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:

Translational control of localized mRNAs: restricting protein synthesis in space and time

Nature Reviews Molecular Cell Biology volume 9, pages 971–980 (2008)Cite this article

Key Points

  • Recent genome-wide analyses in diverse organisms and cell types have revealed that a vast number of mRNAs display specific subcellular localization, and thus that mRNA localization coupled with precise translational control is a major mechanism used by cells to establish functionally distinct compartments and structures.

  • Both the transport and translation of localizing mRNAs are regulated in the context of ribonucleoprotein (RNP) complexes of precise composition. These complexes start assembling in the nucleus and contain trans-acting regulatory factors, both proteins and non-coding RNAs.

  • Translation of mRNAs that are in the process of being localized is blocked by a combination of translational repressors. These bind to their target mRNAs by recognizing specific cis-regulatory motifs. These repressors inhibit translation at various steps, but most block translation initiation.

  • For many localizing mRNAs, translation is directly activated upon arrival at the final destination. This is commonly achieved by spatially restricted phosphorylation of translational repressors and a subsequent decrease in their affinity for target mRNAs.

  • In some cell types, mainly neurons, translation of localized mRNAs is activated only in response to specific external signals. In this case, translational derepression is induced through conserved signalling pathways by regulation both of general components of the translational machinery and of mRNA-specific repressors.

  • Decrypting the combinatorial code of cis-regulatory elements that dictate the specific behaviour of mRNAs is now one of the main challenges.

Abstract

As highlighted by recent genome-wide analyses in diverse organisms and cell types, subcellular targeting of mRNAs has emerged as a major mechanism for cells to establish functionally distinct compartments and structures. For protein synthesis to be spatially restricted, translation of localizing mRNAs is silenced during their transport and is activated when they reach their final destination. Such a precise translation pattern is controlled by repressors, which are specifically recruited to transport ribonucleoprotein particles and block translation at different steps. Functional studies have revealed that the inactivation of these repressors, either by pre-localized proteins or in response to conserved signalling pathways, triggers local protein synthesis.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Spatial translational activation of ASH1 mRNA in budding yeast.
Figure 2: Mechanisms that control translation of localized mRNAs.
Figure 3: Signal-induced translational activation.

Similar content being viewed by others

References

  1. Du, T. G., Schmid, M. & Jansen, R. P. Why cells move messages: the biological functions of mRNA localization. Semin. Cell Dev. Biol. 18, 171–177 (2007).

    Article  CAS  PubMed  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. Horne-Badovinac, S. & Bilder, D. Dynein regulates epithelial polarity and the apical localization of stardust A mRNA. PLoS Genet. 4, e8 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Li, Z., Wang, L., Hays, T. S. & Cai, Y. Dynein-mediated apical localization of crumbs transcripts is required for Crumbs activity in epithelial polarity. J. Cell Biol. 180, 31–38 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Condeelis, J. & Singer, R. H. How and why does β-actin mRNA target? Biol. Cell 97, 97–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. 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 

  7. Wu, K. Y. et al. Local translation of RhoA regulates growth cone collapse. Nature 436, 1020–1024 (2005). Identifies an mRNA that is localized in growth cones and shows that its local translation is physiologically required.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Ephrussi, A., Dickinson, L. K. & Lehmann, R. oskar organizes the germ plasm and directs localization of the posterior determinant nanos. Cell 66, 37–50 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Lambert, J. D. & Nagy, L. M. Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature 420, 682–686 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Long, R. M. et al. Mating type switching in yeast controlled by asymmetric localization of ASH1 mRNA. Science 277, 383–387 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Takizawa, P. A., Sil, A., Swedlow, J. R., Herskowitz, I. & Vale, R. D. Actin-dependent localization of an RNA encoding a cell-fate determinant in yeast. Nature 389, 90–93 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Dictenberg, J. B., Swanger, S. A., Antar, L. N., Singer, R. H. & Bassell, G. J. A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev. Cell 14, 926–939 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Eliscovich, C., Peset, I., Vernos, I. & Mendez, R. Spindle-localized CPE-mediated translation controls meiotic chromosome segregation. Nature Cell Biol. 10, 858–865 (2008).

    Article  CAS  PubMed  Google Scholar 

  15. Huttelmaier, S. et al. Spatial regulation of β-actin translation by Src-dependent phosphorylation of ZBP1. Nature 438, 512–515 (2005). Reveals a direct molecular link between mRNA transport and translational control and proposes a mechanism for spatially controlled translational derepression.

