Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair

A Corrigendum to this article was published on 30 May 2012

An Erratum to this article was published on 03 May 2012

This article has been updated

Key Points

  • Local mRNA translation is a post-transcriptional gene regulatory mechanism that enables autonomous control of local proteomes in subcellular compartments. This mechanism operates in neuronal dendrites and axons to regulate local proteomic homeostasis in response to extrinsic signals.

  • Both developing and mature axons have functional protein synthesis and processing machinery, which may adopt specialized morphologies. The axonal transcriptome is unexpectedly complex and changes with developmental ageing and in response to injury.

  • RNA-binding proteins (RBPs) transport specific mRNAs to axons in a translationally repressed state by binding to the cis-acting elements of mRNAs and to other components of RNA granules. Extrinsic cues influence axonal mRNA repertoires by regulating RBP-mediated axonal transport.

  • Protein synthesis-inducing cues activate diverse signalling pathways that converge on mammalian target of rapamycin (mTOR), the master regulator of cap-dependent mRNA translation. Some guidance cues, such as ephrin A, inhibit mTOR activity and may act antagonistically. Only a selective pool of mRNAs is translated in response to a specific cue.

  • Extrinsic cues are directly linked to translation by the direct binding between cell surface receptors and ribosomes. This mechanism may enhance the spatial precision and specificity of cue-induced mRNA translation.

  • The differential translation model predicts that asymmetric synthesis of positive and negative regulators of cytoskeletal assembly mediates attractive and repulsive chemotropic turning responses of growth cones. Attractive cues (such as netrin 1 and brain-derived neurotrophic factor (BDNF)) induce asymmetric β-actin synthesis, and repulsive cues (such as semaphorin 3A (SEMA3A) and SLIT2) promote local synthesis of actin-depolymerizing proteins (such as RHOA and cofilin).

  • Local synthesis of proteins that support mitochondrial function, such as nuclear-encoded mitochondrial proteins and lamin B2, may play important roles in axon maintenance. Target-derived extrinsic cues can increase local synthesis of mitochondrial proteins in distal axons in vitro, and sustained axonal synthesis of such proteins is required for axon maintenance in vitro and in vivo.

  • The ability of axons to regenerate after axotomy is associated with their ability to locally synthesize proteins. Regenerative axons, such as peripheral axons, upregulate local protein synthesis after injury, whereas non-regenerative axons, such as adult central axons, downregulate protein synthesis.

  • Nerve injury promotes local synthesis of transcription factors, such as signal transducer and activator of transcription 3 (STAT3), which are retrogradely transported into the nucleus and activate injury-responsive gene transcription. Molecular motor complexes that mediate this transport are also regulated by locally synthesized proteins, such as Ran-specific GTPase-activating protein (RANBP1), importin-β and vimentin.

  • Compartmentalized cell culture systems have proved to be invaluable tools to advance our understandings of axonal mRNA translation. Novel techniques or inventive experiments that allow efficient and specific manipulation of axonal mRNA translation in live animals will facilitate extension of these findings to in vivo settings.

Abstract

mRNAs can be targeted to specific neuronal subcellular domains, which enables rapid changes in the local proteome through local translation. This mRNA-based mechanism links extrinsic signals to spatially restricted cellular responses and can mediate stimulus-driven adaptive responses such as dendritic plasticity. Local mRNA translation also occurs in growing axons where it can mediate directional responses to guidance signals. Recent profiling studies have revealed that both growing and mature axons possess surprisingly complex and dynamic transcriptomes, thereby suggesting that axonal mRNA localization is highly regulated and has a role in a broad range of processes, a view that is increasingly being supported by new experimental evidence. Here, we review current knowledge on the roles and regulatory mechanisms of axonal mRNA translation and discuss emerging links to axon guidance, survival, regeneration and neurological disorders.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Growth cone turning regulated by differential mRNA translation.
Figure 2: Axon survival, maintenance and injury-induced responses regulated by local protein synthesis.
Figure 3: Regulation of global translational activity through mTOR.
Figure 4: RNA-specific transport and translation.
Figure 5: Local mRNA translation as a mediator of stimulus-induced axonal responses.

Similar content being viewed by others

Change history

  • 03 May 2012

    In the acknowledgements an omission was made. It should read as follows: We apologize to the authors of papers we could not include in this Review owing to space limitations. We thank J. Hu and C. M. O'Hare for critical reading of the manuscript. This work was supported by a Wellcome Trust Programme Grant (085314/Z/08/Z) to C.E.H.These have been corrected in the online version.

References

  1. Mili, S., Moissoglu, K. & Macara, I. G. Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. Nature 453, 115–119 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Lecuyer, E. et al. Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function. Cell 131, 174–187 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Holt, C. E. & Bullock, S. L. Subcellular mRNA localization in animal cells and why it matters. Science 326, 1212–1216 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sutton, M. A. & Schuman, E. M. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127, 49–58 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Wang, D. O., Martin, K. C. & Zukin, R. S. Spatially restricting gene expression by local translation at synapses. Trends Neurosci. 33, 173–182 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Giuditta, A., Dettbarn, W. D. & Brzin, M. Protein synthesis in the isolated giant axon of the squid. Proc. Natl Acad. Sci. USA 59, 1284–1287 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Koenig, E. Synthetic mechanisms in the axon. IV. In vitro incorporation of [3H]precursors into axonal protein and RNA. J. Neurochem. 14, 437–446 (1967). Together with reference 6, landmark studiesthat showed evidence for axonal protein synthesis. Using metabolic labelling, these studies showed that vertebrate and invertebrate axons without somas are capable of translation-dependent protein synthesis.

