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.
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.
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Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).
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).
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.
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).
Oppenheim, R. W. The neurotrophic theory and naturally occurring motoneuron death. Trends Neurosci. 12, 252–255 (1989).
Buss, R. R. & Oppenheim, R. W. Role of programmed cell death in normal neuronal development and function. Anat. Sci. Int. 79, 191–197 (2004).
Barde, Y. A. Trophic factors and neuronal survival. Neuron 2, 1525–1534 (1989).
Snider, W. D. Functions of the neurotrophins during nervous system development: what the knockouts are teaching us. Cell 77, 627–638 (1994).
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).
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).
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).
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).
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).
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).
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).
Stockel, K., Paravicini, U. & Thoenen, H. Specificity of the retrograde axonal transport of nerve growth factor. Brain Res. 76, 413–421 (1974).
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).
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).
Hendry, I. A., Stockel, K., Thoenen, H. & Iversen, L. L. The retrograde axonal transport of nerve growth factor. Brain Res. 68, 103–121 (1974).
Campenot, R. B. Local control of neurite development by nerve growth factor. Proc. Natl Acad. Sci. USA 74, 4516–4519 (1977).
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).
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).
Zweifel, L. S., Kuruvilla, R. & Ginty, D. D. Functions and mechanisms of retrograde neurotrophin signalling. Nature Rev. Neurosci. 6, 615–625 (2005).
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).
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).
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).
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).
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.
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).
Nikoletopoulou, V. et al. Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature 467, 59–63 (2010).
Deppmann, C. D. et al. A model for neuronal competition during development. Science 320, 369–373 (2008).
Mandai, K. et al. LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development. Neuron 63, 614–627 (2009).
Singh, K. K. et al. Developmental axon pruning mediated by BDNF–p75NTR-dependent axon degeneration. Nature Neurosci. 11, 649–658 (2008).
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.
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).
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).
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).
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).
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).
Wickramasinghe, S. R. et al. Serum response factor mediates NGF-dependent target innervation by embryonic DRG sensory neurons. Neuron 58, 532–545 (2008).
Graef, I. A. et al. Neurotrophins and netrins require calcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113, 657–670 (2003).
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).
Glebova, N. O. & Ginty, D. D. Heterogeneous requirement of NGF for sympathetic target innervation in vivo. J. Neurosci. 24, 743–751 (2004).
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).
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).
Voyvodic, J. T. Peripheral target regulation of dendritic geometry in the rat superior cervical ganglion. J. Neurosci. 9, 1997–2010 (1989).
Purves, D. Functional and structural changes in mammalian sympathetic neurones following interruption of their axons. J. Physiol. 252, 429–463 (1975).
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.
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).
Guo, T. et al. An evolving NGF–Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates. Nature Neurosci. 14, 31–36 (2011).
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).
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).
Apostolova, G. & Dechant, G. Development of neurotransmitter phenotypes in sympathetic neurons. Auton. Neurosci. 151, 30–38 (2009).
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).
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).
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).
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).
Howe, C. L. & Mobley, W. C. Signaling endosome hypothesis: a cellular mechanism for long distance communication. J. Neurobiol. 58, 207–216 (2004).
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).
MacInnis, B. L. & Campenot, R. B. Retrograde support of neuronal survival without retrograde transport of nerve growth factor. Science 295, 1536–1539 (2002).
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).
Doherty, G. J. & McMahon, H. T. Mechanisms of endocytosis. Annu. Rev. Biochem. 78, 857–902 (2009).
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).
Shao, Y. et al. Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J. Cell Biol. 157, 679–691 (2002).
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).
Valdez, G. et al. Pincher-mediated macroendocytosis underlies retrograde signaling by neurotrophin receptors. J. Neurosci. 25, 5236–5247 (2005).
Kaplan, D. R. & Miller, F. D. Neurotrophin signal transduction in the nervous system. Curr. Opin. Neurobiol. 10, 381–391 (2000).
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).
Christoforidis, S. et al. Phosphatidylinositol-3-OH kinases are Rab5 effectors. Nature Cell Biol. 1, 249–252 (1999).
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).
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).
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).
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).
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).
Bunney, T. D. & Katan, M. PLC regulation: emerging pictures for molecular mechanisms. Trends Biochem. Sci. 36, 88–96 (2011).
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).
Zerial, M. & McBride, H. Rab proteins as membrane organizers. Nature Rev. Mol. Cell Biol. 2, 107–117 (2001).
Gorvel, J. P., Chavrier, P., Zerial, M. & Gruenberg, J. rab5 controls early endosome fusion in vitro. Cell 64, 915–925 (1991).
Bucci, C. et al. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell 70, 715–728 (1992).
Bucci, C., Thomsen, P., Nicoziani, P., McCarthy, J. & van Deurs, B. Rab7: a key to lysosome biogenesis. Mol. Biol. Cell 11, 467–480 (2000).
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.
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).
Deinhardt, K. et al. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway. Neuron 52, 293–305 (2006).
Chen, X. Q. et al. Endosome-mediated retrograde axonal transport of P2X3 receptor signals in primary sensory neurons. Cell Res. 22, 677–696 (2011).
Harrington, A. W. et al. Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. Cell 146, 421–434 (2011).
Wu, C., Lai, C. F. & Mobley, W. C. Nerve growth factor activates persistent Rap1 signaling in endosomes. J. Neurosci. 21, 5406–5416 (2001).
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.
Bhattacharyya, A. et al. High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. J. Neurobiol. 51, 302–312 (2002).
O'Brien, J. J. & Nathanson, N. M. Retrograde activation of STAT3 by leukemia inhibitory factor in sympathetic neurons. J. Neurochem. 103, 288–302 (2007).
Murphy, P. G., Grondin, J., Altares, M. & Richardson, P. M. Induction of interleukin-6 in axotomized sensory neurons. J. Neurosci. 15, 5130–5138 (1995).
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).
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).
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).
Andreassi, C. et al. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nature Neurosci. 13, 291–301 (2010).
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).
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.
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).
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).
Svendsen, C. N., Cooper, J. D. & Sofroniew, M. V. Trophic factor effects on septal cholinergic neurons. Ann. NY Acad. Sci. 640, 91–94 (1991).
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).
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).
Cogli, L., Piro, F. & Bucci, C. Rab7 and the CMT2B disease. Biochem. Soc. Trans. 37, 1027–1031 (2009).
Cogli, L. et al. CMT2B-associated Rab7 mutants inhibit neurite outgrowth. Acta Neuropathol. 120, 491–501 (2010).
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).
We thank members of the Ginty laboratory for their helpful comments and suggestions during the preparation of this manuscript.
The authors declare no competing financial interests.
- 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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