    Article  PubMed  CAS  Google Scholar 

  16. Huang, Y. S., Carson, J. H., Barbarese, E. & Richter, J. D. Facilitation of dendritic mRNA transport by CPEB. Genes Dev. 17, 638–653 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kress, T. L., Yoon, Y. J. & Mowry, K. L. Nuclear RNP complex assembly initiates cytoplasmic RNA localization. J. Cell Biol. 165, 203–211 (2004). Provides evidence of the stepwise recruitment of RNP components.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Elvira, G. et al. Characterization of an RNA granule from developing brain. Mol. Cell. Proteomics 5, 635–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513–525 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Wilhelm, J. E. et al. Isolation of a ribonucleoprotein complex involved in mRNA localization in Drosophila oocytes. J. Cell Biol. 148, 427–440 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Clouse, K. N., Ferguson, S. B. & Schupbach, T. Squid, Cup, and PABP55B function together to regulate gurken translation in Drosophila. Dev. Biol. 313, 713–724 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Nakamura, A., Sato, K. & Hanyu-Nakamura, K. Drosophila cup is an eIF4E binding protein that associates with Bruno and regulates oskar mRNA translation in oogenesis. Dev. Cell 6, 69–78 (2004). Shows the direct recruitment of an inhibitory eIF4E-BP on a localizing mRNA by an mRNA-specific translational repressor.

    Article  CAS  PubMed  Google Scholar 

  23. Kuersten, S. & Goodwin, E. B. The power of the 3′ UTR: translational control and development. Nature Rev. Genet. 4, 626–637 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. 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 

  25. Paquin, N. & Chartrand, P. Local regulation of mRNA translation: new insights from the bud. Trends Cell Biol. 18, 105–111 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Barbarese, E. et al. Protein translation components are colocalized in granules in oligodendrocytes. J. Cell Sci. 108, 2781–2790 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Knowles, R. B. et al. Translocation of RNA granules in living neurons. J. Neurosci. 16, 7812–7820 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krichevsky, A. M. & Kosik, K. S. Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32, 683–696 (2001). This pioneering study indicates that neuronal RNA granules contain silenced mRNAs, the translation of which is activated in response to neuronal stimulation.

    Article  CAS  PubMed  Google Scholar 

  29. Braat, A. K., Yan, N., Arn, E., Harrison, D. & Macdonald, P. M. Localization-dependent oskar protein accumulation; control after the initiation of translation. Dev. Cell 7, 125–131 (2004).

    Article  CAS  PubMed  Google Scholar 

  30. Chekulaeva, M., Hentze, M. W. & Ephrussi, A. Bruno acts as a dual repressor of oskar translation, promoting mRNA oligomerization and formation of silencing particles. Cell 124, 521–533 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Cheng, J. G., Tiedge, H. & Brosius, J. Identification and characterization of BC1 RNP particles. DNA Cell Biol. 15, 549–559 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006). Shows microRNA-mediated regulation of a dendritically localized mRNA for the first time.

    Article  CAS  PubMed  Google Scholar 

  33. Hachet, O. & Ephrussi, A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428, 959–963 (2004). Shows the importance of nuclear events in the cytoplasmic targeting of an mRNA.

    Article  CAS  PubMed  Google Scholar 

  34. Lange, S. et al. Simultaneous transport of different localized mRNA species revealed by live-cell imaging. Traffic 9, 1256–1267 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Gao, Y., Tatavarty, V., Korza, G., Levin, M. K. & Carson, J. H. Multiplexed dendritic targeting of α calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway. Mol. Biol. Cell 19, 2311–2327 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Giorgi, C. & Moore, M. J. The nuclear nurture and cytoplasmic nature of localized mRNPs. Semin. Cell Dev. Biol. 18, 186–193 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Du, T. G. et al. Nuclear transit of the RNA-binding protein She2 is required for translational control of localized ASH1 mRNA. EMBO Rep. 9, 781–787 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eberhart, D. E., Malter, H. E., Feng, Y. & Warren, S. T. The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum. Mol. Genet. 5, 1083–1091 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Gu, W., Deng, Y., Zenklusen, D. & Singer, R. H. A new yeast PUF family protein, Puf6p, represses ASH1 mRNA translation and is required for its localization. Genes Dev. 18, 1452–1465 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Huynh, J. R., Munro, T. P., Smith-Litiere, K., Lepesant, J. A. & St Johnston, D. The Drosophila hnRNPA/B homolog, Hrp48, is specifically required for a distinct step in osk mRNA localization. Dev. Cell 6, 625–635 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Macchi, P. et al. The brain-specific double-stranded RNA-binding protein Staufen2: nucleolar accumulation and isoform-specific exportin-5-dependent export. J. Biol. Chem. 279, 31440–31444 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Martel, C., Macchi, P., Furic, L., Kiebler, M. A. & Desgroseillers, L. Staufen1 is imported into the nucleolus via a bipartite nuclear localization signal and several modulatory determinants. Biochem. J. 393, 245–254 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Snee, M., Benz, D., Jen, J. & Macdonald, P. M. Two distinct domains of Bruno bind specifically to the oskar mRNA. RNA Biol. 5, 1–9 (2008).