    Article  CAS  PubMed  Google Scholar 

  8. Edstrom, A. & Sjostrand, J. Protein synthesis in the isolated Mauthner nerve fibre of goldfish. J. Neurochem. 16, 67–81 (1969).

    Article  CAS  PubMed  Google Scholar 

  9. Alvarez, J., Giuditta, A. & Koenig, E. Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype. With a critique of slow transport theory. Prog. Neurobiol. 62, 1–62 (2000).

    Article  CAS  PubMed  Google Scholar 

  10. Campbell, D. S. & Holt, C. E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32, 1013–1026 (2001). First demonstration of a functional role for axonal mRNA translation in mediating chemotropic responses of growth cones to guidance cue gradients. Netrin 1 and SEMA3A increase global translational activity in cultured growth cones by activating mTOR. This study also showed that proteasomal degradation and translation are intricately linked in cue-stimulated axonal responses.

    Article  CAS  PubMed  Google Scholar 

  11. Verma, P. et al. Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J. Neurosci. 25, 331–342 (2005). Key evidence showing that axonal protein synthesis is required for axon regeneration. Comparing regeneration of embryonic and adult, CNS and PNS neuronal axons in culture, with or without translation inhibitors, led to this conclusion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Akten, B. et al. Interaction of survival of motor neuron (SMN) and HuD proteins with mRNA cpg15 rescues motor neuron axonal deficits. Proc. Natl Acad. Sci. USA 108, 10337–10342 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Donnelly, C. J. et al. Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J. 30, 4665–4677 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ben-Yaakov, K. et al. Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO J. 13 Jan 2012 (doi:10.1038/emboj.2011.494).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Andreassi, C. et al. An NGF-responsive element targets myo-inositol monophosphatase-1 mRNA to sympathetic neuron axons. Nature Neurosci. 13, 291–301 (2010). Using sequential analysis of gene expression analysis, this study identified more axonal mRNAs (>11,000 sequence tags), among which IMPA1 mRNA was most abundant. A novel 3′-UTR element mediates axonal transport of IMPA1 mRNA, the axonal translation of which is required for NGF-mediated cell survival.

    Article  CAS  PubMed  Google Scholar 

  16. Zivraj, K. H. et al. Subcellular profiling reveals distinct and developmentally regulated repertoire of growth cone mRNAs. J. Neurosci. 30, 15464–15478 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gumy, L. F. et al. Transcriptome analysis of embryonic and adult sensory axons reveals changes in mRNA repertoire localization. RNA 17, 85–98 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Taylor, A. M. et al. Axonal mRNA in uninjured and regenerating cortical mammalian axons. J. Neurosci. 29, 4697–4707 (2009). References 15–18 were key axonal transcriptome studies. Using compartmentalized culture systems and laser-capture microdissection, these studies provided comprehensive information on the complex and dynamic nature of axonal mRNA repertoires in embryonic and adult, growing and mature PNS and CNS neurons. Additionally, reference 16 showed that the growth cone of embryonic neurons has a translatome distinct from that of the axon shaft.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lasek, R. J., Dabrowski, C. & Nordlander, R. Analysis of axoplasmic RNA from invertebrate giant axons. Nature New Biol. 244, 162–165 (1973).

    Article  CAS  PubMed  Google Scholar 

  20. Giuditta, A., Cupello, A. & Lazzarini, G. Ribosomal RNA in the axoplasm of the squid giant axon. J. Neurochem. 34, 1757–1760 (1980).

    Article  CAS  PubMed  Google Scholar 

  21. Giuditta, A., Hunt, T. & Santella, L. Messenger RNA in squid axoplasm. Neurochem. Int. 8, 435–442 (1986).

    Article  CAS  PubMed  Google Scholar 

  22. Giuditta, A. et al. Active polysomes in the axoplasm of the squid giant axon. J. Neurosci. Res. 28, 18–28 (1991).

    Article  CAS  Google Scholar 

  23. Bassell, G. J. et al. Sorting of β-actin mRNA and protein to neurites and growth cones in culture. J. Neurosci. 18, 251–265 (1998). Together with reference 154, this showed evidence for an isoform-specific axonal transport of β-actin mRNAs that is regulated by extrinsic cues. Binding of ZBP1 to the zipcode in the β-actin 3′-UTR mediates this transport, which is enhanced by NT3 and necessary for growth cone motility.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bunge, M. B. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture. J. Cell Biol. 56, 713–735 (1973).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tennyson, V. M. The fine structure of the axon and growth cone of the dorsal root neuroblast of the rabbit embryo. J. Cell Biol. 44, 62–79 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tcherkezian, J., Brittis, P. A., Thomas, F., Roux., P. P. & Flanagan, J. G. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation. Cell 141, 632–644 (2010). First evidence that guidance cue receptors can directly regulate ribosome activity. DCC inhibits translation by sequestering ribosomes and netrin 1 binding releases ribosomes from DCC, thus providing a novel mechanism to localize mRNA translation in the vicinity of receptor activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yamada, K. M., Spooner, B. S. & Wessells, N. K. Ultrastructure and function of growth cones and axons of cultured nerve cells. J. Cell Biol. 49, 614–635 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Steward, O. & Ribak, C. E. Polyribosomes associated with synaptic specializations on axon initial segments: localization of protein-synthetic machinery at inhibitory synapses. J. Neurosci. 6, 3079–3085 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Koenig, E. & Martin, R. Cortical plaque-like structures identify ribosome-containing domains in the Mauthner cell axon. J. Neurosci. 16, 1400–1411 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Koenig, E., Martin, R., Titmus, M. & Sotelo-Silveira, J. R. Cryptic peripheral ribosomal domains distributed intermittently along mammalian myelinated axons. J. Neurosci. 20, 8390–8400 (2000).

