transducing receptor for nerve growth factor. Science 252, 554–584.PubMedGoogle Scholar
  95. 95.
    Kaplan D. R., Martin-Zanca D., and Parada L. F. (1991b) Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF. Nature 350, 158–160.PubMedGoogle Scholar
  96. 96.
    Jing S., Tapley P., and Barbacid M. (1992) Nerve growth factor mediates signal transduction through trk homodimer receptors. Neuron 9, 1067–1079.PubMedGoogle Scholar
  97. 97.
    van der Geer P., Wiley S., Lai V. K., et al. (1995) A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides. Curr. Biol. 5, 404–412.PubMedGoogle Scholar
  98. 98.
    Borg J. P. and Margolis B. (1998) Function of PTB domains. Curr. Top. Microbiol. Immunol. 228, 23–38.PubMedGoogle Scholar
  99. 99.
    Obermeier A., Lammers R., Wiesmuller K., Jung G., Schlessinger J., and Ullrich A. (1993) Identification of trk binding sites for SHC and phosphatidylinositol 3′-kinase and formation of a multimeric signaling complex. J. Biol. Chem. 268, 22,963–22,966.Google Scholar
  100. 100.
    Stephens R. D., Loeb D., Copeland T., Pawson T., Greene L., and Kaplan D. (1994) Trk receptors use redundant signal transduction pathways involving SHC and PLC gamma 1 to mediate NGF responses. Neuron 12, 691–705.PubMedGoogle Scholar
  101. 101.
    Dikic I., Batzer A. G., Blaikie P., et al. (1995) Shc binding to nerve growth factor receptor is mediated by the phosphotyrosine interaction domain. J. Biol. Chem. 270, 15,125–15,129.Google Scholar
  102. 102.
    Meakin S. O., MacDonald J. I., Gryz E. A., Kubu C. J., and Verdi J. M. (1999) The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. J. Biol. Chem. 274, 9861–9870.PubMedGoogle Scholar
  103. 103.
    Guiton M., Gunn-Moore F. J., Glass D. J., et al. (1995) Naturally occurring tyrosine kinase inserts block high affinity binding of phospholipase C gamma and Shc to TrkC and neurotrophin-3 signaling. J. Biol. Chem. 270, 20,384–20,390.Google Scholar
  104. 104.
    Loeb D. M., Stephens R. M., Copeland T., Kaplan D. R., and Greene L. A. (1994) A trk nerve growth factor (NGF) receptor point mutation affecting interaction with phospholipase C-gamma 1 abolishes NGF-promoted peripherin induction by not neurite out-growth. J. Biol. Chem. 269, 8901–8910.PubMedGoogle Scholar
  105. 105.
    Yamashita T., Tucker K. L., and Barde Y.-A. (1999) Neurotrophin binding to the p75 receptor modulates Rho activity and axonal out-growth. Neuron 24, 585–593.PubMedGoogle Scholar
  106. 106.
    Klesse L. J., Meyers K. A., Marshall C. J., and Parada L. F. (1999) Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells. Oncogene 18, 2055–2068.PubMedGoogle Scholar
  107. 107.
    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.PubMedGoogle Scholar
  108. 108.
    Aloyz R. S., Bamji S. X., Pozniak C. D., et al. (1998) p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. J. Cell Biol. 143, 1691–1703.PubMedGoogle Scholar
  109. 109.
    Chen Y. R., Wang X., Templeton D., Davis R. J., and Tan T. H. (1996) The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J. Biol. Chem. 271, 31,929–31,936.Google Scholar
  110. 110.
    Baxter R. M., Cohen P., Obermeier A., Ullrich A., Downes C. P., and Doza Y. N. (1995) Phosphotyrosine residues in the nerve-growth-factor receptor (Trk-A). Their role in the activation of inositolphospholipid metabolism and protein kinase cascades in phaeochromocytoma (PC12) cells. Eur. J. Biochem. 234, 84–91.PubMedGoogle Scholar
  111. 111.
    Peng X., Greene L. A., Kaplan D. R., and Stephens R. M. (1995) Deletion of a conserved juxtamembrane sequence in Trk abolishes NGF-promoted neuritogenesis. Neuron 15, 395–406.PubMedGoogle Scholar
  112. 112.
    Berninger B., Garcia D. E., Inagaki N., Hahnel C., and Lindholm D. (1993) BDNF and NT-3 induce intracellular Ca2+ elevation in hippocampal neurons. NeuroReport 4, 1303–1306.PubMedGoogle Scholar
  113. 113.
    Berridge M. (1993) Inositol triphosphate and calcium signaling. Nature 361, 315–325.PubMedGoogle Scholar
  114. 114.
    Shieh P. B., Hu S.-C., Bobb K., Timmusk T., and Ghosh A. (1998) Identification of a signalling pathway involved in calcium regulation of BDNF expression. Neuron 20, 727–740.PubMedGoogle Scholar
  115. 115.
    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.PubMedGoogle Scholar
  116. 116.
    Al-Majed A. A., Brushart T. M., and Gordon T. (2000b) Electrical stimulation accelerates and increases expression of BDNF and trkB mRNA in regenerating rat femoral motoneurons. Eur. J. Neurosci. 12, 4381–4390.PubMedGoogle Scholar
  117. 117.
    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 PI3-kinase. Neuron 27, 265–277.PubMedGoogle Scholar
  118. 118.
    Dolcet X., Egea J., Soler R. M., Martin-Zanca D., and Comella J. X. (1999) Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediated brain-derived neurotrophic factor-induced motoneuron survival. J. Neurochem. 73, 521–531.PubMedGoogle Scholar
  119. 119.
    Wiese S., Pei G., Karch C., Toppmair J., Holtmann B., Rapp U. R., and Sendtner M. (2001) Specific function of B-raf in mediating survival of embryonic motoneurons and sensory neurons. Nat. Neurosci. 4, 137–142.PubMedGoogle Scholar
  120. 120.
    Perry D. K. and Hannun Y. A. (1998) The role of ceramide in cell signaling. Biochim. Biophys. Acta. 1436, 233–243.PubMedGoogle Scholar
  121. 121.
    Dobrowsky R. T., Jenkins G. M., and Hannun Y. A. (1995) Neurotrophins induce sphingomyelin hydrolysis: modulation by coexpression of p75NTR with Trk receptors. J. Biol. Chem. 270, 22,135–22,142.Google Scholar
  122. 122.
    Casaccia-Bonnefil P., Carter B. D., Dobrowsky R. T., and Chao M. V. (1996) Death of oligodendrocytes mediated by the interaction of nerve growth factor with its receptor p75. Nature 383, 716–719.PubMedGoogle Scholar
  123. 123.
    Carter B. D., Kaltschmidt C., Kaltschmidt B., et al. (1996) Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Science 272, 542–545.PubMedGoogle Scholar
  124. 124.
    Ping S. E. and Barrett G. L. (1998) Ceramide can induced cell death in sensory neurons, whereas ceramide analogues and sphingosine promote survival. J. Neurosci. Res. 54, 206–213.PubMedGoogle Scholar
  125. 125.
    Brann A. B., Scott R., Neuberger Y., et al. (1999) Ceramide signaling downstream of the p75 neurotrophin receptor mediates the effects of nerve growth factor on outgrowth of cultured hippocampal neurons. J. Neurosci. 19, 8199–8206.PubMedGoogle Scholar
  126. 126.
    MacPhee I. J. and Barker P. A. (1997) Brainderived neurotrophic factor binding to the p75 neurotrophin receptor reduces trkA signaling while increasing serine phosphorylation in the trkA intracellular domain. J. Biol. Chem. 272, 23,547–23,557.Google Scholar
  127. 127.
