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:

Local translation in neurons: visualization and function

Abstract

Neurons are among the most compartmentalized and interactive of all cell types. Like all cells, neurons use proteins as the main sensors and effectors. The modification of the proteome in axons and dendrites is used to guide the formation of synaptic connections and to store information. In this Review, we discuss the data indicating that an important source of protein for dendrites, axons and their associated elements is provided by the local synthesis of proteins. We review the data indicating the presence of the machinery required for protein synthesis, the direct visualization and demonstration of protein synthesis, and the established functional roles for local translation for many different neuronal functions. Finally, we consider the open questions and future directions in this field.

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

Fig. 1: Neurons and numbers.
Fig. 2: The localization of the protein template (mRNA), the machinery (ribosomes) and regulatory elements required for protein synthesis.
Fig. 3: Visualization of local protein synthesis.

Similar content being viewed by others

References

  1. Ishizuka, N., Cowan, W. M. & Amaral, D. G. A quantitative analysis of the dendritic organization of pyramidal cells in the rat hippocampus. J. Comp. Neurol. 362, 17–45 (1995).

    CAS  PubMed  Google Scholar 

  2. Ishizuka, N., Weber, J. & Amaral, D. G. Organization of intrahippocampal projections originating from CA3 pyramidal cells in the rat. J. Comp. Neurol. 295, 580–623 (1990).

    CAS  PubMed  Google Scholar 

  3. Bourne, J. N. & Harris, K. M. Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP. Hippocampus 21, 354–373 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Pielot, R. et al. SynProt: a database for proteins of detergent-resistant synaptic protein preparations. Front. Synaptic Neurosci. 4, 1 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Richter, K. N. et al. Comparative synaptosome imaging: a semi-quantitative method to obtain copy numbers for synaptic and neuronal proteins. Sci. Rep. 8, 14838 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Wilhelm, B. G. et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344, 1023–1028 (2014).

    CAS  PubMed  Google Scholar 

  7. Cheng, D. et al. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol. Cell. Proteom. 5, 1158–1170 (2006).

    CAS  Google Scholar 

  8. Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).

    CAS  PubMed  Google Scholar 

  9. Cohen, L. D. et al. Metabolic turnover of synaptic proteins: kinetics, interdependencies and implications for synaptic maintenance. PLoS One 8, e63191 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Dörrbaum, A. R., Kochen, L., Langer, J. D. & Schuman, E. M. Local and global influences on protein turnover in neurons and glia. eLife 7, e34202 (2018).

    PubMed  PubMed Central  Google Scholar 

  11. Fornasiero, E. F. et al. Precisely measured protein lifetimes in the mouse brain reveal differences across tissues and subcellular fractions. Nat. Commun. 9, 4230 (2018).

    PubMed  PubMed Central  Google Scholar 

  12. Deglincerti, A. et al. Coupled local translation and degradation regulate growth cone collapse. Nat. Commun. 6, 6888 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Davis, H. P. & Squire, L. R. Protein synthesis and memory: a review. Psychol. Bull. 96, 518–559 (1984).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Andersen, P., Sundberg, S. H., Sveen, O. & Wigström, H. Specific long-lasting potentiation of synaptic transmission in hippocampal slices. Nature 266, 736–737 (1977).

    CAS  PubMed  Google Scholar 

  16. Govindarajan, A., Israely, I., Huang, S. Y. & Tonegawa, S. The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP. Neuron 69, 132–146 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Maday, S., Twelvetrees, A. E., Moughamian, A. J. & Holzbaur, E. L. Axonal transport: cargo-specific mechanisms of motility and regulation. Neuron 84, 292–309 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Garner, C. C., Tucker, R. P. & Matus, A. Selective localization of messenger RNA for cytoskeletal protein MAP2 in dendrites. Nature 336, 674–677 (1988).

    CAS  PubMed  Google Scholar 

  19. Burgin, K. E. et al. In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J. Neurosci. 10, 1788–1798 (1990).

    CAS  PubMed  Google Scholar 

  20. Bassell, G. J. et al. Sorting of beta-actin mRNA and protein to neurites and growth cones in culture. J. Neurosci. 18, 251–265 (1998).

