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Long-distance retrograde neurotrophic factor signalling in neurons

Nature Reviews Neuroscience volume 14, pages 177–187 (2013)Cite this article

Subjects

Key Points

  • Neurons require specialized mechanisms of intracellular neurotrophic factor signalling for communication over the long distances between axon terminals and the nucleus.

  • Retrograde neurotrophic factor signalling is essential for neuronal survival, axon and dendrite growth, neuronal subtype specification and synapse formation.

  • Mechanisms of retrograde signalling may vary for different ligand–receptor systems; for neurotrophins, retrograde signalling occurs through an internalized vesicle containing ligand and receptor — an entity termed the 'signalling endosome'.

  • Emerging evidence indicates that defects in trafficking and axonal transport of crucial retrograde trophic factor signals contribute to the pathology of several neurodegenerative diseases.

Abstract

The specialized architecture of neurons necessitates unique modes of intracellular communication to allow for cell survival, the ability to detect and respond to injury and aspects of neuronal development, such as axon and dendrite growth, plasticity, and synapse and circuit formation. Many of these neuronal processes rely on signal transduction pathways and transcriptional programmes that are activated by retrograde signals originating from target-derived cues that act on distal axons. Here, we review the many functions of long-range distal axon-to-cell body signalling and discuss mechanisms of retrograde target-derived growth factor signalling.

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Figure 1: Retrograde signals controlling sensory neuron development.
Figure 2: Retrograde NGF signalling controls sympathetic neuron survival and connectivity.
Figure 3: Mechanisms of neurotrophin internalization, signalling and retrograde transport.

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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. Michaelevski, I., Medzihradszky, K. F., Lynn, A., Burlingame, A. L. & Fainzilber, M. Axonal transport proteomics reveals mobilization of translation machinery to the lesion site in injured sciatic nerve. Mol. Cell Proteomics 9, 976–987 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. De Vos, K. J., Grierson, A. J., Ackerley, S. & Miller, C. C. Role of axonal transport in neurodegenerative diseases. Annu. Rev. Neurosci. 31, 151–173 (2008). This articles provides an excellent review of the pathological effects caused by defects in the axonal transport process as they pertain to various neurodegenerative diseases.

    Article  CAS  PubMed  Google Scholar 

  4. 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 

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

    Article  CAS  PubMed  Google Scholar 

  6. Buss, R. R. & Oppenheim, R. W. Role of programmed cell death in normal neuronal development and function. Anat. Sci. Int. 79, 191–197 (2004).

    Article  PubMed  Google Scholar 

  7. Barde, Y. A. Trophic factors and neuronal survival. Neuron 2, 1525–1534 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Wright, D. E., Zhou, L., Kucera, J. & Snider, W. D. Introduction of a neurotrophin-3 transgene into muscle selectively rescues proprioceptive neurons in mice lacking endogenous neurotrophin-3. Neuron 19, 503–517 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Davis, B. M., Goodness, T. P., Soria, A. & Albers, K. M. Over-expression of NGF in skin causes formation of novel sympathetic projections to trkA-positive sensory neurons. Neuroreport 9, 1103–1107 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Heumann, R., Korsching, S., Scott, J. & Thoenen, H. Relationship between levels of nerve growth factor (NGF) and its messenger RNA in sympathetic ganglia and peripheral target tissues. EMBO J. 3, 3183–3189 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shelton, D. L. & Reichardt, L. F. Expression of the β-nerve growth factor gene correlates with the density of sympathetic innervation in effector organs. Proc. Natl Acad. Sci. USA 81, 7951–7955 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Farinas, I., Yoshida, C. K., Backus, C. & Reichardt, L. F. Lack of neurotrophin-3 results in death of spinal sensory neurons and premature differentiation of their precursors. Neuron 17, 1065–1078 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hendry, I. A. & Campbell, J. Morphometric analysis of rat superior cervical ganglion after axotomy and nerve growth factor treatment. J. Neurocytol. 5, 351–360 (1976).

    Article  CAS  PubMed  Google Scholar 

  15. Vestergaard, S., Tandrup, T. & Jakobsen, J. Effect of permanent axotomy on number and volume of dorsal root ganglion cell bodies. J. Comp. Neurol. 388, 307–312 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Stockel, K., Paravicini, U. & Thoenen, H. Specificity of the retrograde axonal transport of nerve growth factor. Brain Res. 76, 413–421 (1974).