    Article  CAS  Google Scholar 

  31. Kun, A., Otero, L., Sotelo-Silveira, J. R. & Sotelo, J. R. Ribosomal distributions in axons of mammalian myelinated fibers. J. Neurosci. Res. 85, 2087–2098 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Li, Y. C. et al. Subsurface cisterna-lined axonal invaginations and double-walled vesicles at the axonal–myelin sheath interface. Neurosci. Res. 53, 298–303 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Zelena, J. Ribosome-like particles in myelinated axons of the rat. Brain Res. 24, 359–363 (1970).

    Article  CAS  PubMed  Google Scholar 

  34. Walker, B. A. et al. Reprogramming axonal behavior by axon-specific viral transduction. Gene Ther. 26 Jan 2012 (doi:10.1038/gt.2011.217).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koenig, E. & Adams, P. Local protein synthesizing activity in axonal fields regenerating in vitro. J. Neurochem. 39, 386–400 (1982).

    Article  CAS  PubMed  Google Scholar 

  36. Eng, H., Lund, K. & Campenot, R. B. Synthesis of β-tubulin, actin, and other proteins in axons of sympathetic neurons in compartmented cultures. J. Neurosci. 19, 1–9 (1999). Using a highly efficient compartmentalized culture system, now known as the Campenot chamber, this study showed that local protein synthesis occurs and that it is not required for the basal rate of axon growth.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Koenig, E. Evaluation of local synthesis of axonal proteins in the goldfish Mauthner cell axon and axons of dorsal and ventral roots of the rat in vitro. Mol. Cell Neurosci. 2, 384–394 (1991).

    Article  CAS  PubMed  Google Scholar 

  38. Tobias, G. S. & Koenig, E. Influence of nerve cell body and neurolemma cell on local axonal protein synthesis following neurotomy. Exp. Neurol. 49, 235–245 (1975).

    Article  CAS  PubMed  Google Scholar 

  39. Tobias, G. S. & Koenig, E. Axonal protein synthesizing activity during the early outgrowth period following neurotomy. Exp. Neurol. 49, 221–234 (1975).

    Article  CAS  PubMed  Google Scholar 

  40. Van Minnen, J. et al. De novo protein synthesis in isolated axons of identified neurons. Neuroscience 80, 1–7 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Brittis, P. A., Lu, Q. & Flanagan, J. G. Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110, 223–235 (2002). First evidence that extrinsic cues may regulate translation of guidance cue receptor mRNAs in growing axons. The authors suggested an intriguing mechanism by which intermediate targets regulate future responsiveness of pathfinding axons by stimulating local synthesis of new guidance cue receptors needed for the next part of the journey.

    Article  CAS  PubMed  Google Scholar 

  42. Bi, J., Tsai, N. P., Lin, Y. P., Loh, H. H. & Wei, L. N. Axonal mRNA transport and localized translational regulation of κ-opioid receptor in primary neurons of dorsal root ganglia. Proc. Natl Acad. Sci. USA 103, 19919–19924 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zheng, J. Q. et al. A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons. J. Neurosci. 21, 9291–9303 (2001). Landmark study that showed evidence for involvement of axonal protein synthesis in axon regeneration. Adult peripheral sensory neurons can locally synthesize proteins in vitro , and this ability is enhanced by preconditioning nerve injury in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Merianda, T. T. et al. A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins. Mol. Cell Neurosci. 40, 128–142 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Willis, D. et al. Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons. J. Neurosci. 25, 778–791 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Spencer, G. E. et al. Synthesis and functional integration of a neurotransmitter receptor in isolated invertebrate axons. J. Neurobiol. 44, 72–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Lyles, V., Zhao, Y. & Martin, K. C. Synapse formation and mRNA localization in cultured Aplysia neurons. Neuron 49, 349–356 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Lujan, H. D. et al. Developmental induction of Golgi structure and function in the primitive eukaryote Giardia lamblia. J. Biol. Chem. 270, 4612–4618 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Harris, W. A., Holt, C. E. & Bonhoeffer, F. Retinal axons with and without their somata, growing to and arborizing in the tectum of Xenopus embryos: a time-lapse video study of single fibres in vivo. Development 101, 123–133 (1987).

    CAS  PubMed  Google Scholar 

  50. Ming, G. L. et al. Adaptation in the chemotactic guidance of nerve growth cones. Nature 417, 411–418 (2002). First evidence that local mRNA translation may be necessary for the adaptation of growth cones to extracellular signals. Cultured growth cones are desensitized to continuously applied guidance cues but later resensitized to the same cue, and resensitization is blocked by inhibitors of MAPKs and ribosome function.

    Article  CAS  PubMed  Google Scholar 

  51. Campbell, D. S. et al. Semaphorin 3A elicits stage-dependent collapse, turning, and branching in Xenopus retinal growth cones. J. Neurosci. 21, 8538–8547 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hengst, U., Deglincerti, A., Kim, H. J., Jeon, N. L. & Jaffrey, S. R. Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein. Nature Cell Biol. 11, 1024–1030 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Leung, K. M. et al. Asymmetrical β-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nature Neurosci. 9, 1247–1256 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Yao, J., Sasaki, Y., Wen, Z., Bassell, G. J. & Zheng, J. Q. An essential role for β-actin mRNA localization and translation in Ca2+-dependent growth cone guidance. Nature Neurosci. 9, 1265–1273 (2006). Together with reference 53, this provided the first evidence that asymmetric mRNA translation mediates chemotropic growth cone turning. Netrin 1 and BDNF gradients activate asymmetric β-actin synthesis by increasing its transport and translation via ZBP1, a process that is required for attractive growth cone turning towards the sources of gradients.

