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Functions and mechanisms of retrograde neurotrophin signalling

Key Points

  • Limiting amounts of neurotrophins and other neurotrophic growth factors are expressed in target fields. Much of what we know about the functions of target-derived neurotrophic growth factors comes from studies of neurotrophins and the PNS. In the PNS, members of the neurotrophin family signal retrogradely, often across long distances, to support neuronal survival, thereby sculpting connectivity.

  • Target-derived growth factors signal locally, within distal axons, and retrogradely to regulate neuronal specification, axonal extension and branching, elaboration of dendrites, neurotransmitter phenotype, synaptogensis and synaptic function.

  • Considerable evidence from several laboratories supports the view that 'signalling endosomes' that contain both ligand and receptor are essential carriers of retrograde neurotrophin signals. Although there are likely to be other modes of retrograde signalling, their mechanisms have yet to be defined.

  • Growth factors use distinct mechanisms for ligand-dependent receptor internalization and trafficking. There is evidence for both clathrin-dependent and clathrin-independent modes of neurotrophin–tyrosine receptor kinase (Trk receptor) internalization.

  • Although some key events in the formation, sorting and trafficking of the signalling endosome are becoming clearer, the determination of the biochemical composition of this signalling endosome will give us a more complete understanding of retrograde signalling.

  • At present, challenges in the field include establishing the molecular composition of the signalling endosome, defining other modes of retrograde signalling and determining whether defective retrograde trophic factor signalling contributes to neurodegenerative disorders.

Abstract

Neuronal connections are established and refined through a series of developmental programs that involve axon and dendrite specification, process growth, target innervation, cell death and synaptogenesis. Many of these developmental events are regulated by target-derived neurotrophins and their receptors, which signal retrogradely over long distances from distal-most axons to neuronal cell bodies. Recent work has established many of the cellular and molecular events that underlie retrograde signalling and the importance of these events for both development and maintenance of proper neural connectivity.

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Figure 1: Compartmentalized neuronal cell culture system.
Figure 2: Retrograde neurotrophin signalling instructs various developmental programs.
Figure 3: Neurotrophins and their receptors use various modes of internalization.
Figure 4: The signalling endosome.

References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sofroniew, M. V., Howe, C. L. & Mobley, W. C. Nerve growth factor signaling, neuroprotection, and neural repair. Annu. Rev. Neurosci. 24, 1217–1281 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Huang, E. J. & Reichardt, L. F. Trk receptors: roles in neuronal signal transduction. Annu. Rev. Biochem. 72, 609–642 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Hamburger, V. The history of the discovery of the nerve growth factor. J. Neurobiol. 24, 893–897 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Hamburger, V. & Levi-Montalcini, R. Proliferation, differentiation and degeneration in the spinal ganglia of the chick embryo under normal and experimental conditions. J. Exp. Zool. 111, 457–501 (1949).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  8. Oppenheim, R. W. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci. 12, 252–255 (1989).

    Article  CAS  PubMed  Google Scholar 

  9. Snider, W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).

    Article  PubMed  Google Scholar 

  10. Hendry, I. A. The effects of axotomy on the development of the rat superior cervical ganglion. Brain Res. 90, 235–244 (1975).