    Article  CAS  PubMed  Google Scholar 

  17. DiStefano, P. S. et al. The neurotrophins BDNF, NT-3, and NGF display distinct patterns of retrograde axonal transport in peripheral and central neurons. Neuron 8, 983–993 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. Mok, S. A. & Campenot, R. B. A nerve growth factor-induced retrograde survival signal mediated by mechanisms downstream of TrkA. Neuropharmacology 52, 270–278 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Zweifel, L. S., Kuruvilla, R. & Ginty, D. D. Functions and mechanisms of retrograde neurotrophin signalling. Nature Rev. Neurosci. 6, 615–625 (2005).

    Article  CAS  Google Scholar 

  24. Park, J. W., Vahidi, B., Taylor, A. M., Rhee, S. W. & Jeon, N. L. Microfluidic culture platform for neuroscience research. Nature Protoc. 1, 2128–2136 (2006).

    Article  CAS  Google Scholar 

  25. 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 PI3-kinase. Neuron 27, 265–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. 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 

  28. Pazyra-Murphy, M. F. et al. A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. J. Neurosci. 29, 6700–6709 (2009). The authors describe a retrograde-specific transcriptional response initiated by neurotrophins that is important for neuronal survival.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Putcha, G. V., Deshmukh, M. & Johnson, E. M. Jr. BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J. Neurosci. 19, 7476–7485 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nikoletopoulou, V. et al. Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467, 59–63 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Deppmann, C. D. et al. A model for neuronal competition during development. Science 320, 369–373 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mandai, K. et al. LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development. Neuron 63, 614–627 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Singh, K. K. et al. Developmental axon pruning mediated by BDNF–p75NTR-dependent axon degeneration. Nature Neurosci. 11, 649–658 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Sharma, N. et al. Long-distance control of synapse assembly by target-derived NGF. Neuron 67, 422–434 (2010). In this article, the authors propose a novel function for retrograde neurotrophin signalling in controlling upstream synapse formation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ladle, D. R., Pecho-Vrieseling, E. & Arber, S. Assembly of motor circuits in the spinal cord: driven to function by genetic and experience-dependent mechanisms. Neuron 56, 270–283 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Luo, W. et al. A hierarchical NGF signaling cascade controls Ret-dependent and Ret-independent events during development of nonpeptidergic DRG neurons. Neuron 54, 739–754 (2007).

    Article  CAS  PubMed  Google Scholar 

  38. Bodmer, D., Ascano, M. & Kuruvilla, R. Isoform-specific dephosphorylation of dynamin1 by calcineurin couples neurotrophin receptor endocytosis to axonal growth. Neuron 70, 1085–1099 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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 

  40. Wickramasinghe, S. R. et al. Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58, 532–545 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  45. Courchesne, S. L., Karch, C., Pazyra-Murphy, M. F. & Segal, R. A. Sensory neuropathy attributable to loss of Bcl-w. J. Neurosci. 31, 1624–1634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 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 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Vrieseling, E. & Arber, S. Target-induced transcriptional control of dendritic patterning and connectivity in motor neurons by the ETS gene Pea3. Cell 127, 1439–1452 (2006). Here, the authors demonstrate that retrograde growth factor (specifically, GDNF) signalling activates a transcriptional programme leading to specific patterns of motor neuron dendrite arborization.

    Article  CAS  PubMed  Google Scholar 

  49. Lom, B., Cogen, J., Sanchez, A. L., Vu, T. & Cohen-Cory, S. Local and target-derived brain-derived neurotrophic factor exert opposing effects on the dendritic arborization of retinal ganglion cells in vivo. J. Neurosci. 22, 7639–7649 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Guo, T. et al. An evolving NGF–Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates. Nature Neurosci. 14, 31–36 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Luo, W., Enomoto, H., Rice, F. L., Milbrandt, J. & Ginty, D. D. Molecular identification of rapidly adapting mechanoreceptors and their developmental dependence on ret signaling. Neuron 64, 841–856 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin, J. H. et al. Functionally related motor neuron pool and muscle sensory afferent subtypes defined by coordinate ETS gene expression. Cell 95, 393–407 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. Apostolova, G. & Dechant, G. Development of neurotransmitter phenotypes in sympathetic neurons. Auton. Neurosci. 151, 30–38 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. 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 