    Article  CAS  PubMed  Google Scholar 

  55. Wu, K. Y. et al. Local translation of RhoA regulates growth cone collapse. Nature 436, 1020–1024 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Piper, M. et al. Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49, 215–228 (2006). Together with reference 55, these were the first studies to suggest a mechanism for translation-dependent growth cone repulsion. Repulsive cues SEMA3A and SLIT2 increase global translational activity but activate translation of selective mRNAs that encode cytoskeletal-disassembling molecules, such as RHOA and cofilin, respectively.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alvarez-Fischer, D. et al. Engrailed protects mouse midbrain dopaminergic neurons against mitochondrial complex I insults. Nature Neurosci. 14, 1260–1266 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Brunet, I. et al. The transcription factor Engrailed-2 guides retinal axons. Nature 438, 94–98 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wizenmann, A. et al. Extracellular Engrailed participates in the topographic guidance of retinal axons in vivo. Neuron 64, 355–366 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Guirland, C., Buck, K. B., Gibney, J. A., DiCicco-Bloom, E. & Zheng, J. Q. Direct cAMP signaling through G-protein-coupled receptors mediates growth cone attraction induced by pituitary adenylate cyclase-activating polypeptide. J. Neurosci. 23, 2274–2283 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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). Together with references 64 and 130, provided key evidence that axonally synthesized proteins generate retrograde signaling to the nucleus. Axonally synthesized importin-β1 mediates retrograde transport of transcription factors to the cell body, a process essential for axon regeneration after injury in vivo . Axonally synthesized transcription factors CREB and C/EBP1 mediate cell survival in vitro and in vivo , respectively.

    Article  CAS  PubMed  Google Scholar 

  62. Je, H. S. et al. Presynaptic protein synthesis required for NT-3-induced long-term synaptic modulation. Mol. Brain 4, 1 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang, H. L., Singer, R. H. & Bassell, G. J. Neurotrophin regulation of β-actin mRNA and protein localization within growth cones. J. Cell Biol. 147, 59–70 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hanz, S. et al. Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40, 1095–1104 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Perlson, E. et al. Vimentin-dependent spatial translocation of an activated MAP kinase in injured nerve. Neuron 45, 715–726 (2005).

    Article  CAS  PubMed  Google Scholar 

  66. Yudin, D. et al. Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve. Neuron 59, 241–252 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mann, F., Miranda, E., Weinl, C., Harmer, E. & Holt, C. E. B-type Eph receptors and ephrins induce growth cone collapse through distinct intracellular pathways. J. Neurobiol. 57, 323–336 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Strochlic, L., Dwivedy, A., van Horck, F. P., Falk, J. & Holt, C. E. A role for S1P signalling in axon guidance in the Xenopus visual system. Development 135, 333–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Nedelec, S. et al. Concentration-dependent requirement for local protein synthesis in motor neuron subtype-specific response to axon guidance cues. J. Neurosci. 32, 1496–1506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Roche, F. K., Marsick, B. M. & Letourneau, P. C. Protein synthesis in distal axons is not required for growth cone responses to guidance cues. J. Neurosci. 29, 638–652 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Huttelmaier, S. et al. Spatial regulation of β-actin translation by Src-dependent phosphorylation of ZBP1. Nature 438, 512–515 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Welshhans, K. & Bassell, G. J. Netrin-1-induced local β-actin synthesis and growth cone guidance requires zipcode binding protein 1. J. Neurosci. 31, 9800–9813 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lin, A. C. & Holt, C. E. Local translation and directional steering in axons. EMBO J. 26, 3729–3736 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kislauskis, E. H., Zhu, X. & Singer, R. H. β-actin messenger RNA localization and protein synthesis augment cell motility. J. Cell Biol. 136, 1263–1270 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Shestakova, E. A., Singer, R. H. & Condeelis, J. The physiological significance of β-actin mRNA localization in determining cell polarity and directional motility. Proc. Natl Acad. Sci. USA 98, 7045–7050 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Karakozova, M. et al. Arginylation of β-actin regulates actin cytoskeleton and cell motility. Science 313, 192–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. Wang, J. et al. Reversible glutathionylation regulates actin polymerization in A431 cells. J. Biol. Chem. 276, 47763–47766 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Drinjakovic, J. et al. E3 ligase Nedd4 promotes axon branching by downregulating PTEN. Neuron 65, 341–357 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. von Philipsborn, A. & Bastmeyer, M. Mechanisms of gradient detection: a comparison of axon pathfinding with eukaryotic cell migration. Int. Rev. Cytol. 263, 1–62 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Piper, M., Salih, S., Weinl, C., Holt, C. E. & Harris, W. A. Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation. Nature Neurosci. 8, 179–186 (2005).

    Article  CAS  PubMed  Google Scholar 

  81. Hopker, V. H., Shewan, D., Tessier-Lavigne, M., Poo, M. & Holt, C. Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 401, 69–73 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Shewan, D., Dwivedy, A., Anderson, R. & Holt, C. E. Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway. Nature Neurosci. 5, 955–962 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Kamiguchi, H. & Yoshihara, F. The role of endocytic L1 trafficking in polarized adhesion and migration of nerve growth cones. J. Neurosci. 21, 9194–9203 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kuwako, K. et al. Neural RNA-binding protein Musashi1 controls midline crossing of precerebellar neurons through posttranscriptional regulation of Robo3/Rig-1 expression. Neuron 67, 407–421 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Shaw, G. & Bray, D. Movement and extension of isolated growth cones. Exp. Cell Res. 104, 55–62 (1977).