    MacPhee I. J. and Barker P. A. (1999) Extended ceramide exposure activates the trkA receptor by increasing receptor homodimer formation. J. Neurochem. 72, 1423–1430.PubMedGoogle Scholar
  128. 128.
    Reyes J. G., Robayna I. G., Delgado P. S., et al. (1996) c-Jun is a downstream target for ceramide-activated protein phosphatase in A431 cells. J Biol Chem. 271, 21,375–21,380.Google Scholar
  129. 129.
    Zhang Y., Yao B., Delikat S., et al. (1997) Kinase suppressor of Ras is ceramide-activated protein kinase. Cell 89, 63–72.PubMedGoogle Scholar
  130. 130.
    Yao B., Zhang Y., Delikat S., Mathias S., Basu S., and Kolesnick R. (1995) Phosphorylation of Raf by ceramide-activated protein kinase. Nature 378, 307–310.PubMedGoogle Scholar
  131. 131.
    Spiegel S., Foster D., and Kolesnick R. (1996) Signal transduction through lipid second messengers. Curr. Opin. Cell Biol. 8, 159–167.PubMedGoogle Scholar
  132. 132.
    Cuvillier O., Pirianov G., Kleuser B., et al. (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381, 800–803.PubMedGoogle Scholar
  133. 133.
    Edsall L. C., Pirianov G. G., and Spiegel S. (1997) Involvement of sphingosine 1-phosphate in nerve growth factor-mediated neuronal survival and differentiation. J. Neurosci. 17, 6952–6960.PubMedGoogle Scholar
  134. 134.
    Spiegel S. (2000) Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein-coupled receptors Ann. NY Acad. Sci. 905, 54–60.Google Scholar
  135. 135.
    Rothe M., Sarma V., Dixit V. M., and Goeddel D. V. (1995) TRAF2-mediated activation of NF-kappa B by TNF receptor 2 and CD40. Science 269, 1424–1427.PubMedGoogle Scholar
  136. 136.
    Song H. J., Ming G. L., and Poo M. M. (1997) cAMP-induced switching in turning direction of nerve growth cones. Nature 388, 275–259.PubMedGoogle Scholar
  137. 137.
    Khursigara G., Orlinick J. R., and Chao M. V. (1999) Association of the p75 neurotrophin receptor with TRAF6. J. Biol. Chem. 274, 2597–2600.PubMedGoogle Scholar
  138. 138.
    Yamashita J., Avraham S., Jiang S., Dikic I., and Avraham H. (1999) The Csk homologous kinase associates with trkA receptors and is involved in neurite outgrowth of PC12 cells. J. Biol. Chem. 274, 15,059–15,065.Google Scholar
  139. 139.
    Dickson B. J. (2001) Rho GTPases in growth cone guidance. Curr. Opin. Neurobiol. 11, 103–110.PubMedGoogle Scholar
  140. 140.
    Lee K. F., Li E., Huber L. J., Landis S. C., Sharpe A. H., Chao M. V., and Jaenisch R. (1992) Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 69, 737–749.PubMedGoogle Scholar
  141. 141.
    Lee K. F., Davies A. M., and Jaenisch R. (1994) p75-deficient embryonic dorsal root sensory and neonatal sympathetic neurons display a decreased sensitivity to NGF. Development 120, 1027–1033.PubMedGoogle Scholar
  142. 142.
    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.PubMedGoogle Scholar
  143. 143.
    Ferri C. C., Moore F. A., and Bisby M. A. (1998) Effects of facial nerve injury on mouse motoneurons lacking the p75 low affinity neurotrophin receptor. J. Neurobiol. 34, 1–9.PubMedGoogle Scholar
  144. 144.
    Boyd J. G. and Gordon T. (2001) The neurotrophin receptors, trkB and p75, differentially regulate motor axonal regeneration. J. Neurbiol. 49, 314–325.Google Scholar
  145. 145.
    Wiese S., Metzger F., Botmann B., and Sendtner M. (1999) The role of p75NTR in modulating neurotrophin survival effects in developing motoneurons. Eur. J. Neurosci. 11, 1668–1676.PubMedGoogle Scholar
  146. 146.
    Chao M. V. and Hempstead B. L. (1995) p75 and Trk: a two-receptor system. TINS 18, 321–326.PubMedGoogle Scholar
  147. 147.
    Ross G. M., Shamovsky I. L., Lawrance G., et al. (1998) Reciprocal modulation of trkA and p75NTR affinity states is mediated by direct receptor interactions. Eur. J. Neurosci. 10, 890–898.PubMedGoogle Scholar
  148. 148.
    Kohn J., Aloyz R. S., Toma J. G., Haak-Frendscho M., and Miller F. D. (1999) Functionally antagonistic interactions between the trkA and p75 neurotrophin receptors regulate sympathetic neuron growth and target innervation. J. Neurosci. 19, 5393–5408.PubMedGoogle Scholar
  149. 149.
    Bamji S. X., Majdan M., Pozniak C. D., et al. (1998) The p75 neurotrophin receptor mediates neuronal apoptosis and is essential for naturally occurring sympathetic neuron death. J. Cell Biol. 140, 911–923.PubMedGoogle Scholar
  150. 150.
    Kimpinski K., Campenot R. B., and Mearow K. (1997) Effects of the neurotrophins nerve growth factor, neurotrophin-3, and brain-derived neurotrophic factor (BDNF) on neurite growth from adult sensory neurons in compartmented cultures. J. Neurobiol. 33, 395–410.PubMedGoogle Scholar
  151. 151.
    Weskamp G. and Reichardt L. F. (1991) Evidence that biological activity of NGF is mediated through a novel subclass of high affinity receptors. Neuron 6, 649–663.PubMedGoogle Scholar
  152. 152.
    Posse de Chaves E. I., Bussiere M., Vance D. E., Campenot R. B., and Vance J. E. (1997) Elevation of ceramide within distal neurites inhibits neurite growth in cultured rat sympathetic neurons. J. Biol. Chem. 272, 3028–3035.Google Scholar
  153. 153.
    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 p75 neurotrophin receptor. J. Neurosci. 19, 4155–4168.PubMedGoogle Scholar
  154. 154.
    Bilderback T. R., Gazula V. R., and Dobrowsky R. T. (2001) Phosphoinositide 3-kinase regulates crosstalk between Trk A tyrosine kinase and p75(NTR)-dependent sphingolipid signaling pathways. J. Neurochem. 76, 1540–1551.PubMedGoogle Scholar
  155. 155.
    Song H. Y., Regnier C. H., Kirschning C. J., Goeddel D. V., and Rothe M. (1997) Tumor necrosis factor (TNF)-mediated kinase cascades: bifurcation of nuclear factor-kappaB and c-jun N-terminal kinase (JNK/SAPK) pathways at TNF receptor-associated factor 2. Proc. Natl. Acad. Sci. USA 94, 9792–9796.PubMedGoogle Scholar
  156. 156.
    Ming G., Song H., Beringer B., Inagaki N., Tessier-Lavigne M., and Poo M. M. (1999) Phospholipase C-γ and phosphoinositide 3-kinase mediated cytoplasmic signaling in nerve growth cone guidance. Neuron 23, 139–148.PubMedGoogle Scholar
  157. 157.
    Zheng M. and Kuffler D. P. (2000) Guidance of regenerating motor axons in vivo by gradients of diffusible peripheral nerve-derived factors. J. Neurobiol. 42, 212–219.PubMedGoogle Scholar
  158. 158.
    Tucker K. L., Meyer M., and Barde Y.-A. (2001) Neurotrophins are required for nerve growth during development. Nat. Neurosci. 4, 29–37.PubMedGoogle Scholar
  159. 159.