    CAS  PubMed  Google Scholar 

  21. Moccia, R. et al. An unbiased cDNA library prepared from isolated Aplysia sensory neuron processes is enriched for cytoskeletal and translational mRNAs. J. Neurosci. 23, 9409–9417 (2003).

    CAS  PubMed  Google Scholar 

  22. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Poon, M. M., Choi, S. H., Jamieson, C. A., Geschwind, D. H. & Martin, K. C. Identification of process-localized mRNAs from cultured rodent hippocampal neurons. J. Neurosci. 26, 13390–13399 (2006).

    CAS  PubMed  Google Scholar 

  26. Zhong, J., Zhang, T. & Bloch, L. M. Dendritic mRNAs encode diversified functionalities in hippocampal pyramidal neurons. BMC Neurosci. 7, 17 (2006).

    PubMed  PubMed Central  Google Scholar 

  27. Taylor, A. M. et al. Axonal mRNA in uninjured and regenerating cortical mammalian axons. J. Neurosci. 29, 4697–4707 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cajigas, I. J. et al. The local transcriptome in the synaptic neuropil revealed by deep sequencing and high-resolution imaging. Neuron 74, 453–466 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hafner, A. S., Donlin-Asp, P. G., Leitch, B., Herzog, E. & Schuman, E. M. Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments. Science 364, eaau3644 (2019).

    PubMed  Google Scholar 

  30. Eom, T., Antar, L. N., Singer, R. H. & Bassell, G. J. Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses. J. Neurosci. 23, 10433–10444 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  32. Taliaferro, J. M. et al. Distal alternative last exons localize mRNAs to neural projections. Mol. Cell 61, 821–833 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tushev, G. et al. Alternative 3′ UTRs modify the localization, regulatory potential, stability, and plasticity of mRNAs in neuronal compartments. Neuron 98, 495–511.e6 (2018).

    CAS  PubMed  Google Scholar 

  34. Fontes, M. M. et al. Activity-dependent regulation of alternative cleavage and polyadenylation during hippocampal long-term potentiation. Sci. Rep. 7, 17377 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. Kislauskis, E. H., Zhu, X. & Singer, R. H. Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. J. Cell Biol. 127, 441–451 (1994).

    CAS  PubMed  Google Scholar 

  36. Turner-Bridger, B. et al. Single-molecule analysis of endogenous β-actin mRNA trafficking reveals a mechanism for compartmentalized mRNA localization in axons. Proc. Natl Acad. Sci. USA 115, E9697–E9706 (2018).

    CAS  PubMed  Google Scholar 

  37. Andreassi, C. et al. 3′UTR cleavage of transcripts localized in axons of sympathetic neurons. Preprint at bioRxiv https://doi.org/10.1101/170100 (2019).

  38. Bodian, D. A Suggestive relationship of nerve cell RNA with specific synaptic sites. Proc. Natl Acad. Sci. USA 53, 418–425 (1965).

    CAS  PubMed  Google Scholar 

  39. Steward, O. & Levy, W. B. Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. J. Neurosci. 2, 284–291 (1982).

    CAS  PubMed  Google Scholar 

  40. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Shigeoka, T. et al. Dynamic axonal translation in developing and mature visual circuits. Cell 166, 181–192 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Ostroff, L. E., Fiala, J. C., Allwardt, B. & Harris, K. M. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron 35, 535–545 (2002).

    CAS  PubMed  Google Scholar 

  44. Walker, B. A. et al. Reprogramming axonal behavior by axon-specific viral transduction. Gene Ther. 19, 947–955 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Koppers, M. et al. Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons. Preprint at bioRxiv https://doi.org/10.1101/673798 (2019).

  46. Heyer, E. E. & Moore, M. J. Redefining the translational status of 80S monosomes. Cell 164, 757–769 (2016).

    CAS  PubMed  Google Scholar 

  47. Gardiol, A., Racca, C. & Triller, A. Dendritic and postsynaptic protein synthetic machinery. J. Neurosci. 19, 168–179 (1999).