  56. Watson, F. L. et al. Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J. Neurosci. 19, 889–7900 (1999).

    Article  Google Scholar 

  57. Yuen, E. C., Howe, C. L., Li, Y., Holtzman, D. M. & Mobley, W. C. Nerve growth factor and the neurotrophic factor hypothesis. Brain Dev. 18, 362–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  58. Howe, C. L. & Mobley, W. C. Signaling endosome hypothesis: a cellular mechanism for long distance communication. J. Neurobiol. 58, 207–216 (2004).

    Article  PubMed  Google Scholar 

  59. 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 

  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. 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 

  62. Doherty, G. J. & McMahon, H. T. Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009).

    CAS  PubMed  Google Scholar 

  63. 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 

  64. Shao, Y. et al. Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J. Cell Biol. 157, 679–691 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Orth, J. D., Krueger, E. W., Weller, S. G. & McNiven, M. A. A novel endocytic mechanism of epidermal growth factor receptor sequestration and internalization. Cancer Res. 66, 3603–3610 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. 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 

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

    Article  CAS  PubMed  Google Scholar 

  68. Krag, C., Malmberg, E. K. & Salcini, A. E. PI3KC2α, a class II PI3K, is required for dynamin-independent internalization pathways. J. Cell Sci. 123, 4240–4250 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Christoforidis, S. et al. Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nature Cell Biol. 1, 249–252 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Abe, N., Inoue, T., Galvez, T., Klein, L. & Meyer, T. Dissecting the role of PtdIns(4,5)P2 in endocytosis and recycling of the transferrin receptor. J. Cell Sci. 121, 1488–1494 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Radhakrishnan, A., Stein, A., Jahn, R. & Fasshauer, D. The Ca2+ affinity of synaptotagmin 1 is markedly increased by a specific interaction of its C2B domain with phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 284, 25749–25760 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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 

  73. Bethoney, K. A., King, M. C., Hinshaw, J. E., Ostap, E. M. & Lemmon, M. A. A possible effector role for the pleckstrin homology (PH) domain of dynamin. Proc. Natl Acad. Sci. USA 106, 13359–13364 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Vetter, M. L., Martin-Zanca, D., Parada, L. F., Bishop, J. M. & Kaplan, D. R. Nerve growth factor rapidly stimulates tyrosine phosphorylation of phospholipase C-γ1 by a kinase activity associated with the product of the trk protooncogene. Proc. Natl Acad. Sci. USA 88, 5650–5654 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bunney, T. D. & Katan, M. PLC regulation: emerging pictures for molecular mechanisms. Trends Biochem. Sci. 36, 88–96 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Choi, J. H. et al. Phospholipase C-γ1 is a guanine nucleotide exchange factor for dynamin-1 and enhances dynamin-1-dependent epidermal growth factor receptor endocytosis. J. Cell Sci. 117, 3785–3795 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).

    Article  CAS  Google Scholar 

  78. Gorvel, J. P., Chavrier, P., Zerial, M. & Gruenberg, J. rab5 controls early endosome fusion in vitro. Cell 64, 915–925 (1991).

    Article  CAS  PubMed  Google Scholar 

  79. Bucci, C. et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70, 715–728 (1992).

    Article  CAS  PubMed  Google Scholar 

  80. Bucci, C., Thomsen, P., Nicoziani, P., McCarthy, J. & van Deurs, B. Rab7: a key to lysosome biogenesis. Mol. Biol. Cell 11, 467–480 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rink, J., Ghigo, E., Kalaidzidis, Y. & Zerial, M. Rab conversion as a mechanism of progression from early to late endosomes. Cell 122, 735–749 (2005). An important study demonstrating a switch in RAB proteins during maturation of endosomes.