    Song H. J. and Poo M. M. (1999) Signal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363.PubMedGoogle Scholar
  160. 160.
    Airaksinen M. S., Titievsky A., and Saarma M. (1999) GDNF family neurotrophic factor signaling: four masters, one servant? Mol. Cell. Neurosci. 13, 313–325.PubMedGoogle Scholar
  161. 161.
    Asai N., Iwashita T., Murakami H., et al. (1999) Mechanism of Ret activation by a mutation at aspartic acid 631 identified in sporadic pheochromocytoma. Biochem. Biophys. Res. Commun. 255, 587–590.PubMedGoogle Scholar
  162. 162.
    Borrello M. G., Alberti L., Arighi E., et al. (1996) The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase C gamma. Mol. Cell. Biol. 16, 2151–2163.PubMedGoogle Scholar
  163. 163.
    Durick K., Wu R. Y., Gill G. N., and Taylor S. S. (1996) Mitogenic signaling by Ret/ptc2 requires association with enigma via a LIM domain. J. Biol. Chem. 271, 12,691–12,694.Google Scholar
  164. 164.
    Pandey A., Liu X., Dixon J. E., Di Fiore P. P., and Dixit V. M., (1996) Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7. J. Biol. Chem. 271, 10,607–10,610.Google Scholar
  165. 165.
    Arighi E., Alberti L., Torriti F., et al. (1997) Identification of Shc docking site on Ret tyrosine kinase. Oncogene 14, 773–782.PubMedGoogle Scholar
  166. 166.
    Lorenzo M. J., Gish G. D., Houghton C., et al. (1997) RET alternate splicing influences the interaction of activated RET with the SH2 and PTB domains of Shc, and the SH2 domain of Grb2. Oncogene 14, 763–771.PubMedGoogle Scholar
  167. 167.
    Ohiwa M., Murakami H., Iwashita T., et al. (1997) Characterization of Ret-Shc-Grb2 complex induced by GDNF, MEN 2A, and MEN 2B mutations. Biochem. Biophys. Res. Commun. 237, 747–751.PubMedGoogle Scholar
  168. 168.
    Alberti L., Borrello M. G., Ghizzoni S., Torriti F., Rizzetti M. G., and Pierotti M. A. (1998) Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene 17, 1079–1087.PubMedGoogle Scholar
  169. 169.
    Xing S., Furminger T. L., Tong Q., Jhiang S. M. (1998) Signal transduction pathways activated by RET oncoproteins in PC12 pheochromocytoma cells. J. Biol. Chem. 273, 4909–4914.PubMedGoogle Scholar
  170. 170.
    Santoro M., Wong W. T., Aroca P., et al. (1994) An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway. Mol. Cell Biol. 14, 663–675.PubMedGoogle Scholar
  171. 171.
    Worby C. A., Vega Q. C., Zhao Y., Chao H. H., Seasholtz A. F., and Dixon J. E. (1996) Glial cell line-derived neurotrophic factor signals through the RET receptor and activates mitogen-activated protein kinase. J. Biol. Chem. 271, 23,619–23,622.Google Scholar
  172. 172.
    Soler R. M., Dolcet X., Encinas M., Joaquim E., Bayascas J. R., and Comella J. X. (1999) Receptors of the glial cell line-derived neurotrophic factor family of neurotrophic factors signal cell survival through the phosphatidylinositol 3-kinase pathway in spinal cord motoneurons. J. Neurosci. 19, 9160–9169.PubMedGoogle Scholar
  173. 173.
    Trupp M., Scott R., Whittemore S. R., and Ibanez C. F. (1999) Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. J. Biol. Chem. 274, 20,885–20,894.Google Scholar
  174. 174.
    van Weering D. H. and Bos J. L. (1997) Glial cell line-derived neurotrophic factor induces Ret-mediated lamellipodia formation. J. Biol. Chem. 272, 249–254.PubMedGoogle Scholar
  175. 175.
    Encinas M., Tansey M. G., Tsui-Pierchala B. A., et al. (2001) c-Src is required for glial cell line-derived neurotrophic factor (GDNF) family ligand-mediated neuronal survival via a phosphatidylinositol-3 kinase (Pl-3K)-dependent pathway. J. Neurosci. 21, 1464–1472.PubMedGoogle Scholar
  176. 176.
    Chiariello M., Visconti R., Carlomagno F., et al. (1998) Signalling of the ret receptor tyrosine kinase through the c-jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the erks and JNKs pathways induced by ret. Oncogene 16, 2435–2445.PubMedGoogle Scholar
  177. 177.
    Yoon S. O., Casaccia-Bonnefil P., Carter B., and Chao M. V. (1998) Competitive signaling between TrkA and p75 nerve growth factor receptors determines cell survival. J Neurosci. 18, 3273–3281.PubMedGoogle Scholar
  178. 178.
    Creedon D. J., Tansey M. G., Baloh R. H., et al. (1997) Neurturin shares receptors and signal transduction pathways with glial cell line-derived neurotrophic factor in sympathetic neurons. Proc. Natl. Acad. Sci. USA 94, 7018–7023.PubMedGoogle Scholar
  179. 179.
    van Weering D. H., de Rooij J., Marte B., Downward J., Bos J. L., and Burgering B. M. (1998) Protein kinase B activation and lamellipodium formation are independent phosphoinositide 3-kinase-mediated events differentially regulated by endogenous Ras. Mol. Cell. Biol. 18, 1802–1811.PubMedGoogle Scholar
  180. 180.
    Jacobson K. and Dietrich C. (1999) Looking at lipid rafts? Trends Cell Biol. 9, 87–91.PubMedGoogle Scholar
  181. 181.
    Poteryaev D., Titevsky A., Sun Y. F., et al. (1999) GDNF triggers a novel ret-independent src kinase family-coupled signaling via a GPI-linked GDNF receptor α1. FEBS Lett. 463, 63–66.PubMedGoogle Scholar
  182. 182.
    Tansey M. G., Baloh R. H., Milbrandt J., and Johnson E. M. Jr. (2000) GFRα-mediated localization of RET to lipid rafts is reuqired for effective downstream signaling, differentiation, and neuronal survival. Neuron 25, 611–623.PubMedGoogle Scholar
  183. 183.
    Turney A. M. and Bartlett P. F. (2000) Cytokines that signal through the leukemia inhibitory factor receptor-beta complex in the nervous system. J. Neurochem. 74, 889–899.Google Scholar
  184. 184.
    Ernst M., Oates A., and Dunn A. R. (1996) Gp130-mediated signal transduction in embryonic stem cells involves activation of Jak and Ras/mitogen-activated protein kinase pathways. J. Biol. Chem. 271, 30,136–30,143.Google Scholar
  185. 185.
    Kim H., Hawley T. S., Hawley R. G., and Baumann H. (1999) Protein tyrosine phosphatase 2 (SHP-2) moderates signaling by gp130 but is not required for the induction of acute-phase plasma protein genes in hepatic cells. Mol. Cell. Biol. 18, 1525–1533.Google Scholar
  186. 186.
    Hermanns H. M., Radtke S., Schaper F., Heinrich P. C., and Behrmann I. (2000) Non-redundant signal transduction of interleukin-6-type cytokines. The adapter protein Shc is specifically recruited to the oncostatin M receptor. J. Biol. Chem. 275, 40,742–40,748.Google Scholar
  187. 187.
    Hama T., Miyamoto M., Tsukui H., Nishio C., and Tatanka H. (1989) Interleukin-6 as a neurotrophic factor for promoting the survival of cultured basal forebrain cholinergic neurons from postnatal rats. Neurosci. Lett. 104, 340–344.PubMedGoogle Scholar
  188. 188.