    CAS  PubMed  Google Scholar 

  48. Horton, A. C. & Ehlers, M. D. Dual modes of endoplasmic reticulum-to-Golgi transport in dendrites revealed by live-cell imaging. J. Neurosci. 23, 6188–6199 (2003).

    CAS  PubMed  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. Cioni, J. M. et al. Late endosomes act as mRNA translation platforms and sustain mitochondria in axons. Cell 176, 56–72.e15 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Hanus, C. & Ehlers, M. D. Secretory outposts for the local processing of membrane cargo in neuronal dendrites. Traffic 9, 1437–1445 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Hanus, C. et al. Unconventional secretory processing diversifies neuronal ion channel properties. eLife 5, e20609 (2016).

    PubMed  PubMed Central  Google Scholar 

  53. Mikhaylova, M., Bera, S., Kobler, O., Frischknecht, R. & Kreutz, M. R. A dendritic Golgi satellite between ERGIC and retromer. Cell Rep. 14, 189–199 (2016).

    CAS  PubMed  Google Scholar 

  54. Koenig, E. Synthetic mechanisms in the axon. I. Local axonal synthesis of acetylcholinesterase. J. Neurochem. 12, 343–355 (1965).

    CAS  PubMed  Google Scholar 

  55. 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).

    CAS  PubMed  Google Scholar 

  56. Rao, A. & Steward, O. Evidence that protein constituents of postsynaptic membrane specializations are locally synthesized: analysis of proteins synthesized within synaptosomes. J. Neurosci. 11, 2881–2895 (1991).

    CAS  PubMed  Google Scholar 

  57. Weiler, I. J. & Greenough, W. T. Potassium ion stimulation triggers protein translation in synaptoneurosomal polyribosomes. Mol. Cell. Neurosci. 2, 305–314 (1991).

    CAS  PubMed  Google Scholar 

  58. Torre, E. R. & Steward, O. Demonstration of local protein synthesis within dendrites using a new cell culture system that permits the isolation of living axons and dendrites from their cell bodies. J. Neurosci. 12, 762–772 (1992).

    CAS  PubMed  Google Scholar 

  59. Kang, H. & Schuman, E. M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273, 1402–1406 (1996).

    CAS  PubMed  Google Scholar 

  60. Huber, K. M., Kayser, M. S. & Bear, M. F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288, 1254–1257 (2000).

    CAS  PubMed  Google Scholar 

  61. Martin, K. C. et al. Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938 (1997).

    CAS  PubMed  Google Scholar 

  62. Eng, H., Lund, K. & Campenot, R. B. Synthesis of beta-tubulin, actin, and other proteins in axons of sympathetic neurons in compartmented cultures. J. Neurosci. 19, 1–9 (1999).

    CAS  PubMed  Google Scholar 

  63. 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).

    CAS  PubMed  Google Scholar 

  64. Yoon, B. C. et al. Local translation of extranuclear lamin B promotes axon maintenance. Cell 148, 752–764 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Shigeoka, T., Jung, J., Holt, C. E. & Jung, H. Axon-TRAP-RiboTag: affinity purification of translated mRNAs from neuronal axons in mouse in vivo. Methods Mol. Biol. 1649, 85–94 (2018).

    CAS  PubMed  Google Scholar 

  66. Cagnetta, R., Frese, C. K., Shigeoka, T., Krijgsveld, J. & Holt, C. E. Rapid cue-specific remodeling of the nascent axonal proteome. Neuron 99, 29–46.e4 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Hughes, C. S., Sorensen, P. H. & Morin, G. B. A standardized and reproducible proteomics protocol for bottom-up quantitative analysis of protein samples using SP3 and mass spectrometry. Methods Mol. Biol. 1959, 65–87 (2019).

    PubMed  Google Scholar 

  68. Aakalu, G., Smith, W. B., Nguyen, N., Jiang, C. & Schuman, E. M. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30, 489–502 (2001).

    CAS  PubMed  Google Scholar 

  69. Wang, D. O. et al. Synapse- and stimulus-specific local translation during long-term neuronal plasticity. Science 324, 1536–1540 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Kim, S. & Martin, K. C. Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome. eLife 4, e04158 (2015).