    Article  PubMed  Google Scholar 

  44. Pan, F., Huttelmaier, S., Singer, R. H. & Gu, W. ZBP2 facilitates binding of ZBP1 to β-actin mRNA during transcription. Mol. Cell. Biol. 27, 8340–8351 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Oleynikov, Y. & Singer, R. H. Real-time visualization of ZBP1 association with β-actin mRNA during transcription and localization. Curr. Biol. 13, 199–207 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kim-Ha, J., Kerr, K. & Macdonald, P. M. Translational regulation of oskar mRNA by bruno, an ovarian RNA-binding protein, is essential. Cell 81, 403–412 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Paquin, N. et al. Local activation of yeast ASH1 mRNA translation through phosphorylation of Khd1p by the casein kinase Yck1p. Mol. Cell 26, 795–809 (2007). Provides molecular mechanisms for translational repression and spatially controlled derepression of a localizing mRNA.

    Article  CAS  PubMed  Google Scholar 

  48. Tange, T. O., Nott, A. & Moore, M. J. The ever-increasing complexities of the exon junction complex. Curr. Opin. Cell Biol. 16, 279–284 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. 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 

  50. Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Palacios, I. M., Gatfield, D., St Johnston, D. & Izaurralde, E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Schratt, G. M., Nigh, E. A., Chen, W. G., Hu, L. & Greenberg, M. E. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin–phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J. Neurosci. 24, 7366–7377 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Clark, I. E., Wyckoff, D. & Gavis, E. R. Synthesis of the posterior determinant Nanos is spatially restricted by a novel cotranslational regulatory mechanism. Curr. Biol. 10, 1311–1314 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Richter, J. D. & Sonenberg, N. Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433, 477–480 (2005).

    Article  CAS  PubMed  Google Scholar 

  55. Nelson, M. R., Leidal, A. M. & Smibert, C. A. Drosophila Cup is an eIF4E-binding protein that functions in Smaug-mediated translational repression. EMBO J. 23, 150–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Jung, M. Y., Lorenz, L. & Richter, J. D. Translational control by neuroguidin, a eukaryotic initiation factor 4E and CPEB binding protein. Mol. Cell. Biol. 26, 4277–4287 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lin, D., Pestova, T. V., Hellen, C. U. & Tiedge, H. Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Mol. Cell. Biol. 28, 3008–3019 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Deng, Y., Singer, R. H. & Gu, W. Translation of ASH1 mRNA is repressed by Puf6p–Fun12p/eIF5B interaction and released by CK2 phosphorylation. Genes Dev. 22, 1037–1050 (2008). Provides molecular mechanisms for translational repression and spatially controlled derepression of a localizing mRNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Piccioni, F., Zappavigna, V. & Verrotti, A. C. Translational regulation during oogenesis and early development: the cap–poly(A) tail relationship. C. R. Biol. 328, 863–881 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Castagnetti, S. & Ephrussi, A. Orb and a long poly(A) tail are required for efficient oskar translation at the posterior pole of the Drosophila oocyte. Development 130, 835–843 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Wu, L. et al. CPEB-mediated cytoplasmic polyadenylation and the regulation of experience-dependent translation of α -CaMKII mRNA at synapses. Neuron 21, 1129–1139 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Zaessinger, S., Busseau, I. & Simonelig, M. Oskar allows nanos mRNA translation in Drosophila embryos by preventing its deadenylation by Smaug/CCR4. Development 133, 4573–4583 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Vardy, L. & Orr-Weaver, T. L. Regulating translation of maternal messages: multiple repression mechanisms. Trends Cell Biol. 17, 547–554 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. White, R. et al. Activation of oligodendroglial Fyn kinase enhances translation of mRNAs transported in hnRNP A2-dependent RNA granules. J. Cell Biol. 181, 579–586 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dahanukar, A., Walker, J. A. & Wharton, R. P. Smaug, a novel RNA-binding protein that operates a translational switch in Drosophila. Mol. Cell 4, 209–218 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Bramham, C. R. & Wells, D. G. Dendritic mRNA: transport, translation and function. Nature Rev. Neurosci. 8, 776–789 (2007).