    Arakawa Y., Sendtner M., and Thoenen H. (1990) Survival effect of ciliary neurotrophic factor (CNTF) on chick embryonic motoneurons in culture: comparison with other neurotrophic factors and cytokines. J. Neurosci. 10, 3507–3515.PubMedGoogle Scholar
  189. 189.
    Ip N. Y., Li Y. P., van de Stadt I., Panayotatos N., Alderson R. F., and Lindsay R. M. (1991) Ciliary neurotrophic factor enhances neuronal survival in embryonic rat hippocampal cultures. J. Neurosci. 11, 3124–3134.PubMedGoogle Scholar
  190. 190.
    Sendtner M., Kreutzberg G. W., and Thoenen H. (1990) Ciliary neurotrophic factor prevents the degeneration of motor neurons after axotomy. Nature 345, 440–441.PubMedGoogle Scholar
  191. 191.
    Martinou J. C., Martinou I., and Kato A. C. (1992) Cholinergic differentiation factor (CDF/LIF) promotes survival of isolated rat embryonic motoneurons in vitro. Neuron 8, 737–744.PubMedGoogle Scholar
  192. 192.
    Clatterbuck R. E., Price D. L., and Koliatsos V. E. (1993) Ciliary neurotrophic factor prevents retrograde neuronal death in the adult central nervous system. Proc Natl Acad Sci USA 90, 2222–2226.PubMedGoogle Scholar
  193. 193.
    Curtis R., Scherer S. S., Somogyi R., et al. (1994) Retrograde axonal transport of LIF is increased by peripheral nerve injury: correlation with increased LIF expression in distal nerve. Neuron 12, 191–294.PubMedGoogle Scholar
  194. 194.
    Hirota H., Kiyama H., Kishimoto T., and Taga T. (1996) Accelerated nerve regeneration in mice by upregulated expression of interleukin(IL)-6 and IL-6 receptor after trauma. J. Exp. Med. 183, 2627–2634.PubMedGoogle Scholar
  195. 195.
    Thier M., Marz P., Otten U., Weis J., and Rose-John S. (1999) Interleukin-6 and its soluble receptor support survival of sensory neurons. J. Neurosci Res. 55, 411–422.PubMedGoogle Scholar
  196. 196.
    Pennica D., Arce V., Swanson T. A., et al. (1996) Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons. Neuron 17, 63–74.PubMedGoogle Scholar
  197. 197.
    Arce V., Carces A., de Bovis B., Filippi P., Henderson C., Pettmann B., and deLapeyriere O. (1999) Cardiotrophin-1 requires LIFRβ to promote survival of mouse motoneurons purified by a novel technique. J. Neurosci. Res. 55, 119–126.PubMedGoogle Scholar
  198. 198.
    Oppenheim R. W., Wiese S., Prevette D., et al. (2001) Cardiotrophin-1, a muscle-derived cytokine, is required for the survival of subpopulations of developing motoneurons. J Neurosci. 21, 1283–1291.PubMedGoogle Scholar
  199. 199.
    Marz P., Herget T., Lang E., Otten U., and Rose-John S. (1998) Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation. Eur. J. Neurosci. 10, 2765–2773.Google Scholar
  200. 200.
    Zurn A. D., Winkel L., Menoud A., Djabali K., and Aebischer P. (1996) Combined effects of BDNF, GDNF and CNTF on motoneuron differentiation in vitro. J. Neurosci. Res. 44, 133–141.PubMedGoogle Scholar
  201. 201.
    Arce V., Pollock R. A., Philippe J-M., Pennica D., Henderson C. E., and deLaperyriere O. (1998) Synergistic effects of Schwann- and muscle-derived factors on motoneuron survival involve GDNF and cardiotrophin-1 (CT-1) J. Neurosci. 18, 1440–1448.PubMedGoogle Scholar
  202. 202.
    Murphy P. G., Borthwick L. A., Altares M., Gauldie J., Kaplan D., and Richardson P. M. (2000) Reciprocal actions of interleukin-6 and brain-derived neurotrophic factor on rat and mouse primary sensory neurons. Eur. J. Neurosci. 12, 1891–1899.PubMedGoogle Scholar
  203. 203.
    Funakoshi H., Frisen J., Barbany G., Timmusk T., Zacrisson O., Verge V., and Persson H. (1993) Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J. Cell Biol. 123, 455–465.PubMedGoogle Scholar
  204. 204.
    Escandon E., Soppet D., Rosenthal A., et al. (1994) Regulation of neurotrophin receptor expression during embryonic and postnatal development. J Neurosci. 14, 2054–2068.PubMedGoogle Scholar
  205. 205.
    Kobayashi N. R., Bedard A. N., Hincke M. T., and Tetzlaff W. (1996) Increased expression of BDNF and trkB mRNA in rat facial motoneurons after axotomy. Eur. J. Neurosci. 8, 1018–1029.PubMedGoogle Scholar
  206. 206.
    Al-Majed A. A., Neumann C. M., Brushart T. M., and Gordon T. (2000a) Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J. Neurosci. 20, 2602–2608.PubMedGoogle Scholar
  207. 207.
    Hammarberg H., Piehl F., Risling M., and Cullheim S. (2000) Differential regulation of trophic factor receptor mRNAs in spinal motoneurons after sciatic nerve transection and ventral root avulsion in the rat. J. Comp. Neurol. 426, 587–601.PubMedGoogle Scholar
  208. 208.
    Fernandes K. J., Kobayashi N. R., Jasmin B. J., and Tetzlaff W. (1998) Acetylcholinesterase gene expression in axotomized rat facial motoneurons is differentially regulated by neurotrophins: correlation with trkB and trkC mRNA levels and isoforms. J Neurosci. 18, 9936–9947.PubMedGoogle Scholar
  209. 209.
    Raivich G., and Kreutzberg G. W. (1987) Expression of growth factor receptors in injured nervous tissue I. Axotomy leads to a shift in the cellular distribution of specific β-nerve growth factor binding in the injured and regenerating PNS. J. Neurocytol. 16, 689–700.PubMedGoogle Scholar
  210. 210.
    Yan Q., and Johnson E. M. Jr. (1988) An immunohisotchemical study of the nerve growth factor receptor in developing rats. J. Neurosci. 8, 3481–3498.PubMedGoogle Scholar
  211. 211.
    Ernfors P., Henschen A., Olson L., and Persson H. (1989) Expression of nerve growth factor receptors mRNA is developmentally regulated and increased after axotomy in rat spinal cord motoneurons. Neuron 2, 1605–1613.PubMedGoogle Scholar
  212. 212.
    Koliatsos V. E., Crawford T. O., and Price D. L. (1991) Axotomy induces nerve growth factor receptor immunoreactivity in spinal motor neurons. Brain Res. 549, 297–304.PubMedGoogle Scholar
  213. 213.
    Rende M., Hagg T., Manthorpe M., and Varon S. (1992) Nerve growth factor receptor immunoreactivity in neurons of the normal adult rat spinal cord and its modulation after peripheral nerve lesions. J. Comp. Neurol. 319, 285–298.PubMedGoogle Scholar
  214. 214.
    Rende M., Giambanco I., Buratta M., and Tonali P. (1995) Axotomy induces a different modulation of low-affinity nerve growth factor receptor and choline acetyltransferase between adult rat spinal and brainstem motoneurons. J. Comp. Neurol. 363, 249–263.PubMedGoogle Scholar
  215. 215.