    Article  CAS  PubMed  Google Scholar 

  86. van Kesteren, R. E. et al. Local synthesis of actin-binding protein β-thymosin regulates neurite outgrowth. J. Neurosci. 26, 152–157 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang, X. & Poo, M. M. Localized synaptic potentiation by BDNF requires local protein synthesis in the developing axon. Neuron 36, 675–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Sebeo, J. et al. Requirement for protein synthesis at developing synapses. J. Neurosci. 29, 9778–9793 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Crispino, M. et al. Active polysomes are present in the large presynaptic endings of the synaptosomal fraction from squid brain. J. Neurosci. 17, 7694–7702 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hu, J. Y., Meng, X. & Schacher, S. Target interaction regulates distribution and stability of specific mRNAs. J. Neurosci. 22, 2669–2678 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Schacher, S., Wu, F., Panyko, J. D., Sun, Z. Y. & Wang, D. Expression and branch-specific export of mRNA are regulated by synapse formation and interaction with specific postsynaptic targets. J. Neurosci. 19, 6338–6347 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lee, W., Jones, A. M., Ono, J. K. & Wayne, N. L. Regional differences in processing of locally translated prohormone in peptidergic neurons of Aplysia californica. J. Neurochem. 83, 1423–1430 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Cheng, L., Locke, C. & Davis, G. W. S6 kinase localizes to the presynaptic active zone and functions with PDK1 to control synapse development. J. Cell Biol. 194, 921–935 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Ronesi, J. A. & Huber, K. M. Metabotropic glutamate receptors and fragile X mental retardation protein: partners in translational regulation at the synapse. Sci. Signal. 1, pe6 (2008).

    Article  PubMed  Google Scholar 

  95. Bassell, G. J. & Warren, S. T. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60, 201–214 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Antar, L. N., Li, C., Zhang, H., Carroll, R. C. & Bassell, G. J. Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol. Cell. Neurosci. 32, 37–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Li, C., Bassell, G. J. & Sasaki, Y. Fragile X mental retardation protein is involved in protein synthesis-dependent collapse of growth cones induced by semaphorin-3A. Front. Neural Circuits 3, 11 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Christie, S. B., Akins, M. R., Schwob, J. E. & Fallon, J. R. The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits. J. Neurosci. 29, 1514–1524 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hanson, J. E. & Madison, D. V. Presynaptic Fmr1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome. J. Neurosci. 27, 4014–4018 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Fallini, C. et al. The survival of motor neuron (SMN) protein interacts with the mRNA-binding protein HuD and regulates localization of poly(A) mRNA in primary motor neuron axons. J. Neurosci. 31, 3914–3925 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zhang, H. et al. Multiprotein complexes of the survival of motor neuron protein SMN with Gemins traffic to neuronal processes and growth cones of motor neurons. J. Neurosci. 26, 8622–8632 (2006).

    Article  CAS  Google Scholar 

  102. Aronov, S., Aranda, G., Behar, L. & Ginzburg, I. Visualization of translated tau protein in the axons of neuronal P19 cells and characterization of tau RNP granules. J. Cell Sci. 115, 3817–3827 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Smith, C. L. et al. GAP-43 mRNA in growth cones is associated with HuD and ribosomes. J. Neurobiol. 61, 222–235 (2004).

    Article  CAS  Google Scholar 

  104. Droz, B. & Barondes, S. M. Nerve endings: rapid appearance of labeled protein shown by electron microscope radioautography. Science 165, 1131–1133 (1969).

    Article  CAS  PubMed  Google Scholar 

  105. Thoenen, H., Mueller, R. A. & Axelrod, J. Phase difference in the induction of tyrosine hydroxylase in cell body and nerve terminals of sympathetic neurones. Proc. Natl Acad. Sci. USA 65, 58–62 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Koenig, E. & Koelle, G. B. Acetylcholinesterase regeneration in peripheral nerve after irreversible inactivation. Science 132, 1249–1250 (1960).

    Article  CAS  PubMed  Google Scholar 

  107. Melia, K. R., Trembleau, A., Oddi, R., Sanna, P. P. & Bloom, F. E. Detection and regulation of tyrosine hydroxylase mRNA in catecholaminergic terminal fields: possible axonal compartmentalization. Exp. Neurol. 130, 394–406 (1994).

    Article  CAS  PubMed  Google Scholar 

  108. Jirikowski, G. F., Sanna, P. P. & Bloom, F. E. mRNA coding for oxytocin is present in axons of the hypothalamo–neurohypophysial tract. Proc. Natl Acad. Sci. USA 87, 7400–7404 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Trembleau, A., Melia, K. R. & Bloom, F. E. BC1 RNA and vasopressin mRNA in rat neurohypophysis: axonal compartmentalization and differential regulation during dehydration and rehydration. Eur. J. Neurosci. 7, 2249–2260 (1995).

    Article  CAS  PubMed  Google Scholar 

  110. Trembleau, A., Morales, M. & Bloom, F. E. Differential compartmentalization of vasopressin messenger RNA and neuropeptide within the rat hypothalamo–neurohypophysial axonal tracts: light and electron microscopic evidence. Neuroscience 70, 113–125 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Mohr, E., Fehr, S. & Richter, D. Axonal transport of neuropeptide encoding mRNAs within the hypothalamo–hypophyseal tract of rats. EMBO J. 10, 2419–2424 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mohr, E. & Richter, D. Diversity of mRNAs in the axonal compartment of peptidergic neurons in the rat. Eur. J. Neurosci. 4, 870–876 (1992).

    Article  PubMed  Google Scholar 

  113. Dirks, R. W. et al. Ultrastructural evidence for the axonal localization of caudodorsal cell hormone mRNA in the central nervous system of the mollusc Lymnaea stagnalis. Microsc. Res. Tech. 25, 12–18 (1993).