    PubMed Central  Google Scholar 

  72. Wong, H. H. et al. RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron 95, 852–868.e8 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Tatavarty, V. et al. Single-molecule imaging of translational output from individual RNA granules in neurons. Mol. Biol. Cell 23, 918–929 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ifrim, M. F., Williams, K. R. & Bassell, G. J. Single-molecule imaging of PSD-95 mRNA translation in dendrites and its dysregulation in a mouse model of fragile X syndrome. J. Neurosci. 35, 7116–7130 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ströhl, F. et al. Single molecule translation imaging visualizes the dynamics of local β-actin synthesis in retinal axons. Sci. Rep. 7, 709 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. Wu, B., Eliscovich, C., Yoon, Y. J. & Singer, R. H. Translation dynamics of single mRNAs in live cells and neurons. Science 352, 1430–1435 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dieterich, D. C., Link, A. J., Graumann, J., Tirrell, D. A. & Schuman, E. M. Selective identification of newly synthesized proteins in mammalian cells using bioorthogonal noncanonical amino acid tagging (BONCAT). Proc. Natl Acad. Sci. USA 103, 9482–9487 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Nathans, D. Puromycin inhibition of protein synthesis: incorporation of puromycin into peptide chains. Proc. Natl Acad. Sci. USA 51, 585–592 (1964).

    CAS  PubMed  Google Scholar 

  80. Smith, W. B., Starck, S. R., Roberts, R. W. & Schuman, E. M. Dopaminergic stimulation of local protein synthesis enhances surface expression of GluR1 and synaptic transmission in hippocampal neurons. Neuron 45, 765–779 (2005).

    CAS  PubMed  Google Scholar 

  81. David, A. et al. Nuclear translation visualized by ribosome-bound nascent chain puromycylation. J. Cell Biol. 197, 45–57 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. tom Dieck, S. et al. Direct visualization of newly synthesized target proteins in situ. Nat. Methods 12, 411–414 (2015).

    CAS  PubMed  Google Scholar 

  83. Sambandan, S. et al. Activity-dependent spatially localized miRNA maturation in neuronal dendrites. Science 355, 634–637 (2017).

    CAS  PubMed  Google Scholar 

  84. Batista, A. F. R., Martínez, J. C. & Hengst, U. Intra-axonal SYnthesis of SNAP25 is required for the formation of presynaptic terminals. Cell Rep. 20, 3085–3098 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, C. & Götz, J. Somatodendritic accumulation of Tau in Alzheimer’s disease is promoted by Fyn-mediated local protein translation. EMBO J. 36, 3120–3138 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Rajgor, D., Sanderson, T. M., Amici, M., Collingridge, G. L. & Hanley, J. G. NMDAR-dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity. EMBO J. 37, e97943 (2018).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Piper, M. et al. Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49, 215–228 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Schanzenbächer, C. T., Langer, J. D. & Schuman, E. M. Time- and polarity-dependent proteomic changes associated with homeostatic scaling at central synapses. eLife 7, e33322 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Schanzenbächer, C. T., Sambandan, S., Langer, J. D. & Schuman, E. M. Nascent proteome remodeling following homeostatic scaling at hippocampal synapses. Neuron 92, 358–371 (2016).

    PubMed  PubMed Central  Google Scholar 

  92. Bellon, A. et al. miR-182 regulates Slit2-mediated axon guidance by modulating the local translation of a specific mRNA. Cell Rep. 18, 1171–1186 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Yu, C. C. et al. Epigenetic modulation on tau phosphorylation in Alzheimer’s disease. Neural Plast. 2019, 6856327 (2019).