    Friedman B., Kleinfeld D., Ip N. Y., et al. (1995) BDNF and NT-4/5 exert neurotrophic influence on injured spinal motoneurons. J. Neurosci. 15, 1044–1056.PubMedGoogle Scholar
  216. 216.
    Wu W. (1996) Potential roles of gene expression change in adult rat spinal motoneurons following axonal injury: a comparison among c-jun, off-affinity nerve growth factor receptor (LNGFR), and nitric oxide synthase (NOS). Exp. Neurol. 141, 190–200.PubMedGoogle Scholar
  217. 217.
    Trupp M., Belluardo N., Funakoshi H., and Ibanez C. F. (1997) Complementary and overlapping expression of glial cell line-derived neurotrophic factor (GDNF), c-ret proto-oncogene, and GDNF receptor-alpha indicates multiple mechanisms of trophic actions in the adult rat CNS. J Neurosci. 17, 3554–3567.PubMedGoogle Scholar
  218. 218.
    Burazin T. C. D., and Gundlach A. L. (1998) Up-regulation of GDNF-α and c-ret mRNA in facial motor neurons following facial nerve injury in the rat. Mol. Brain Res. 55, 331–336.PubMedGoogle Scholar
  219. 219.
    Tsujino H., Mansur K., Kiryu-Seo S., et al. (1999) Discordant expression of c-Ret and glial cell line-derived neurotrophic factor receptor alpha-1 mRNAs in response to motor nerve injury in neonate rats. Mol. Brain Res. 70, 298–303.PubMedGoogle Scholar
  220. 220.
    Naveilhan P., ElShamy W. E., and Ernfors P. (1997) Differential regulation of mRNAs for GDNF and its receptors Ret and GDNFRα after sciatic nerve lesion in the mouse. Eur. J. Neurosci. 9, 1450–1460.PubMedGoogle Scholar
  221. 221.
    Keifer R., Lindholm D., and Kreutzberg G. W. (1993) Interleukin-6 and transforming growth factor-beta1 mRNAs are induced in rat facial nucleus following motoneuron axotomy. Eur. J. Neurosci. 5, 775–781.Google Scholar
  222. 222.
    Duberly R. M., and Johnson I. P. (1996) Increased expression of the alpha subunit of the ciliary neurotrophic factor (CNTF) receptor by rat facial motoneurons after neonatal axotomy and CNTF treatment. Neurosci. Lett. 218, 188–192.Google Scholar
  223. 223.
    Haas C. A., Hofmann H. D., and Kirsch M. (1999) Expression of CNTF/LIF-receptor components and activation of STAT3 signaling in axotomized facial motoneurons: evidence for a sequential postlesional function of the cytokines. J Neurobiol. 41, 559–571.PubMedGoogle Scholar
  224. 224.
    Schwaiger F. W., Schmitt G. H., Horvat A., et al. (2000) Peripheral but not central axotomy induces changes in Janus kinases (JAK) and signal transducers and activators of transcription (STAT). Eur. J. Neurosci. 12, 1165–1176.PubMedGoogle Scholar
  225. 225.
    Tanabe K., Kiryu-Seo S., Nakmura T., Mori N., Tsujino H., Ochi T., and Kiyama H. (1998) Alternative expression of Shc family members in nerve injured motoneurons. Br. Res. Mol. Br. Res. 53, 291–296.Google Scholar
  226. 226.
    Kiryo S., Morita N., Ohno K., Maeno H., and Kiyama H. (1996) Regulation of mRNA expression involved in Ras and PKA signal transduction pathways during rat hypoglossal nerve regeneration. Br. Res. Mol. Br. Res. 29, 147–156.Google Scholar
  227. 227.
    Ito Y., Sakagami H., and Kondo H. (1996) Enhanced gene expression for phosphatidylinositol 3-kinase in th hypoglossal motoneurons following axonal crush. Br. Res. Mol. Br. Res. 37, 329–332.Google Scholar
  228. 228.
    Owada Y., Utsunomiya A., Yoshimoto T., and Kondo H. (1997) Expression of mRNA for Akt, serine-threonine protein kinase, in the brain during development and its transient enhancement following axotomy of the hypoglossal nerve. J. Mol. Neurosci. 9, 27–33.PubMedGoogle Scholar
  229. 229.
    Ihle J. N. (2001) The Stat family in cytokine signaling. Curr. Opin. Cell Biol. 13, 211–217.PubMedGoogle Scholar
  230. 230.
    Bunge M. B., Bunge R. P., Kleitman N., and Dean A. C. (1989) Role of peripheral nerve extracellular matrix in Schwann cell function and in neurite regeneration. Dev. Neurosci. 11, 348–360.PubMedGoogle Scholar
  231. 231.
    Heumann R., Korsching S., Bandtlow C., and Thoenen H. (1987a) Changes of nerve growth factor synthesis in nonneural cells in response to sciatic nerve transection. J. Cell Biol. 104, 1623–1631.PubMedGoogle Scholar
  232. 232.
    Heumann R., Lindhom D., Bandtlow C., et al. (1987b) Differential regulation of mRNA encoding nerve growth factor and its receptor in rat sciatic nerves during development, degeneration and regeneration: role of macrophages. Proc. Natl. Acad. Sci. USA 84, 8735–8739.PubMedGoogle Scholar
  233. 233.
    Meyer M., Matsuoka I., Wetmore C., Olson L., and Thoenen H. (1992) Enhanced synthesis of brain-derived neurotrophic factor in the lesioned peripheral nerve: different mechanisms are responsible for the regulation of BDNF and NGF mRNA. J. Cell Biol. 119, 45–54.PubMedGoogle Scholar
  234. 234.
    Lindholm D., Heumann R., Meyer M., and Thoenen H. (1987) Interleukin-1 regulates synthesis of nerve growth factor in nonneuronal cells of rat sciatic nerve. Nature 330, 658–659.PubMedGoogle Scholar
  235. 235.
    Frisen J., Verge V. M. K., Fried K., et al. (1993) Characterization of glial trkB receptors: differential response to injury in the central and peripheral nervous systems. Proc. Natl. Acad. Sci. USA 90, 4971–4975.PubMedGoogle Scholar
  236. 236.
    Taniuchi M., Clark H. B., Schwitzer J. B., and Johnson E. M., Jr. (1988) Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by axonal contact, and binding properties. J. Neurosci. 8, 664–681.PubMedGoogle Scholar
  237. 237.
    Toma J. G., Pareek S., Barker P., Mathew T. C., Murphy R. A., Acheson A., and Miller F. D. (1992) Spatiotemporal increases in epidermal growth factor receptors following peripheral nerve injury. J. Neurosci. 12, 2504–2515.PubMedGoogle Scholar
  238. 238.
    Robertson M. D., Toews A. D., Bouldin T. W., Weaver J., Goins N. D., and Morell P. (1995) NGFR-mRNA expression in sciatic nerve: a sensitive indicator of early stages of axonopathy. Mol. Brain Res. 28, 231–238.Google Scholar
  239. 239.
    You S., Petrov T., Chung P. H., and Gordon T. (1997) The expression of the low affinity nerve growth factor receptor in long-term denervated Schwann cells. Glia 20, 87–100.PubMedGoogle Scholar
  240. 240.
    Taniuchi M., Clark H. B., Schwitzer J. B., and Johnson E. M., Jr. (1986) Induction of nerve growth factor receptor in Schwann cells after axotomy. Proc. Natl. Acad. Sci. USA 83, 4094–4098.PubMedGoogle Scholar
  241. 241.
    Anton E. S., Weskamp G., Reichardt L. F., and Matthew W. D. (1994) Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc. Natl. Acad. Sci. USA 91, 2795–2799.PubMedGoogle Scholar
  242. 242.