    Article  CAS  PubMed  Google Scholar 

  114. Twiss, J. L. & Shooter, E. M. Nerve growth factor promotes neurite regeneration in PC12 cells by translational control. J. Neurochem. 64, 550–557 (1995).

    Article  CAS  PubMed  Google Scholar 

  115. Gioio, A. E. et al. Local synthesis of nuclear-encoded mitochondrial proteins in the presynaptic nerve terminal. J. Neurosci. Res. 64, 447–453 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Aschrafi, A., Natera-Naranjo, O., Gioio, A. E. & Kaplan, B. B. Regulation of axonal trafficking of cytochrome c oxidase IV mRNA. Mol. Cell Neurosci. 43, 422–430 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hillefors, M., Gioio, A. E., Mameza, M. G. & Kaplan, B. B. Axon viability and mitochondrial function are dependent on local protein synthesis in sympathetic neurons. Cell. Mol. Neurobiol. 27, 701–716 (2007). Together with reference 118, this showed that mitochondria in distal axons are maintained by locally synthesized nuclear-encoded proteins. Blocking either local protein synthesis or protein import in distal axons leads to mitochondrial dysfunction and axon degeneration.

    Article  CAS  PubMed  Google Scholar 

  118. Yoon, B. C. et al. Local translation of extranuclear lamin B promotes axon maintenance. Cell 148, 1–13 (2012).

    Article  CAS  Google Scholar 

  119. Pareyson, D. & Marchesi, C. Diagnosis, natural history, and management of Charcot–Marie–Tooth disease. Lancet Neurol. 8, 654–667 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Capell, B. C. & Collins, F. S. Human laminopathies: nuclei gone genetically awry. Nature Rev. Genet. 7, 940–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, W., van Niekerk, E., Willis, D. E. & Twiss, J. L. RNA transport and localized protein synthesis in neurological disorders and neural repair. Dev. Neurobiol. 67, 1166–1182 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Gumy, L. F., Tan, C. L. & Fawcett, J. W. The role of local protein synthesis and degradation in axon regeneration. Exp. Neurol. 223, 28–37 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Christie, K. J., Webber, C. A., Martinez, J. A., Singh, B. & Zochodne, D. W. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J. Neurosci. 30, 9306–9315 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Court, F. A., Hendriks, W. T., MacGillavry, H. D., Alvarez, J. & van Minnen, J. Schwann cell to axon transfer of ribosomes: toward a novel understanding of the role of glia in the nervous system. J. Neurosci. 28, 11024–11029 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Court, F. A. et al. Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons. Glia 59, 1529–1539 (2011).

    Article  PubMed  Google Scholar 

  126. Vassar, R. et al. Topographic organization of sensory projections to the olfactory bulb. Cell 79, 981–991 (1994).

    Article  CAS  PubMed  Google Scholar 

  127. Wensley, C. H. et al. Olfactory marker protein mRNA is found in axons of olfactory receptor neurons. J. Neurosci. 15, 4827–4837 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Dubacq, C., Jamet, S. & Trembleau, A. Evidence for developmentally regulated local translation of odorant receptor mRNAs in the axons of olfactory sensory neurons. J. Neurosci. 29, 10184–10190 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Michaelevski, I. et al. Signaling to transcription networks in the neuronal retrograde injury response. Sci. Signal 3, ra53 (2011).

    Google Scholar 

  130. Yan, D., Wu, Z., Chisholm, A. D. & Jin, Y. The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 138, 1005–1018 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol. Cell 40, 310–322 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Hay, N. & Sonenberg, N. Upstream and downstream of mTOR. Genes Dev. 18, 1926–1945 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Tohda, C. et al. Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J. Neurochem. 76, 1628–1635 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Ruangsri, S. et al. Relationship of axonal voltage-gated sodium channel 1.8 (NaV1.8) mRNA accumulation to sciatic nerve injury-induced painful neuropathy in rats. J. Biol. Chem. 286, 39836–39847 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Geranton, S. M. et al. A rapamycin-sensitive signaling pathway is essential for the full expression of persistent pain states. J. Neurosci. 29, 15017–15027 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jimenez-Diaz, L. et al. Local translation in primary afferent fibers regulates nociception. PLoS One 3, e1961 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Melemedjian, O. K. et al. IL-6- and NGF-induced rapid control of protein synthesis and nociceptive plasticity via convergent signaling to the eIF4F complex. J. Neurosci. 30, 15113–15123 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Bi, J., Hu, X., Loh, H. H. & Wei, L. N. Mouse κ-opioid receptor mRNA differential transport in neurons. Mol. Pharmacol. 64, 594–599 (2003).

    Article  CAS  PubMed  Google Scholar 

  140. Bear, M. F., Dolen, G., Osterweil, E. & Nagarajan, N. Fragile X: translation in action. Neuropsychopharmacology 33, 84–87 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Liu-Yesucevitz, L. et al. Local RNA translation at the synapse and in disease. J. Neurosci. 31, 16086–16093 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).

    Article  CAS  PubMed  Google Scholar 

  143. Pellizzoni, L., Kataoka, N., Charroux, B. & Dreyfuss, G. A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing. Cell 95, 615–624 (1998).

    Article  CAS  PubMed  Google Scholar 

  144. Sharma, A. et al. A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells. Exp. Cell Res. 309, 185–197 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Rossoll, W. et al. SMN, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of β-actin mRNA in growth cones of motoneurons. J. Cell Biol. 163, 801–812 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Piazzon, N. et al. In vitro and in cellulo evidences for association of the survival of motor neuron complex with the fragile X mental retardation protein. J. Biol. Chem. 283, 5598–5610 (2008).