    Article  CAS  PubMed  Google Scholar 

  11. Campenot, R. B. Local control of neurite development by nerve growth factor. Proc. Natl Acad. Sci. USA 74, 4516–4519 (1977).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Deckwerth, T. L., Easton, R. M., Knudson, C. M., Korsmeyer, S. J. & Johnson, E. M. Jr. Placement of the BCL2 family member BAX in the death pathway of sympathetic neurons activated by trophic factor deprivation. Exp. Neurol. 152, 150–162 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Deshmukh, M. & Johnson, E. M. Jr. Evidence of a novel event during neuronal death: development of competence-to-die in response to cytoplasmic cytochrome c. Neuron 21, 695–705 (1998).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Vogelbaum, M. A., Tong, J. X. & Rich, K. M. Developmental regulation of apoptosis in dorsal root ganglion neurons. J. Neurosci. 18, 8928–8935 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lonze, B. E., Riccio, A., Cohen, S. & Ginty, D. D. Apoptosis, axonal growth defects, and degeneration of peripheral neurons in mice lacking CREB. Neuron 34, 371–385 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Riccio, A., Pierchala, B. A., Ciarallo, C. L. & Ginty, D. D. An NGF-TrkA-mediated retrograde signal to transcription factor CREB in sympathetic neurons. Science 277, 1097–1100 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Watson, F. L. et al. Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J. Neurosci. 19, 7889–7900 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Kuruvilla, R., Ye, H. & Ginty, D. D. Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron 27, 499–512 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Watson, F. L. et al. Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nature Neurosci. 4, 981–988 (2001). Shows that distinct effector pathways are activated by local and retrograde neurotrophin signalling. Neurotrophin stimulation of axon terminals activates ERK1 and 2 locally in axons but neuronal survival responses are mediated by the retrograde activation of ERK5 in cell bodies.

    Article  CAS  PubMed  Google Scholar 

  22. Glebova, N. O. & Ginty, D. D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kuruvilla, R. et al. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Cell 118, 243–255 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Patel, T. D., Jackman, A., Rice, F. L., Kucera, J. & Snider, W. D. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 25, 345–357 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Patel, T. D. et al. Peripheral NT3 signaling is required for ETS protein expression and central patterning of proprioceptive sensory afferents. Neuron 38, 403–416 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Lonze, B. E. & Ginty, D. D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 35, 605–623 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Graef, I. A. et al. Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113, 657–670 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Haase, G. et al. GDNF acts through PEA3 to regulate cell body positioning and muscle innervation of specific motor neuron pools. Neuron 35, 893–905 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Voyvodic, J. T. Target size regulates calibre and myelination of sympathetic axons. Nature 342, 430–433 (1989).

    Article  CAS  PubMed  Google Scholar 

  30. Voyvodic, J. T. Peripheral target regulation of dendritic geometry in the rat superior cervical ganglion. J. Neurosci. 9, 1997–2010 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ruit, K. G., Osborne, P. A., Schmidt, R. E., Johnson, E. M. Jr. & Snider, W. D. Nerve growth factor regulates sympathetic ganglion cell morphology and survival in the adult mouse. J. Neurosci. 10, 2412–2419 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ruit, K. G. & Snider, W. D. Administration or deprivation of nerve growth factor during development permanently alters neuronal geometry. J. Comp. Neurol. 314, 106–113 (1991).

    Article  CAS  PubMed  Google Scholar 

  33. Snider, W. D. Nerve growth factor enhances dendritic arborization of sympathetic ganglion cells in developing mammals. J. Neurosci. 8, 2628–2634 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lein, P., Johnson, M., Guo, X., Rueger, D. & Higgins, D. Osteogenic protein-1 induces dendritic growth in rat sympathetic neurons. Neuron 15, 597–605 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Purves, D. Functional and structural changes in mammalian sympathetic neurones following interruption of their axons. J. Physiol. (Lond.) 252, 429–463 (1975).

    Article  CAS  Google Scholar 

  36. Purves, D. Functional and structural changes in mammalian sympathetic neurones following colchicine application to post-ganglionic nerves. J. Physiol. (Lond.) 259, 159–175 (1976).

    Article  CAS  Google Scholar 

  37. Purves, D. & Lichtman, J. W. Elimination of synapses in the developing nervous system. Science 210, 153–157 (1980).

    Article  CAS  PubMed  Google Scholar 

  38. Nja, A. & Purves, D. The effects of nerve growth factor and its antiserum on synapses in the superior cervical ganglion of the guinea-pig. J. Physiol. (Lond.) 277, 55–75 (1978).