    Ferri C. C. and Bisby M. A. (1999) Improved survival of injured sciatic nerve Schwann cells in mice lacking the p75 receptor. Neurosci. Lett. 272, 191–194.PubMedGoogle Scholar
  243. 243.
    Soilu-Hanninen M., Ekert P., Bucci T., Syroid D., Bartlett P. F., Kilpatrick T. J. (1999) Nerve growth factor signaling through p75 induces apoptosis in Schwann cells via a Bcl-2 independent pathway. J. Neurosci. 19, 4828–4838.PubMedGoogle Scholar
  244. 244.
    Hoke A., Gordon T., Zochodne D. W., and Sulaiman O. A. (2002) A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Exp Neurol. 173, 77–85.PubMedGoogle Scholar
  245. 245.
    Ito Y., Yamamoto M., Li M., Doyu M., Tanaka F., Mutch T., Mitsuma T., and Sobue G. (1998) Differential expression of mRNAs for ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), interleukin-6 (IL-6), and their receptors (CNTFRα, LIFRβ, IL-6Rα and gp130) in injured peripheral nerves. Brain Res. 793, 321–327.PubMedGoogle Scholar
  246. 246.
    Friedman B., Scherer S. S., Rudge J. S., et al. (1992) Regulation of ciliary neurotrophic factor expression in myelin-related Schwann cell in vivo. Neuron 9, 295–305.PubMedGoogle Scholar
  247. 247.
    Sendtner M., Stockli K. A., and Thoenen H. (1992a) Synthesis and localization of ciliary neurotrophic factor in the sciatic nerve of the adult rat after lesion and during regeneration. J. Cell Biol. 118, 139–148.PubMedGoogle Scholar
  248. 248.
    Seniuk N., Altares M., Dunn R., and Richardson P. M. (1992) Decreased synthesis of ciliary neurotrophic factor in degenerating peripheral nerves. Brain Res. 572, 300–302.PubMedGoogle Scholar
  249. 249.
    Reichart F., Levitzky R., and Rotzhenker S. (1996) Interleukin 6 in intact and injured mouse peripheral nerves. Eur. J. Neurosci. 8, 530–535.Google Scholar
  250. 250.
    Sendtner M., Gotz R., Holtmann B., Thoenen H. (1997) Endogenous ciliary neurotrophic factor is a lesion factor for axotomized motoneurons in adult mice. J Neurosci. 17, 6999–7006.PubMedGoogle Scholar
  251. 251.
    Ekstrom P. A., Kerekes N., and Hokfelt T. (2000) Leukemia inhibitory factor null mice: unhampered in vitro outgrowth of sensory axons but reduced stimulatory potential by nerve segments. Neurosci Lett. 281, 107–110.PubMedGoogle Scholar
  252. 252.
    Kishino A., Ishige Y., Tatsuno T., Nakayama C., and Noguchi H. (1997) BDNF prevents and reverses adult rat motor neurons degeneration and induces axonal outgrowth. Exp. Neurol. 144, 273–286.PubMedGoogle Scholar
  253. 253.
    Novikov L., Novikova L., and Kellerth J.-O. (1997) Brain derived neurotrophic factor promotes axonal regeneration and long-term survival of adult rat spinal motoneurons in vivo. Neuroscience 79, 765–774.PubMedGoogle Scholar
  254. 254.
    Novikova L., Novikov L., and Kellerth J.-O. (1997) Effects of neurotransplants and BDNF on the survival and regeneration of injured adult spinal motoneurons. Eur. J. Neurosci. 9, 2774–2777.PubMedGoogle Scholar
  255. 255.
    Carlsson J., Lais A. C., Dyck P. J. (1979) Axonal atrophy from permanent peripheral axotomy in adult cat. J. Neuropathol. Exp. Neurol. 38, 579–588.Google Scholar
  256. 256.
    Gordon T., Gillespie J., Orozco R., and Davis L. (1991) Axotomy induced changes in rabbit hindlimb nerves and the effects of chronic electrical stimulation. J. Neurosci. 11, 2157–2169.PubMedGoogle Scholar
  257. 257.
    Vanden Noven S., Wallace N., Muccio D., Turtz A., Pinter M. J. (1993) Adult spinal motoneurons remain viable despite prolonged absence of functional synaptic contact with muscle. Exp. Neurol. 123, 147–156.Google Scholar
  258. 258.
    Miyata Y., Kashihara Y., Homma S., Kuno M. (1986) Effects of nerve growth factor on the survival and synaptic function of la sensory neurons axotomized in neonatal rats. J Neurosci. 6, 2012–2018.PubMedGoogle Scholar
  259. 259.
    Sendtner M., Holtmann B., Kolbeck R., Thoenen H., and Barde Y.-A. (1992b) Brain-derived neurotrophic factor prevents the death of motoneurons in newborn rats after nerve section. Nature 360, 757–759.PubMedGoogle Scholar
  260. 260.
    Henderson C. E., Camu W., Mettling C., et al. (1993) Neurotrophins promote motor neurons survival and are present in embryonic limb bud. Nature 363, 768–783.Google Scholar
  261. 261.
    Terrado J., Monnier D., Perrelet D., Sagot Y., Mattenberger L., King B., and Kato A. C. (2000) NGF-induced motoneuron cell death depends on the genetic background and motoneuron sub-type. Neuroreport. 11, 1473–1477.PubMedGoogle Scholar
  262. 262.
    Sendtner M., Hotmann G., Hughes R. A. 1996) The response of motoneurons to neurotrophins. Neurochem. Res. 21, 831–841.PubMedGoogle Scholar
  263. 263.
    Koliatsos V. E., Clatterbuck R. E., Winslow J. W., Cayouette M. H., and Price D. L. (1993) Evidence that brain-derived neurotrophic factor is a trophic factor for motoneurons in vivo. Neuron 10, 359–367.PubMedGoogle Scholar
  264. 264.
    Yan Q., Elliott J. L., Matheson C., Sun J., Zhang L., Mu X., Rex K. L., and Snider W. D. (1993) Influences of neurotrophins on mammalian motoneurons in vivo. J. Neurobiol. 24, 1555–1577.PubMedGoogle Scholar
  265. 265.
    Vejsada R., Sagot Y., and Kato A. C. (1995) Quantitative comparison of the transient rescue effects of neurotrophic factors on axotomized motoneurons in vivo. Eur. J. Neurosci. 7, 108–115.PubMedGoogle Scholar
  266. 266.
    Vejsada R., Tseng J., Lindsay R. M., Acheson A., Aebischer P., and Kato A. C. (1998) Synergistic but transient rescue effects of BDNF and GDNF on axotomized neonatal motoneurons. Neurosci. 84, 129–139.Google Scholar
  267. 267.
    Yuan Q., Wu W., So K. F., Cheung A. L., Prevette D. M., and Oppenheim R. W. (2000) Effects of neurotrophic factors on motoneuron survival following axonal injury in newborn rats. Neuroreport. 11, 2237–2241.PubMedGoogle Scholar
  268. 268.
    Chai H., Wu W., So K. F., Prevette D. M., and Oppenheim R. W. (1999) Long-term effects of a single dose of brain-derived neurotrophic factor on motoneuron survival following spinal root avulsion in the adult rat. Neurosci. Lett. 274, 147–150.PubMedGoogle Scholar
  269. 269.
    Alcantara S., Frisen J., del Rio J. A., Soriano E., Barbacid M., and Silos-Santiago I. (1997) TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death. J. Neurosci. 17, 3623–3633.PubMedGoogle Scholar
  270. 270.
    Hughes R. A., Sendtner M., and Thoenen H. (1993) Members of several gene families influence survival of rat motoneurons in vitro and in vivo. J. Neurosci. Res. 36, 663–671.PubMedGoogle Scholar
  271. 271.