    Article  CAS  Google Scholar 

  68. Piper, M. & Holt, C. RNA translation in axons. Annu. Rev. Cell Dev. Biol. 20, 505–523 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Klann, E. & Dever, T. E. Biochemical mechanisms for translational regulation in synaptic plasticity. Nature Rev. Neurosci. 5, 931–942 (2004).

    Article  CAS  Google Scholar 

  70. Scheper, G. C. & Proud, C. G. Does phosphorylation of the cap-binding protein eIF4E play a role in translation initiation? Eur. J. Biochem. 269, 5350–5359 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Gebauer, F. & Hentze, M. W. Molecular mechanisms of translational control. Nature Rev. Mol. Cell Biol. 5, 827–835 (2004).

    Article  CAS  Google Scholar 

  72. Marin, P. et al. Glutamate-dependent phosphorylation of elongation factor-2 and inhibition of protein synthesis in neurons. J. Neurosci. 17, 3445–3454 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Park, S. et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR–LTD. Neuron 59, 70–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Scheetz, A. J., Nairn, A. C. & Constantine-Paton, M. NMDA receptor-mediated control of protein synthesis at developing synapses. Nature Neurosci. 3, 211–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Inamura, N., Nawa, H. & Takei, N. Enhancement of translation elongation in neurons by brain-derived neurotrophic factor: implications for mammalian target of rapamycin signaling. J. Neurochem. 95, 1438–1445 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Sutton, M. A., Taylor, A. M., Ito, H. T., Pham, A. & Schuman, E. M. Postsynaptic decoding of neural activity: eEF2 as a biochemical sensor coupling miniature synaptic transmission to local protein synthesis. Neuron 55, 648–661 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Kanhema, T. et al. Dual regulation of translation initiation and peptide chain elongation during BDNF-induced LTP in vivo: evidence for compartment-specific translation control. J. Neurochem. 99, 1328–1337 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Takei, N. et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J. Neurosci. 24, 9760–9769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. 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). Reveals the asymmetric translation of an axon growth cone-localized mRNA and suggests its regulation by a combination of mRNA-specific and global changes in translational efficiency.

    Article  CAS  PubMed  Google Scholar 

  80. Dever, T. E. Gene-specific regulation by general translation factors. Cell 108, 545–556 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. Dyer, J. R. et al. An activity-dependent switch to cap-independent translation triggered by eIF4E dephosphorylation. Nature Neurosci. 6, 219–220 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Pinkstaff, J. K., Chappell, S. A., Mauro, V. P., Edelman, G. M. & Krushel, L. A. Internal initiation of translation of five dendritically localized neuronal mRNAs. Proc. Natl Acad. Sci. USA 98, 2770–2775 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. 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 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. Link, W. et al. Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc. Natl Acad. Sci. USA 92, 5734–5738 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Rook, M. S., Lu, M. & Kosik, K. S. CaMKIIα 3′ untranslated region-directed mRNA translocation in living neurons: visualization by GFP linkage. J. Neurosci. 20, 6385–6393 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tongiorgi, E., Righi, M. & Cattaneo, A. Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons. J. Neurosci. 17, 9492–9505 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Grooms, S. Y. et al. Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons. J. Neurosci. 26, 8339–8351 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Willis, D. E. et al. Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs. J. Cell Biol. 178, 965–980 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Mendez, R. & Richter, J. D. Translational control by CPEB: a means to the end. Nature Rev. Mol. Cell Biol. 2, 521–529 (2001).