    Article  Google Scholar 

  39. Causing, C. G. et al. Synaptic innervation density is regulated by neuron-derived BDNF. Neuron 18, 257–267 (1997).

    Article  CAS  PubMed  Google Scholar 

  40. Wetmore, C. & Olson, L. Neuronal and nonneuronal expression of neurotrophins and their receptors in sensory and sympathetic ganglia suggest new intercellular trophic interactions. J. Comp. Neurol. 353, 143–159 (1995).

    Article  CAS  PubMed  Google Scholar 

  41. Schober, A. et al. TrkB and neurotrophin-4 are important for development and maintenance of sympathetic preganglionic neurons innervating the adrenal medulla. J. Neurosci. 18, 7272–7284 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schober, A. et al. Expression of neurotrophin receptors trkB and trkC and their ligands in rat adrenal gland and the intermediolateral column of the spinal cord. Cell Tissue Res. 296, 271–279 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Roosen, A. et al. Lack of neurotrophin-4 causes selective structural and chemical deficits in sympathetic ganglia and their preganglionic innervation. J. Neurosci. 21, 3073–3084 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Acheson, A. L., Naujoks, K. & Thoenen, H. Nerve growth factor-mediated enzyme induction in primary cultures of bovine adrenal chromaffin cells: specificity and level of regulation. J. Neurosci. 4, 1771–1780 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Otten, U., Schwab, M., Gagnon, C. & Thoenen, H. Selective induction of tyrosine hydroxylase and dopamine β-hydroxylase by nerve growth factor: comparison between adrenal medulla and sympathetic ganglia of adult and newborn rats. Brain Res. 133, 291–303 (1977).

    Article  CAS  PubMed  Google Scholar 

  46. Francis, N. J. & Landis, S. C. Cellular and molecular determinants of sympathetic neuron development. Annu. Rev. Neurosci. 22, 541–566 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Ehlers, M. D., Kaplan, D. R., Price, D. L. & Koliatsos, V. E. NGF-stimulated retrograde transport of trkA in the mammalian nervous system. J. Cell Biol. 130, 149–156 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Halegoua, S., Armstrong, R. C. & Kremer, N. E. Dissecting the mode of action of a neuronal growth factor. Curr. Top. Microbiol. Immunol. 165, 119–170 (1991).

    CAS  PubMed  Google Scholar 

  49. Hendry, I. A., Stockel, K., Thoenen, H. & Iversen, L. L. The retrograde axonal transport of nerve growth factor. Brain Res. 68, 103–121 (1974).

    Article  CAS  PubMed  Google Scholar 

  50. von Bartheld, C. S. et al. Retrograde transport of neurotrophins from the eye to the brain in chick embryos: roles of the p75NTR and trkB receptors. J. Neurosci. 16, 2995–3008 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yip, H. K. & Johnson, E. M. Jr. Comparative dynamics of retrograde transport of nerve growth factor and horseradish peroxidase in rat lumbar dorsal root ganglia. J. Neurocytol. 15, 789–798 (1986).

    Article  CAS  PubMed  Google Scholar 

  52. Ginty, D. D. & Segal, R. A. Retrograde neurotrophin signaling: Trk-ing along the axon. Curr. Opin. Neurobiol. 12, 268–274 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Ye, H., Kuruvilla, R., Zweifel, L. S. & Ginty, D. D. Evidence in support of signaling endosome-based retrograde survival of sympathetic neurons. Neuron 39, 57–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Senger, D. L. & Campenot, R. B. Rapid retrograde tyrosine phosphorylation of trkA and other proteins in rat sympathetic neurons in compartmented cultures. J. Cell Biol. 138, 411–421 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Heerssen, H. M., Pazyra, M. F. & Segal, R. A. Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nature Neurosci. 7, 596–604 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Valdez, G. et al. Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. J. Neurosci. 25, 5236–5247 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhang, Y., Moheban, D. B., Conway, B. R., Bhattacharyya, A. & Segal, R. A. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J. Neurosci. 20, 5671–5678 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hafezparast, M. et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300, 808–812 (2003). Shows that mutations in dynein, which disrupt retrograde transport, lead to degeneration of projection neurons in mice.