    Li L., Wu W., Lin L.-F., Lei M., Oppenheim R. W., and Houenou L. J. (1995) Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proc. Natl. Acad. Sci. USA 92, 9771–9775.PubMedGoogle Scholar
  272. 272.
    Baumgartner B. J., and Shine H. D. (1998a) Permanent rescue of lesioned neonatal motoneurons and enhanced axonal regeneration by adenovirus-mediated expression of glial cell-line-derived neurotrophic factor. J. Neurosci. Res. 54, 766–777.PubMedGoogle Scholar
  273. 273.
    Baumgartner B. J. and Shine H. D. (1998b) Neuroprotection of spinal motoneurons following targeted transduction with an denoviral vector carrying the gene for glial cell line-derived neurotrophic factor. Exp. Neurol. 153, 102–112.PubMedGoogle Scholar
  274. 274.
    Sakamoto T., Watabe K., Ohashi T., Kawazoe Y., Oyanagi K., Inoue K., and Eto Y. (2000) Adenoviral vector-mediated GDNF gene transfer prevents death of adult facial motoneurons. Neuroreport. 11, 1857–1860.PubMedGoogle Scholar
  275. 275.
    Watabe K., Ohashi T., Sakamoto T., et al. (2000) Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor. J. Neurosci. Res. 60, 511–519.PubMedGoogle Scholar
  276. 276.
    Hottinger A. F., Azzouz M., Deglon N., Aebischer P., and Zurn A. D. (2000) Complete and long-term rescue of lesioned adult motoneurons by lentiviral-mediated expression of glial cell line-derived neurotrophic factor in the facial nucleus. J. Neurosci. 20, 5587–5593.PubMedGoogle Scholar
  277. 277.
    Cacalano G., Farinas I., Wang L. C., et al. (1998) GFRalphal is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21, 53–62.PubMedGoogle Scholar
  278. 278.
    Enomoto H., Araki T., Jackman A., Heuckeroth R. O., Snider W. D., Johnson E. M. Jr., and Millbrandt J. (1998) GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21, 317–324.PubMedGoogle Scholar
  279. 279.
    Li L., Oppenheim R. W., Lei M., and Houenou L. J. (1994) Neurotrophic agents prevent motoneuron death following sciatic nerve section in the neonatal mouse. J. Neurobiol. 25, 759–766.PubMedGoogle Scholar
  280. 280.
    Sendtner M., Arakawa Y., Stockli K. A., Kreutzberg G. W., and Thoenen H. (1991) Effect of ciliary neurotrophic factor (CNTF) on motoneuron survival. J. Cell Sci. Suppl. 15, 103–109.PubMedGoogle Scholar
  281. 281.
    Cheema S. S., Richards L. J., Murphy M., and Bartlett P. F. (1994) Leukaemia inhibitory factor rescues motoneurones from axotomy-induced cell death. Neuroreport 5, 989–992.PubMedGoogle Scholar
  282. 282.
    Gravel C., Gotz R., Lorrain A., and Sendtner M. (1997) Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons. Nat. Med. 3, 765–770.PubMedGoogle Scholar
  283. 283.
    Borke R. C., Curtis M., and Ginsberg C. (1993) Choline acetyltransferase and calcitonin generelated peptide immunoreactivity in motoneurons after different types of nerve injury. J. Neurocytol. 22, 141–153.PubMedGoogle Scholar
  284. 284.
    Tuszynski M. H., Mafong, E., and Meyer S. (1996) Central infusions of brain-derived neurotrophic factor and neurotrophin-4/5, but not nerve growth factor and neurotrophin-3, prevent loss of the cholinergic phenotype in injured adult motor neurons. Neuroscience 71, 761–771.PubMedGoogle Scholar
  285. 285.
    Jacobsson G., Piehl F., and Meister B. (1998) VAMP-1 and VAMP-2 gene expression in rat spinal motoneurones: differential regulation after neuronal injury. Eur. J. Neurosci. 10, 301–316.PubMedGoogle Scholar
  286. 286.
    Miller F. D., Tetzlaff W., Bisby M. A., Fawcett J. W., and Milner R. J. (1989) Rapid induction of the major embryonic alpha-tubulin mRNA, T alpha 1, during nerve regeneration in adult rats. J. Neurosci. 9, 1452–1463.PubMedGoogle Scholar
  287. 287.
    Tetzlaff W., Alexander S. W., Miller F. D., and Bisby M. A. (1991) Response of facial and rubrospinal neurons to axotomy: changes in mRNA expression for cytoskeletal proteins and GAP-43. J. Neurosci. 11, 2528–2544.PubMedGoogle Scholar
  288. 288.
    Bisby M. A., and Tetzlaff W. (1992) Changes in cytoskeletal protein synthesis following axon injury and during axon regeneration. Mol. Neurobiol. 6, 107–123.PubMedGoogle Scholar
  289. 289.
    Kishino A., Toma S., Ishiyama T., et al. (1998) Differential dose-dependent effects of BDNF on motor neuron survival and axonal outgrowth after spinal root avulsion in rats. Soc. Neurosc. Abs. 23.5.Google Scholar
  290. 290.
    Mendell L. M., Taylor J. S., Johnson R. D., and Munson J. B. (1995) Rescue of motoneuron and muscle afferent function in cats by regeneration into skin. II. Ia-motoneuron synapse. J. Neurophysiol. 73, 662–673.PubMedGoogle Scholar
  291. 291.
    Munson J. B., Shelton D. L., and McMahon S. B. (1997) Adult mammalian sensory and motor neurons: roles of endogenous neurotrophins and rescue by exogenous neurotrophins after axotomy. J. Neurosci. 17, 470–477.PubMedGoogle Scholar
  292. 292.
    Demetriou T., Duberly R. M., and Johnson I. P. (1996) Minimal effect of CNTF on the ultrastructure of axotomised motoneurons in the adult rat. Brain Res. 733, 312–317.PubMedGoogle Scholar
  293. 293.
    Ulenkate H. J. L. M., Gispen W.-H., and Jennekens F. G. I. (1996) Effects of ciliary neurotrophic factor on retrograde cell reaction after facial nerve crush in young adult rats. Brain Res. 717, 29–37.PubMedGoogle Scholar
  294. 294.
    Shirley D. M., Williams S. A., and Santos P. M. (1996) Brain-derived neurotrophic factor and peripheral nerve regeneration: a functional evaluation. Laryngoscope 106, 629–632.PubMedGoogle Scholar
  295. 295.
    Lewin S. L., Utley D. S., Cheng E. T., Verity A. N., and Terris D. J. (1997) Simultaneous treatment with BDNF and CNTF after peripheral nerve transection and repair enhances rate of functional recovery compared with BDNF treatment alone. Laryngoscope 107, 992–997.PubMedGoogle Scholar
  296. 296.
    Utley D. S., Lewin S. L., Cheng E. T., Verity A. N., Sierra D., and Terris D. J. (1996) Brain-derived neurotrophic factor and collagen tubulization enhance functional recovery after peripheral nerve transection and repair. Arch. Otolaryngol. Head Neck Surg. 122, 407–413.PubMedGoogle Scholar
  297. 297.
    Moir M. S., Wang M. Z., To M., Lum J., and Terris D. J. (2000) Delayed repair of transected nerves: effects of brain derived neurotrophic factor. Arch. Otolaryngol. Head Neck Surg. 126, 501–505.PubMedGoogle Scholar
  298. 298.