    PubMed  PubMed Central  Google Scholar 

  94. Cagnetta, R. et al. Noncanonical modulation of the eIF2 pathway controls an increase in local translation during neural wiring. Mol. Cell 73, 474–489.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lepelletier, L. et al. Sonic hedgehog guides axons via zipcode binding protein 1-mediated local translation. J. Neurosci. 37, 1685–1695 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Richter, J. D., Bassell, G. J. & Klann, E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat. Rev. Neurosci. 16, 595–605 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Gkogkas, C., Sonenberg, N. & Costa-Mattioli, M. Translational control mechanisms in long-lasting synaptic plasticity and memory. J. Biol. Chem. 285, 31913–31917 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Vickers, C. A., Dickson, K. S. & Wyllie, D. J. Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones. J. Physiol. (Lond.) 568, 803–813 (2005).

    CAS  Google Scholar 

  100. Bradshaw, K. D., Emptage, N. J. & Bliss, T. V. A role for dendritic protein synthesis in hippocampal late LTP. Eur. J. Neurosci. 18, 3150–3152 (2003).

    CAS  PubMed  Google Scholar 

  101. Sutton, M. A. et al. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 125, 785–799 (2006).

    CAS  PubMed  Google Scholar 

  102. Sutton, M. A., Wall, N. R., Aakalu, G. N. & Schuman, E. M. Regulation of dendritic protein synthesis by miniature synaptic events. Science 304, 1979–1983 (2004).

    CAS  PubMed  Google Scholar 

  103. Scarnati, M. S., Kataria, R., Biswas, M. & Paradiso, K. G. Active presynaptic ribosomes in the mammalian brain, and altered transmitter release after protein synthesis inhibition. eLife 7, e36697 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Younts, T. J. et al. Presynaptic protein synthesis is required for long-term plasticity of GABA release. Neuron 92, 479–492 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Goard, M. et al. Light-mediated inhibition of protein synthesis. Chem. Biol. 12, 685–693 (2005).

    CAS  PubMed  Google Scholar 

  106. Elamri, I. et al. A new photocaged puromycin for an efficient labeling of newly translated proteins in living neurons. Chembiochem 19, 2458–2464 (2018).

    CAS  PubMed  Google Scholar 

  107. Ouyang, Y., Rosenstein, A., Kreiman, G., Schuman, E. M. & Kennedy, M. B. Tetanic stimulation leads to increased accumulation of Ca2+/calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons. J. Neurosci. 19, 7823–7833 (1999).

    CAS  PubMed  Google Scholar 

  108. Miller, S. et al. Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation. Neuron 36, 507–519 (2002).

    CAS  PubMed  Google Scholar 

  109. Kuklin, E. A. et al. The long 3’UTR mRNA of CaMKII is essential for translation-dependent plasticity of spontaneous release in Drosophila melanogaster. J. Neurosci. 37, 10554–10566 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  111. Yao, J., Sasaki, Y., Wen, Z., Bassell, G. J. & Zheng, J. Q. An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance. Nat. Neurosci. 9, 1265–1273 (2006).

    CAS  PubMed  Google Scholar 

  112. Perry, R. B. et al. Subcellular knockout of importin β1 perturbs axonal retrograde signaling. Neuron 75, 294–305 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Koley, S., Rozenbaum, M., Fainzilber, M. & Terenzio, M. Translating regeneration: local protein synthesis in the neuronal injury response. Neurosci. Res. 139, 26–36 (2019).

    CAS  PubMed  Google Scholar 

  114. Willis, D. E. & Twiss, J. L. The evolving roles of axonally synthesized proteins in regeneration. Curr. Opin. Neurobiol. 16, 111–118 (2006).

    CAS  PubMed  Google Scholar 

  115. Cosker, K. E., Fenstermacher, S. J., Pazyra-Murphy, M. F., Elliott, H. L. & Segal, R. A. The RNA-binding protein SFPQ orchestrates an RNA regulon to promote axon viability. Nat. Neurosci. 19, 690–696 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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).

    CAS  PubMed  Google Scholar 

  117. Poulopoulos, A. et al. Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex. Nature 565, 356–360 (2019).

    CAS  PubMed  Google Scholar 

  118. Shigeoka, T. et al. On-site ribosome remodeling by locally synthesized ribosomal proteins in axons. Preprint at bioRxiv https://doi.org/10.1101/500033 (2018).