    Article  CAS  PubMed  Google Scholar 

  59. MacInnis, B. L., Senger, D. L. & Campenot, R. B. Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons. Neuropharmacology 45, 995–1010 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. MacInnis, B. L. & Campenot, R. B. Retrograde support of neuronal survival without retrograde transport of nerve growth factor. Science 295, 1536–1539 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Delcroix, J. D. et al. NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39, 69–84 (2003). Provides biochemical insight into the nature of the 'signalling endosomes' that carry NGF and TrkA. Using an intact nerve preparation, the authors isolated retrogradely transported NGF–TrkA-containing vesicles, which were shown to carry not only activated signalling effectors but also markers of early endosomes such as Rab5 and EEA1.

    Article  CAS  PubMed  Google Scholar 

  62. Wu, C., Lai, C. F. & Mobley, W. C. Nerve growth factor activates persistent Rap1 signaling in endosomes. J. Neurosci. 21, 5406–5416 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Johanson, S. O., Crouch, M. F. & Hendry, I. A. Retrograde axonal transport of signal transduction proteins in rat sciatic nerve. Brain Res. 690, 55–63 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Delcroix, J. D. et al. Axonal transport of activating transcription factor-2 is modulated by nerve growth factor in nociceptive neurons. J. Neurosci. 19, RC24 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wiley, H. S. & Burke, P. M. Regulation of receptor tyrosine kinase signaling by endocytic trafficking. Traffic 2, 12–18 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Beattie, E. C., Howe, C. L., Wilde, A., Brodsky, F. M. & Mobley, W. C. NGF signals through TrkA to increase clathrin at the plasma membrane and enhance clathrin-mediated membrane trafficking. J. Neurosci. 20, 7325–7333 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Howe, C. L., Valletta, J. S., Rusnak, A. S. & Mobley, W. C. NGF signaling from clathrin-coated vesicles: evidence that signaling endosomes serve as a platform for the Ras-MAPK pathway. Neuron 32, 801–814 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Nabi, I. R. & Le, P. U. Caveolae/raft-dependent endocytosis. J. Cell Biol. 161, 673–677 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shao, Y. et al. Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J. Cell Biol. 157, 679–691 (2002). This paper identifies a novel protein, Pincher, that promotes clathrin-independent macropinocytosis of NGF and TrkA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Aguilar, R. C. & Wendland, B. Endocytosis of membrane receptors: two pathways are better than one. Proc. Natl Acad. Sci. USA 102, 2679–2680 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sigismund, S. et al. Clathrin-independent endocytosis of ubiquitinated cargos. Proc. Natl Acad. Sci. USA 102, 2760–2765 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Reynolds, A. J., Bartlett, S. E. & Hendry, I. A. Signalling events regulating the retrograde axonal transport of 125I-β nerve growth factor in vivo. Brain Res. 798, 67–74 (1998).

    Article  CAS  PubMed  Google Scholar 

  73. Du, J. et al. Regulation of TrkB receptor tyrosine kinase and its internalization by neuronal activity and Ca2+ influx. J. Cell Biol. 163, 385–395 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jullien, J. et al. Trafficking of TrkA-green fluorescent protein chimerae during nerve growth factor-induced differentiation. J. Biol. Chem. 278, 8706–8716 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Kahle, P., Barker, P. A., Shooter, E. M. & Hertel, C. p75 nerve growth factor receptor modulates p140trkA kinase activity, but not ligand internalization, in PC12 cells. J. Neurosci. Res. 38, 599–606 (1994).