    Article  CAS  Google Scholar 

  92. Richter, J. D. CPEB: a life in translation. Trends Biochem. Sci. 32, 279–285 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Huang, Y. S., Jung, M. Y., Sarkissian, M. & Richter, J. D. N-methyl-D-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and α CaMKII mRNA polyadenylation at synapses. EMBO J. 21, 2139–2148 (2002). Provides evidence for a signal-specific and mRNA-specific translational derepression mechanism in mammalian neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Atkins, C. M., Davare, M. A., Oh, M. C., Derkach, V. & Soderling, T. R. Bidirectional regulation of cytoplasmic polyadenylation element-binding protein phosphorylation by Ca2+/calmodulin-dependent protein kinase II and protein phosphatase 1 during hippocampal long-term potentiation. J. Neurosci. 25, 5604–5610 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Atkins, C. M., Nozaki, N., Shigeri, Y. & Soderling, T. R. Cytoplasmic polyadenylation element binding protein-dependent protein synthesis is regulated by calcium/calmodulin-dependent protein kinase II. J. Neurosci. 24, 5193–5201 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Godfraind, J. M. et al. Long-term potentiation in the hippocampus of fragile X knockout mice. Am. J. Med. Genet. 64, 246–251 (1996).

    Article  CAS  PubMed  Google Scholar 

  97. Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 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 

  99. Ceman, S. et al. Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum. Mol. Genet. 12, 3295–3305 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. Ashraf, S. I., McLoon, A. L., Sclarsic, S. M. & Kunes, S. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 124, 191–205 (2006).

    Article  CAS  PubMed  Google Scholar 

  101. Keene, J. D. Ribonucleoprotein infrastructure regulating the flow of genetic information between the genome and the proteome. Proc. Natl Acad. Sci. USA 98, 7018–7024 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Pique, M., Lopez, J. M., Foissac, S., Guigo, R. & Mendez, R. A combinatorial code for CPE-mediated translational control. Cell 132, 434–448 (2008). Identifies a combinatorial code of cis -regulatory elements that determine the translational repression and activation pattern of mRNAs in X. laevis oocytes.

    Article  CAS  PubMed  Google Scholar 

  103. An, J. J. et al. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134, 175–187 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Kolev, N. G. & Huber, P. W. VgRBP71 stimulates cleavage at a polyadenylation signal in Vg1 mRNA, resulting in the removal of a cis-acting element that represses translation. Mol. Cell 11, 745–755 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Ding, D., Parkhurst, S. M., Halsell, S. R. & Lipshitz, H. D. Dynamic Hsp83 RNA localization during Drosophila oogenesis and embryogenesis. Mol. Cell. Biol. 13, 3773–3781 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Forrest, K. M. & Gavis, E. R. Live imaging of endogenous RNA reveals a diffusion and entrapment mechanism for nanos mRNA localization in Drosophila. Curr. Biol. 13, 1159–1168 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Chang, P. et al. Localization of RNAs to the mitochondrial cloud in Xenopus oocytes through entrapment and association with endoplasmic reticulum. Mol. Biol. Cell 15, 4669–4681 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. St Johnston, D. Moving messages: the intracellular localization of mRNAs. Nature Rev. Mol. Cell Biol. 6, 363–375 (2005).

    Article  CAS  Google Scholar 

  109. Bullock, S. L. Translocation of mRNAs by molecular motors: think complex? Semin. Cell Dev. Biol. 18, 194–201 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Bullock, S. L., Nicol, A., Gross, S. P. & Zicha, D. Guidance of bidirectional motor complexes by mRNA cargoes through control of dynein number and activity. Curr. Biol. 16, 1447–1452 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Delanoue, R. & Davis, I. Dynein anchors its mRNA cargo after apical transport in the Drosophila blastoderm embryo. Cell 122, 97–106 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Eulalio, A., Behm-Ansmant, I. & Izaurralde, E. P bodies: at the crossroads of post-transcriptional pathways. Nature Rev. Mol. Cell Biol. 8, 9–22 (2007).

    Article  CAS  Google Scholar 

  113. Lin, M. D., Fan, S. J., Hsu, W. S. & Chou, T. B. Drosophila decapping protein 1, dDcp1, is a component of the oskar mRNP complex and directs its posterior localization in the oocyte. Dev. Cell 10, 601–613 (2006).