  119. Shi, Z. & Barna, M. Translating the genome in time and space: specialized ribosomes, RNA regulons, and RNA-binding proteins. Annu. Rev. Cell Dev. Biol. 31, 31–54 (2015).

    CAS  PubMed  Google Scholar 

  120. Dominissini, D. et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature 485, 201–206 (2012).

    CAS  PubMed  Google Scholar 

  121. Meyer, K. D. et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3′ UTRs and near stop codons. Cell 149, 1635–1646 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang, Y. & Zhao, J. C. Update: mechanisms underlying N6-methyladenosine modification of eukaryotic mRNA. Trends Genet. 32, 763–773 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Merkurjev, D. et al. Synaptic N 6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts. Nat. Neurosci. 21, 1004–1014 (2018).

    CAS  PubMed  Google Scholar 

  124. Holt, C. E. & Schuman, E. M. The central dogma decentralized: new perspectives on RNA function and local translation in neurons. Neuron 80, 648–657 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Ashley, J. et al. Retrovirus-like Gag Protein Arc1 binds RNA and traffics across synaptic boutons. Cell 172, 262–274.e11 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Pastuzyn, E. D. et al. The neuronal gene Arc encodes a repurposed retrotransposon gag protein that mediates intercellular RNA transfer. Cell 172, 275–288.e18 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    CAS  PubMed  Google Scholar 

  128. Alberti, S. & Hyman, A. A. Are aberrant phase transitions a driver of cellular aging? BioEssays 38, 959–968 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88, 678–690 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Qamar, S. et al. FUS phase separation is modulated by a molecular chaperone and methylation of arginine cation-pi Interactions. Cell 173, 720–734.e15 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Seidler, P. M. et al. Structure-based inhibitors of tau aggregation. Nat. Chem. 10, 170–176 (2018).

    CAS  PubMed  Google Scholar 

  132. Cioni, J. M., Koppers, M. & Holt, C. E. Molecular control of local translation in axon development and maintenance. Curr. Opin. Neurobiol. 51, 86–94 (2018).

    CAS  PubMed  Google Scholar 

  133. Leung, L. C. et al. Coupling of NF-protocadherin signaling to axon guidance by cue-induced translation. Nat. Neurosci. 16, 166–173 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Meer, E. J. et al. Identification of a cis-acting element that localizes mRNA to synapses. Proc. Natl Acad. Sci. USA 109, 4639–4644 (2012).

    CAS  PubMed  Google Scholar 

  135. Aakalu, G., Smith, W. B., Nguyen, N., Jiang, C. & Schuman, E. M. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30, 489–502 (2001).

    CAS  PubMed  Google Scholar 

  136. Seo, J. Y. et al. DAP5 increases axonal outgrowth of hippocampal neurons by enhancing the cap-independent translation of DSCR1.4 mRNA. Cell Death Dis. 10, 49 (2019).

    PubMed  PubMed Central  Google Scholar 

  137. Ciolli Mattioli, C. et al. Alternative 3′ UTRs direct localization of functionally diverse protein isoforms in neuronal compartments. Nucleic Acids Res. 47, 2560–2573 (2019).

    PubMed  Google Scholar 

  138. Jones, K. J. et al. Rapid, experience-dependent translation of neurogranin enables memory encoding. Proc. Natl Acad. Sci. USA 115, E5805–E5814 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratories, particularly S. tom Dieck for help with Fig. 1 and Table 1. C.E.H. is funded by the Wellcome Trust (203249/Z/16/Z) and an Advanced Investigator Award from the European Research council (322817). K.C.M. is funded by NIH R01MH077022 and NIH R21MH113102. E.M.S. is funded by the Max Planck Society, an Advanced Investigator Award from the European Research Council (743216), and DFG CRC 1080 and CRC 902.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Christine E. Holt, Kelsey C. Martin or Erin M. Schuman.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information: Katarzyna Marcinkiewicz was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Holt, C.E., Martin, K.C. & Schuman, E.M. Local translation in neurons: visualization and function. Nat Struct Mol Biol 26, 557–566 (2019). https://doi.org/10.1038/s41594-019-0263-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41594-019-0263-5

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