    Article  CAS  PubMed  Google Scholar 

  76. Saxena, S. et al. Differential endocytic sorting of p75NTR and TrkA in response to NGF: a role for late endosomes in TrkA trafficking. Mol. Cell. Neurosci. 28, 571–587 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Bronfman, F. C., Tcherpakov, M., Jovin, T. M. & Fainzilber, M. Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome. J. Neurosci. 23, 3209–3220 (2003). Provides evidence that NGF–p75NTR complexes are internalized at a much slower rate than that of NGF–TrkA complexes, which indicates that internalized p75NTR and TrkA receptors might localize to distinct endosomal compartments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Marsh, M. & McMahon, H. T. The structural era of endocytosis. Science 285, 215–220 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Confalonieri, S., Salcini, A. E., Puri, C., Tacchetti, C. & Di Fiore, P. P. Tyrosine phosphorylation of Eps15 is required for ligand-regulated, but not constitutive, endocytosis. J. Cell Biol. 150, 905–912 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wilde, A. et al. EGF receptor signaling stimulates SRC kinase phosphorylation of clathrin, influencing clathrin redistribution and EGF uptake. Cell 96, 677–687 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Chen, X. et al. A chemical-genetic approach to studying neurotrophin signaling. Neuron 46, 13–21 (2005).

    Article  PubMed  CAS  Google Scholar 

  82. Tsui-Pierchala, B. A. & Ginty, D. D. Characterization of an NGF-P-TrkA retrograde-signaling complex and age-dependent regulation of TrkA phosphorylation in sympathetic neurons. J. Neurosci. 19, 8207–8218 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ure, D. R. & Campenot, R. B. Retrograde transport and steady-state distribution of 125I-nerve growth factor in rat sympathetic neurons in compartmented cultures. J. Neurosci. 17, 1282–1290 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Sandow, S. L. et al. Signalling organelle for retrograde axonal transport of internalized neurotrophins from the nerve terminal. Immunol. Cell Biol. 78, 430–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Weible, M. W., 2nd, Ozsarac, N., Grimes, M. L. & Hendry, I. A. Comparison of nerve terminal events in vivo effecting retrograde transport of vesicles containing neurotrophins or synaptic vesicle components. J. Neurosci. Res. 75, 771–781 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Bhattacharyya, A. et al. High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. J. Neurobiol. 51, 302–312 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. York, R. D. et al. Role of phosphoinositide 3-kinase and endocytosis in nerve growth factor-induced extracellular signal-regulated kinase activation via Ras and Rap1. Mol. Cell. Biol. 20, 8069–8083 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cullen, P. J., Cozier, G. E., Banting, G. & Mellor, H. Modular phosphoinositide-binding domains — their role in signalling and membrane trafficking. Curr. Biol. 11, R882–R893 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Simonsen, A. et al. EEA1 links PI(3)K function to Rab5 regulation of endosome fusion. Nature 394, 494–498 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Christoforidis, S., McBride, H. M., Burgoyne, R. D. & Zerial, M. The Rab5 effector EEA1 is a core component of endosome docking. Nature 397, 621–625 (1999).

    Article  CAS  PubMed  Google Scholar 

  91. Overly, C. C. & Hollenbeck, P. J. Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons. J. Neurosci. 16, 6056–6064 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Overly, C. C., Lee, K. D., Berthiaume, E. & Hollenbeck, P. J. Quantitative measurement of intraorganelle pH in the endosomal-lysosomal pathway in neurons by using ratiometric imaging with pyranine. Proc. Natl Acad. Sci. USA 92, 3156–3160 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zapf-Colby, A. & Olefsky, J. M. Nerve growth factor processing and trafficking events following TrkA-mediated endocytosis. Endocrinology 139, 3232–3240 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Yano, H. et al. Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor. J. Neurosci. 21, RC125 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Claude, P., Hawrot, E., Dunis, D. A. & Campenot, R. B. Binding, internalization, and retrograde transport of 125I-nerve growth factor in cultured rat sympathetic neurons. J. Neurosci. 2, 431–442 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Stoeckel, K. & Thoenen, H. Retrograde axonal transport of nerve growth factor: specificity and biological importance. Brain Res. 85, 337–341 (1975).