    Article  CAS  PubMed  Google Scholar 

  114. Nakamura, A., Amikura, R., Hanyu, K. & Kobayashi, S. Me31B silences translation of oocyte-localizing RNAs through the formation of cytoplasmic RNP complex during Drosophila oogenesis. Development 128, 3233–3242 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Barbee, S. A. et al. Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic P bodies. Neuron 52, 997–1009 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zeitelhofer, M. et al. Dynamic interaction between P-bodies and transport ribonucleoprotein particles in dendrites of mature hippocampal neurons. J. Neurosci. 28, 7555–7562 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Lin, M. D. et al. Drosophila processing bodies in oogenesis. Dev. Biol. 322, 276–288 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  Google Scholar 

  119. Raab-Graham, K. F., Haddick, P. C., Jan, Y. N. & Jan, L. Y. Activity- and mTOR-dependent suppression of Kv1.1 channel mRNA translation in dendrites. Science 314, 144–148 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. 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).

    Article  CAS  PubMed  Google Scholar 

  121. Rodriguez, A. J., Shenoy, S. M., Singer, R. H. & Condeelis, J. Visualization of mRNA translation in living cells. J. Cell Biol. 175, 67–76 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ju, W. et al. Activity-dependent regulation of dendritic synthesis and trafficking of AMPA receptors. Nature Neurosci. 7, 244–253 (2004).

    Article  CAS  PubMed  Google Scholar 

  123. Blower, M. D., Feric, E., Weis, K. & Heald, R. Genome-wide analysis demonstrates conserved localization of messenger RNAs to mitotic microtubules. J. Cell Biol. 179, 1365–1373 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors apologize to those whose work could not be cited owing to space constraints. F.B. was supported by fellowships from the Federation of European Biochemical Societies (FEBS) and the Human Frontier Science Program Organization.

Author information

Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, 69117, Germany

    Florence Besse & Anne Ephrussi

  2. Institute of Developmental Biology and Cancer, CNRS UMR6543, University of Nice Sophia Antipolis, Parc Valrose, 06108, Nice cedex 2, France

    Florence Besse

Authors
  1. Florence Besse
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne Ephrussi
    View author publications

    You can also search for this author in PubMed Google Scholar

Supplementary information

41580_2008_BFnrm2548_MOESM5_ESM.pdf

Supplementary information S1 (Table) | Genome-wide searches for localized mRNAs and locally translated mRNAs (PDF 190 kb)

Supplementary information S2 (box) | Regulation of translation and the cytoskeleton (PDF 158 kb)

Related links

Related links

DATABASES

OMIM

fragile X

FURTHER INFORMATION

Florence Besse's homepage

Anne Ephrussi's homepage

Glossary

Ribonucleoprotein complex

A multimolecular complex that is composed of mRNAs and associated trans-acting factors (proteins or non-coding RNAs).

Processing body

(P body). A cytoplasmic site for mRNA degradation and the storage of translationally silenced mRNAs.

Exon junction complex

Following splicing, this multiprotein complex is deposited on RNAs 20–24 nucleotides upstream of exonic splice donor sites.

Polysomal fraction

A heavy fraction of a sucrose gradient that is enriched in polysomes and mRNAs that are undergoing translation.

Cap

Methylated guanosine (m7G) that is found at the 5′ end of mRNA molecules and is recognized by eukaryotic translation initiation factors, such as eIF4E.

FRET

(Fluorescence resonance energy transfer). The transfer of energy between a donor and an acceptor fluorophore in close proximity (<10 nm). FRET is used to monitor physical interaction between two tagged proteins in living cells.

NMDAR

(N-methyl-D-aspartate receptor). An ionotropic Glu receptor that is specifically activated by the Glu analogue NMDA.

mGluR

(Metabotropic Glu receptor). A G-protein-coupled Glu receptor.

Neurotrophin

A secreted protein that prevents neuronal cell death and promotes neuronal growth.

Internal ribosomal entry site

(IRES). A 5′ untranslated region-located RNA sequence that recruits the 40S ribosomal subunit independently of the cap structure.

Long-term potentiation

A long-term increase in synaptic strength that is characterized by a protein synthesis-dependent late phase.

Long-term depression

A long-term decrease in synaptic activity that is characterized by a protein synthesis-dependent late phase.

AMPAR

(α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor). An ionotropic Glu receptor that is specifically activated by the agonist AMPA.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Besse, F., Ephrussi, A. Translational control of localized mRNAs: restricting protein synthesis in space and time. Nat Rev Mol Cell Biol 9, 971–980 (2008). https://doi.org/10.1038/nrm2548

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm2548

This article is cited by

Search

Advanced 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