    Rafuse V. F., Gordon T., and Orozco R. (1992) Proportional enlargement of motor units after partial denervation of cat triceps surae muscles. J. Neurophysiol. 68, 1261–1276.PubMedGoogle Scholar
  299. 299.
    Rafuse V. F. and Gordon T. (1996a) Self-reinnervated cat medial gastrocnemius muscles. II. analysis of the mechanisms and significance of fiber type grouping in reinnervated muscles. J. Neurophysiol. 75, 282–297.PubMedGoogle Scholar
  300. 300.
    Rafuse V. F. and Gordon T. (1996b) Self-reinnervated cat medial gastrocnemius muscles. I. comparisons of the capacity for regenerating nerves to form enlarged motor units after extensive peripheral nerve injuries. J. Neurophysiol. 75, 268–281.PubMedGoogle Scholar
  301. 301.
    Boyd J. G. and Gordon T. (2002) Dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor. Eur. J. Neurosci. 15, 613–626.PubMedGoogle Scholar
  302. 302.
    Zhang J.-Y., Luo X.-G., Xian C. J., Liu Z.-H., and Zhou X.-F. (2000) Endogenous BDNF is required for myelination and regeneration of injured sciatic nerve in rodents. Eur. J. Neurosci. 12, 4171–4180.PubMedGoogle Scholar
  303. 303.
    Sterne G. D., Brown R. A., Green C. J., and Terenghi G. (1997a) Neurotrophin-3 delivered locally via fibronectin mats enhances peripheral nerve regeneration. Eur. J. Neurosci. 9, 1388–1396.PubMedGoogle Scholar
  304. 304.
    Sterne G. D., Coulton G. R., Brown R. A., Green C. J., and Terenghi G. (1997b) Neurotrophin-3-enhanced nerve regeneration selectively improves recovery of muscle fibres expression myosin heavy chains 2b. J. Cell Biol. 139, 709–715.PubMedGoogle Scholar
  305. 305.
    Simon M., Terenghi G., Green C. J., and Coulton G. R. (2000) Differential effects of NT-3 on reinnervation of the fast extensor digitorum longus (EDL) and the slow soleus muscle of rat. Eur. J. Neurosci. 12, 863–871.PubMedGoogle Scholar
  306. 306.
    Ibanez C. F., Ilag L. L., Murray-Rust J., and Persson H. (1993) An extended surface of binding to Trk tyrosine kinase receptors in NGF and BDNF allows the engineering of a multifunctional pan-neurotrophin. EMBO J. 12, 2281–2293.PubMedGoogle Scholar
  307. 307.
    Funakoshi H., Risling M., Carlstedt T., et al. (1998) Targeted expression of a multifunctional chimeric neurotrophin in the lesioned sciatic nerve accelerates regeneration of sensory and motor axons. Proc. Natl. Acad. Sci. USA 95, 5269–5274.PubMedGoogle Scholar
  308. 308.
    Fu S. Y. and Gordon T. (1995) Contributing factors to poor functional recovery after delayed nerve repair: prolonged axotomy. J. Neurosci. 15, 3876–3885.PubMedGoogle Scholar
  309. 309.
    Boyd J. G. and Gordon T. (2000) The combined effects of brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF) on motor axonal regeneration after chronic axotomy. Exp. Neurol. (In press.)Google Scholar
  310. 310.
    Boyd J. G., Posse de Chaves EIP, and Gordon T. (2000) In vivo evidence that high dose brain derived neurotrophic factor (BDNF) binding to p75 receptors inhibits motor axonal regeneration: a ceramide-dependent mechanism. Soc. Neurosci Abs. 317.10.Google Scholar
  311. 311.
    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.PubMedGoogle Scholar
  312. 312.
    Griesbeck O., Parsadanian A. S., Sendtner M., and Thoenen H. (1995) Expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 42, 21–33.PubMedGoogle Scholar
  313. 313.
    Holmquist B., Kanje M., Kerns J. M., and Danielsen N. (1993) A mathematical model for regeneration rate and initial delay following surgical repair of peripheral nerves. J. Neurosci. Meth. 48, 27–33.Google Scholar
  314. 314.
    Kim D. S., Kim S. Y., Moon S. J., Chung J. H., Kim K. H., Cho K. H., and Park K. C. (2001) Ceramide inhibits cell proliferation through Akt/PKB inactivation and decreases melanin synthesis in Mel-Ab cells. Pigment Cell Res. 14, 110–115.PubMedGoogle Scholar
  315. 315.
    Zinda M. J., Vlahos C. J., and Lai M. T. (2001) Ceramide induces the dephosphorylation and inhibition of constitutively activated Akt in PTEN negative U87mg cells. Biochem. Biophys. Res. Commun. 280, 1107–1115.PubMedGoogle Scholar
  316. 316.
    Schubert K. M., Scheid M. P., and Duronio V. (2000) Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J. Biol. Chem. 275, 13,330–13,335.Google Scholar
  317. 317.
    Sanes J. R. and Lichtman J. W. (1999) Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389–442.PubMedGoogle Scholar
  318. 318.
    Nguyen Q. T., Paradanian A. S., Snider W. D., and Lichtman J. W. (1998) Hyperinnervation of neuromuscular junctions cause by GDNF overexpression in muscle. Science 279, 1725–1729.PubMedGoogle Scholar
  319. 319.
    Keller-Peck C. R., Feng G., Sanes J. R., Yan Q., Lichtman J. W., and Snider W. D. (2001) Glial cell line-derived neurotrophic factor administration in postnatal life results in motor unit enlargement and continuous synaptic remodeling at the neuromuscular junction. J. Neurosci. 21, 6136–6146.PubMedGoogle Scholar
  320. 320.
    Gurney M. E., Yamamoto H., and Kwon Y (1992). Induction of motor neuron sprouting in vivo by ciliary neurotrophic factor and basic fibroblast growth factor. J. Neurosci. 12, 3241–3247.PubMedGoogle Scholar
  321. 321.
    Siegel S. G., Patton B., and English A. W. (2000) Ciliary neurotrophic factor is required for motoneuron sprouting. Exp. Neurol. 166, 205–212.PubMedGoogle Scholar
  322. 322.
    Edds M. V. (1950) Collateral sprouting of residual motor axons in partially denervated muscles. J. Exp. Zool. 113, 517–552.Google Scholar
  323. 323.
    Ho P.-R., Coan G. M., Cheng E. T., Niell C., Tarn D. M., Zhou H., Sierra D., and Terris D. J. (1998) Repair with collagen tubules linked with brain-derived neurotrophic factor and ciliary neurotrophic factor in a rat sciatic nerve injury model. Arch. Otolaryngol. Head Neck Surg. 124, 761–766.PubMedGoogle Scholar
  324. 324.
    Yao M., Moir M. S., Wang M. Z., To M. P., and Terris D. J. (1999) Peripheral nerve regeneration in CNTF knockout mice. Laryngoscope 109, 1263–1268.PubMedGoogle Scholar
  325. 325.
    Zhong J., Dietzel I. D., Wahle P., Kopf F., and Heumann R. (1999) Sensory impairments and delayed regeneration of sensory axons in interleukin-6 deficient mice. J. Neurosci. 19, 4305–4313.PubMedGoogle Scholar
  326. 326.
    Inserra M. M., Yao M., Murray R., and Terris D. J. (2000) Peripheral nerve regeneration in interleukin-6 knockout mice. Arch. Otolaryngol. Head Neck Surg. 126, 1112–1116.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • J. Gordon Boyd
    • 1
  • Tessa Gordon
    • 2
  1. 1.Department of Anatomy and Cell BiologyQueen’s UniversityKingstonCanada
  2. 2.University Centre for NeuroscienceUniversity of AlbertaEdmontonCanada

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