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Deinhardt, K. et al. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Chen, X. Q. et al. Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell Res. 22, 677–696 (2011).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Harrington, A. W. et al. Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146, 421–434 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 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 

  87. Delcroix, J. D. et al. NGF signaling in sensory neurons: evidence that early endosomes carry NGF retrograde signals. Neuron 39, 69–84 (2003). In this article, the authors characterize the retrogradely transported NGF vesicle in sciatic nerve, showing that it associates with components of TRKA signalling pathways and has properties of an early endosome.

    Article  CAS  PubMed  Google Scholar 

  88. 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 

  89. O'Brien, J. J. & Nathanson, N. M. Retrograde activation of STAT3 by leukemia inhibitory factor in sympathetic neurons. J. Neurochem. 103, 288–302 (2007).

    CAS  PubMed  Google Scholar 

  90. Murphy, P. G., Grondin, J., Altares, M. & Richardson, P. M. Induction of interleukin-6 in axotomized sensory neurons. J. Neurosci. 15, 5130–5138 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Walker, B. A., Ji, S. J. & Jaffrey, S. R. Intra-axonal translation of RhoA promotes axon growth inhibition by CSPG. J. Neurosci. 32, 14442–14447 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Smith, R. B., Machamer, J. B., Kim, N. C., Hays, T. S. & Marques, G. Relay of retrograde synaptogenic signals through axonal transport of BMP receptors. J. Cell Sci. 125, 3752–3764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Cox, L. J., Hengst, U., Gurskaya, N. G., Lukyanov, K. A. & Jaffrey, S. R. Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nature Cell Biol. 10, 149–159 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Andreassi, C. et al. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nature Neurosci. 13, 291–301 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Deinhardt, K., Reversi, A., Berninghausen, O., Hopkins, C. R. & Schiavo, G. Neurotrophins redirect p75NTR from a clathrin-independent to a clathrin-dependent endocytic pathway coupled to axonal transport. Traffic 8, 1736–1749 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Salehi, A. et al. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51, 29–42 (2006). An important article providing evidence for the idea that defects in NGF axonal transport are a contributing factor in the pathogenesis of Alzhiemer's disease.

    Article  CAS  PubMed  Google Scholar 

  97. 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 

  98. Counts, S. E. et al. Reduction of cortical TrkA but not p75NTR protein in early-stage Alzheimer's disease. Ann. Neurol. 56, 520–531 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Svendsen, C. N., Cooper, J. D. & Sofroniew, M. V. Trophic factor effects on septal cholinergic neurons. Ann. NY Acad. Sci. 640, 91–94 (1991).

    Article  CAS  PubMed  Google Scholar 

  100. Topp, J. D., Gray, N. W., Gerard, R. D. & Horazdovsky, B. F. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J. Biol. Chem. 279, 24612–24623 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Devon, R. S. et al. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl Acad. Sci. USA 103, 9595–9600 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Cogli, L., Piro, F. & Bucci, C. Rab7 and the CMT2B disease. Biochem. Soc. Trans. 37, 1027–1031 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Cogli, L. et al. CMT2B-associated Rab7 mutants inhibit neurite outgrowth. Acta Neuropathol. 120, 491–501 (2010).

    Article  CAS  PubMed  Google Scholar 

  104. BasuRay, S., Mukherjee, S., Romero, E., Wilson, M. C. & Wandinger-Ness, A. Rab7 mutants associated with Charcot-Marie-Tooth disease exhibit enhanced NGF-stimulated signaling. PLoS ONE 5, e15351 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank members of the Ginty laboratory for their helpful comments and suggestions during the preparation of this manuscript.

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  1. The Solomon H. Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Anthony W. Harrington & David D. Ginty

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Glossary

Neurotrophic factor hypothesis

Neurons are overproduced during development. The neurotrophic factor hypothesis states that neurons that successfully compete for limiting amounts of target-derived survival factor gain a competitive advantage over others and survive, whereas those that fail to compete die.

Retrograde transport

The directed, coordinated movement of proteins or vesicles from distal axons towards the neuronal soma.

Signalling endosome

A term referring to endosomes containing active ligand–receptor complexes that associate with and activate components of downstream growth and survival signalling pathways as they traffic within axons and cell bodies.

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Harrington, A., Ginty, D. Long-distance retrograde neurotrophic factor signalling in neurons. Nat Rev Neurosci 14, 177–187 (2013). https://doi.org/10.1038/nrn3253

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