    Article  CAS  PubMed  Google Scholar 

  147. Cleveland, D. W. & Rothstein, J. D. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nature Rev. Neurosci. 2, 806–819 (2001).

    Article  CAS  Google Scholar 

  148. Chen-Plotkin, A. S., Lee, V. M. & Trojanowski, J. Q. TAR DNA-binding protein 43 in neurodegenerative disease. Nature Rev. Neurol. 6, 211–220 (2010).

    Article  CAS  Google Scholar 

  149. Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411–413 (2006).

    Article  CAS  PubMed  Google Scholar 

  150. Emara, M. M. et al. Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly. J. Biol. Chem. 285, 10959–10968 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Campbell, D. S. & Holt, C. E. Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37, 939–952 (2003).

    Article  CAS  PubMed  Google Scholar 

  152. Nie, D. et al. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature Neurosci. 13, 163–172 (2010). First evidence showing that some guidance cues can repress mRNA translation. Ephrin A represses mTOR by inhibiting MAPK ERK1/2, providing a mechanism by which multiple cues regulate local protein synthesis in axons and growth cones by modulating diverse pathways that converge on mTOR.

    Article  CAS  PubMed  Google Scholar 

  153. Kim, S. & Coulombe, P. A. Emerging role for the cytoskeleton as an organizer and regulator of translation. Nature Rev. Mol. Cell Biol. 11, 75–81 (2010).

    Article  CAS  Google Scholar 

  154. Zhang, H. L. et al. Neurotrophin-induced transport of a β-actin mRNP complex increases β-actin levels and stimulates growth cone motility. Neuron 31, 261–275 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Vuppalanchi, D. et al. Conserved 3′-untranslated region sequences direct subcellular localization of chaperone protein mRNAs in neurons. J. Biol. Chem. 285, 18025–18038 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Willis, D. E. et al. Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs. J. Cell Biol. 178, 965–980 (2007). Comprehensive profiling study that showed extrinsic cues can influence the axonal transcriptome. Systematic analysis of axons treated with NGF, BDNF, NT3, MAG and SEMA3A showed that these cues regulate axonal transport of 50 candidate mRNAs in culture.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Sotelo-Silveira, J. R., Calliari, A., Kun, A., Koenig, E. & Sotelo, J. R. RNA trafficking in axons. Traffic 7, 508–515 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. van Niekerk, E. A. et al. Sumoylation in axons triggers retrograde transport of the RNA-binding protein La. Proc. Natl Acad. Sci. USA 104, 12913–12918 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Meyuhas, O. Synthesis of the translational apparatus is regulated at the translational level. Eur. J. Biochem. 267, 6321–6330 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Vuppalanchi, D., Willis, D. E. & Twiss, J. L. Regulation of mRNA transport and translation in axons. Results Probl. Cell Differ. 48, 193–224 (2009).

    CAS  PubMed  Google Scholar 

  161. Krichevsky, A. M. & Kosik, K. S. Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32, 683–696 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Kilchert, C. & Spang, A. Cotranslational transport of ABP140 mRNA to the distal pole of S. cerevisiae. EMBO J. 30, 3567–3580 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Parker, R. & Sheth, U. P bodies and the control of mRNA translation and degradation. Mol. Cell 25, 635–646 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Tsai, N. P., Bi, J. & Wei, L. N. The adaptor Grb7 links netrin-1 signaling to regulation of mRNA translation. EMBO J. 26, 1522–1531 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Buckley, P. T. et al. Cytoplasmic intron sequence-retaining transcripts can be dendritically targeted via ID element retrotransposons. Neuron 69, 877–884 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Chen, Z., Gore, B. B., Long, H., Ma, L. & Tessier-Lavigne, M. Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion. Neuron 58, 325–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  167. Giorgi, C. et al. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 130, 179–191 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Kiebler, M. A. & Bassell, G. J. Neuronal RNA granules: movers and makers. Neuron 51, 685–690 (2006).

    Article  CAS  PubMed  Google Scholar 

  169. Sasaki, Y. et al. Phosphorylation of zipcode binding protein 1 is required for brain-derived neurotrophic factor signaling of local β-actin synthesis and growth cone turning. J. Neurosci. 30, 9349–9358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Chao, J. A. et al. ZBP1 recognition of β-actin zipcode induces RNA looping. Genes Dev. 24, 148–158 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Melko, M. & Bardoni, B. The role of G-quadruplex in RNA metabolism: involvement of FMRP and FMR2P. Biochimie 92, 919–926 (2010).

    Article  CAS  PubMed  Google Scholar 

  172. Narayanan, U. et al. S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. J. Biol. Chem. 283, 18478–18482 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Richter, J. D. Cytoplasmic polyadenylation in development and beyond. Microbiol. Mol. Biol. Rev. 63, 446–456 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Kundel, M., Jones, K. J., Shin, C. Y. & Wells, D. G. Cytoplasmic polyadenylation element-binding protein regulates neurotrophin-3-dependent β-catenin mRNA translation in developing hippocampal neurons. J. Neurosci. 29, 13630–13639 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lin, A. C. et al. Cytoplasmic polyadenylation and cytoplasmic polyadenylation element-dependent mRNA regulation are involved in Xenopus retinal axon development. Neural Dev. 4, 8 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Alexandrov, I. M. et al. Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance. PLoS Genet. 8, e1002457 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006).

    Article  CAS  PubMed  Google Scholar 

  178. Aschrafi, A. et al. MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J. Neurosci. 28, 12581–12590 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Ashley, C. T., Jr, Wilkinson, K. D., Reines, D. & Warren, S. T. FMR1 protein: conserved RNP family domains and selective RNA binding. Science 262, 563–566 (1993).