    Article  CAS  PubMed  Google Scholar 

  97. Grimes, M. L. et al. Endocytosis of activated TrkA: evidence that nerve growth factor induces formation of signaling endosomes. J. Neurosci. 16, 7950–7964 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang, Y., Pennock, S., Chen, X. & Wang, Z. Endosomal signaling of epidermal growth factor receptor stimulates signal transduction pathways leading to cell survival. Mol. Cell. Biol. 22, 7279–7290 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. York, R. D. et al. Rap1 mediates sustained MAP kinase activation induced by nerve growth factor. Nature 392, 622–626 (1998).

    Article  CAS  PubMed  Google Scholar 

  100. Barbieri, M. A. et al. Epidermal growth factor and membrane trafficking. EGF receptor activation of endocytosis requires Rab5a. J. Cell Biol. 151, 539–550 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lanzetti, L. et al. The Eps8 protein coordinates EGF receptor signalling through Rac and trafficking through Rab5. Nature 408, 374–377 (2000).

    Article  CAS  PubMed  Google Scholar 

  102. Lippe, R., Miaczynska, M., Rybin, V., Runge, A. & Zerial, M. Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex. Mol. Biol. Cell 12, 2219–2228 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Salehi, A., Delcroix, J. D. & Swaab, D. F. Alzheimer's disease and NGF signaling. J. Neural. Transm. 111, 323–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  104. Cooper, J. D. et al. Failed retrograde transport of NGF in a mouse model of Down's syndrome: reversal of cholinergic neurodegenerative phenotypes following NGF infusion. Proc. Natl Acad. Sci. USA 98, 10439–10444 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Siegel, G. J. & Chauhan, N. B. Neurotrophic factors in Alzheimer's and Parkinson's disease brain. Brain Res. Brain Res. Rev. 33, 199–227 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Mufson, E. J., Conner, J. M. & Kordower, J. H. Nerve growth factor in Alzheimer's disease: defective retrograde transport to nucleus basalis. Neuroreport 6, 1063–1066 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Campenot, R. B. Independent control of the local environment of somas and neurites. Methods Enzymol. 58, 302–307 (1979).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank C. Deppmann, N. Glebova and K. Scangos for comments on the manuscript. The authors' work is supported by a National Institutes of Health grant. D.G.G. is an investigator of the Howard Hughes Medical Institute.

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DATABASES

Entrez Gene

Akt

ATF2

Bax

Bcl2

BDNF

CGRP

CNTF

CREB

EEA1

ERK1

ERK2

EGF

FRS2

GDNF

LIF

NGF

NT3

NT4

PEA3

PI3K

PLCγ

p75NTR

Shc

TrkA

TrkB

TrkC

Glossary

PRONEUROTROPHINS

Uncleaved forms of the neurotrophins that bind with high affinity to p75NTR.

BAX

Pro-apoptotic BCL2 family member. BAX translocation from the cytosol to the mitochondria facilitates cytochrome c release.

APOPTOSOME

Heteromeric protein complex containing cytochrome c, APAF-1 and procaspase-9. Triggers a cascade of caspase activation and proteolysis.

Ras, Rap

Small GTPases that are involved in growth, differentiation and cellular signalling. They require the binding of GTP to enter into their active state.

MITOGEN-ACTIVATED PROTEIN KINASE SIGNALLING

A signalling cascade that relays signals from the plasma membrane to the nucleus. Mitogen-activated protein kinases (MAPKs), which represent the last step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals. ERKs are among the best-characterized MAPKs.

SH2 AND PTB DOMAINS

Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains bind directly to canonical sites of tyrosine phosphorylation (pYXN and NPXpY, respectively, where p represents phosphorylation) that are found in many tyrosine kinases. These domains are commonly found in adaptor proteins such as Shc and FRS2. For the Trk receptors, Shc and FRS2 bind to Y-490.

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Zweifel, L., Kuruvilla, R. & Ginty, D. Functions and mechanisms of retrograde neurotrophin signalling. Nat Rev Neurosci 6, 615–625 (2005). https://doi.org/10.1038/nrn1727

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