    Article  CAS  PubMed  Google Scholar 

  180. Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neurosci. 7, 113–117 (2004).

    Article  CAS  PubMed  Google Scholar 

  181. Kondrashov, N. et al. Ribosome-mediated specificity in Hox mRNA translation and vertebrate tissue patterning. Cell 145, 383–397 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Tsurugi, K. & Ogata, K. Evidence for the exchangeability of acidic ribosomal proteins on cytoplasmic ribosomes in regenerating rat liver. J. Biochem. 98, 1427–1431 (1985).

    Article  CAS  PubMed  Google Scholar 

  183. Taylor, A. M. et al. A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nature Methods 2, 599–605 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. 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 

  185. Campenot, R. B., Lund, K. & Mok, S. A. Production of compartmented cultures of rat sympathetic neurons. Nature Protoc. 4, 1869–1887 (2009).

    Article  CAS  Google Scholar 

  186. Willis, D. E. et al. Axonal localization of transgene mRNA in mature PNS and CNS neurons. J. Neurosci. 31, 14481–14487 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Dmochowski, I. J. & Tang, X. Taking control of gene expression with light-activated oligonucleotides. Biotechniques 43, 161–171 (2007).

    Article  CAS  PubMed  Google Scholar 

  188. Je, H. S. et al. Chemically inducible inactivation of protein synthesis in genetically targeted neurons. J. Neurosci. 29, 6761–6766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Campenot, R. B. NGF and the local control of nerve terminal growth. J. Neurobiol. 25, 599–611 (1994).

    Article  CAS  PubMed  Google Scholar 

  190. Leung, K. M. & Holt, C. E. Live visualization of protein synthesis in axonal growth cones by microinjection of photoconvertible Kaede into Xenopus embryos. Nature Protoc. 3, 1318–1327 (2008).

    Article  CAS  Google Scholar 

  191. Park, H. Y., Buxbaum, A. R. & Singer, R. H. Single mRNA tracking in live cells. Methods Enzymol. 472, 387–406 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Bi, J., Tsai, N. P., Lu, H. Y., Loh, H. H. & Wei, L. N. Copb1-facilitated axonal transport and translation of κ opioid-receptor mRNA. Proc. Natl Acad. Sci. USA 104, 13810–13815 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Lionnet, T. et al. A transgenic mouse for in vivo detection of endogenous labeled mRNA. Nature Methods 8, 165–170 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Lee, S. K. & Hollenbeck, P. J. Organization and translation of mRNA in sympathetic axons. J. Cell Sci. 116, 4467–4478 (2003).

    Article  CAS  PubMed  Google Scholar 

  195. Dieterich, D. C. et al. In situ visualization and dynamics of newly synthesized proteins in rat hippocampal neurons. Nature Neurosci. 13, 897–905 (2010).

    Article  CAS  PubMed  Google Scholar 

  196. Heiman, M. et al. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135, 738–748 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Twiss, J. L., Smith, D. S., Chang, B. & Shooter, E. M. Translational control of ribosomal protein L4 mRNA is required for rapid neurite regeneration. Neurobiol. Dis. 7, 416–428 (2000).

    Article  CAS  PubMed  Google Scholar 

  198. Natera-Naranjo, O. et al. Local translation of ATP synthase subunit 9 mRNA alters ATP levels and the production of ROS in the axon. Mol. Cell Neurosci. 49, 263–270 (2012).

    Article  CAS  PubMed  Google Scholar 

  199. Giustetto, M. et al. Axonal transport of eukaryotic translation elongation factor 1α mRNA couples transcription in the nucleus to long-term facilitation at the synapse. Proc. Natl Acad. Sci. USA 100, 13680–13685 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Sotelo-Silveira, J. R. et al. Neurofilament mRNAs are present and translated in the normal and severed sciatic nerve. J. Neurosci. Res. 62, 65–74 (2000).

    Article  CAS  PubMed  Google Scholar 

  201. Aronov, S., Aranda, G., Behar, L. & Ginzburg, I. Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. J. Neurosci. 21, 6577–6587 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to the authors of papers we could not include in this Review owing to space limitations. We thank J. Hu and C. M. O'Hare for critical reading of the manuscript. This work was supported by a Wellcome Trust Programme Grant (085314/Z/08/Z) to C.E.H.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine E. Holt.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Christine E. Holt's homepage

Glossary

Polysomes

Strings of 80S ribosomes bound to mRNA molecules.

Ribosomes

Large RNA–protein complexes (80S) at which mRNA translation occurs. They contain 4 rRNAs and more than 79 proteins and are composed of a large (60S) subunit and a small (40S) subunit.

RNA-binding protein

(RBP). A protein that binds RNAs. Most RBPs have modular structures containing specific RNA-binding domains, catalytic domains and/or protein-binding domains.

Small nuclear ribonucleoproteins

(snRNPs). Complexes that are composed of a small nuclear RNA and a specific set of proteins.

RNA granules

Intermediate RNA–protein complexes that regulate RNA transport, translation and degradation. RNA granules include transport ribonucleoproteins, stress granules and processing bodies.

Stress granules

Dense cytosolic proteins and RNA aggregations that appear under conditions of cellular stress. The RNA molecules are thought to be stalled translation pre-initiation complexes.

MicroRNAs

Non-coding RNA molecules of 21–24 nucleotides in length that inhibit mRNA expression.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jung, H., Yoon, B. & Holt, C. Axonal mRNA localization and local protein synthesis in nervous system assembly, maintenance and repair. Nat Rev Neurosci 13, 308–324 (2012). https://doi.org/10.1038/nrn3210

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn3210

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing