Advertisement

Local Translation and mRNA Trafficking in Axon Pathfinding

  • Byung C. Yoon
  • Krishna H. Zivraj
  • Christine E. HoltEmail author
Chapter
Part of the Results and Problems in Cell Differentiation book series (RESULTS, volume 48)

Abstract

Axons and their growth cones are specialized neuronal sub-compartments that possess translation machinery and have distinct messenger RNAs (mRNAs). Several classes of mRNAs have been identified using candidate-based, as well as unbiased genome-wide-based approaches. Axonal mRNA localization serves to regulate spatially the protein synthesis; thereby, providing axons with a high degree of functional autonomy from the soma during axon pathfinding. Importantly, de novo protein synthesis in navigating axonal growth cones is necessary for chemotropic responses to various axon guidance cues. This chapter discusses the molecular components involved in regulating axonal mRNA trafficking, targeting, and translation, and focuses on RNA binding proteins (RNBPs) and microRNAs. The functional significance of local mRNA translation in the directional response of growth cones to a gradient is highlighted along with the downstream signaling events that mediate local protein synthesis. The view that emerges is that local translation is tightly coupled to extracellular cues, enabling growth cones to respond to new signals with exquisite adaptability and spatiotemporal control.

Keywords

Growth Cone Local Translation Growth Cone Collapse Axon Pathfinding Axonal Growth Cone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Alvarez J, Giuditta A, Koenig E (2000) Protein synthesis in axons and terminals: significance for maintenance, plasticity and regulation of phenotype. With a critique of slow transport theory. Prog Neurobiol 62:1–62PubMedCrossRefGoogle Scholar
  2. Ando R, Hama H, Yamamoto-Hino M, Mizuno H, Miyawaki A (2002) An optical marker based on the UV-induced green-to-red photoconversion of a fluorescent protein. Proc Natl Acad Sci USA 99:12651–12656PubMedCrossRefGoogle Scholar
  3. Antar LN, Li C, Zhang H, Carroll RC, Bassell GJ (2006) Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci 32:37–48PubMedCrossRefGoogle Scholar
  4. Aronov S, Marx R, Ginzburg I (1999) Identification of 3′UTR region implicated in tau mRNA stabilization in neuronal cells. J Mol Neurosci 12:131–145PubMedCrossRefGoogle Scholar
  5. Aschrafi A, Schwechter AD, Mameza MG, Natera-Naranjo O, Gioio AE, Kaplan BB (2008) MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J Neurosci 28:12581–12590PubMedCrossRefGoogle Scholar
  6. Baas PW, Deitch JS, Black MM, Banker GA (1988) Polarity orientation of microtubules in hippocampal neurons: uniformity in the axon and nonuniformity in the dendrite. Proc Natl Acad Sci USA 85:8335–8339PubMedCrossRefGoogle Scholar
  7. Bassell GJ, Kelic S (2004) Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological disease. Curr Opin Neurobiol 14:574–581PubMedCrossRefGoogle Scholar
  8. Bassell GJ, Zhang H, Byrd AL, Femino AM, Singer RH, Taneja KL, Lifshitz LM, Herman IM, Kosik KS (1998) Sorting of beta-actin mRNA and protein to neurites and growth cones in culture. J Neurosci 18:251–265PubMedGoogle Scholar
  9. Bi J, Tsai NP, Lin YP, Loh HH, Wei LN (2006) Axonal mRNA transport and localized translational regulation of kappa-opioid receptor in primary neurons of dorsal root ganglia. Proc Natl Acad Sci USA 103:19919–19924PubMedCrossRefGoogle Scholar
  10. Bodian D (1965) A suggestive relationship of nerve cell RNA with specific synaptic sites. Proc Natl Acad Sci USA 53:418–425PubMedCrossRefGoogle Scholar
  11. Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8:776–789PubMedCrossRefGoogle Scholar
  12. Brittis PA, Lu Q, Flanagan JG (2002) Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110:223–235PubMedCrossRefGoogle Scholar
  13. Brunet I, Weinl C, Piper M, Trembleau A, Volovitch M, Harris W, Prochiantz A, Holt C (2005) The transcription factor Engrailed-2 guides retinal axons. Nature 438:94–98PubMedCrossRefGoogle Scholar
  14. Campbell DS, Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026PubMedCrossRefGoogle Scholar
  15. Campbell DS, Holt CE (2003) Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37:939–952PubMedCrossRefGoogle Scholar
  16. Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40PubMedCrossRefGoogle Scholar
  17. Cox LJ, Hengst U, Gurskaya NG, Lukyanov KA, Jaffrey SR (2008) Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell BiolGoogle Scholar
  18. Dickson BJ (2002) Molecular mechanisms of axon guidance. Science 298:1959–1964PubMedCrossRefGoogle Scholar
  19. Dodd J, Morton SB, Karagogeos D, Yamamoto M, Jessell TM (1988) Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons. Neuron 1:105–116PubMedCrossRefGoogle Scholar
  20. Eng H, Lund K, Campenot RB (1999) Synthesis of beta-tubulin, actin, and other proteins in axons of sympathetic neurons in compartmented cultures. J Neurosci 19:1–9PubMedGoogle Scholar
  21. Eom T, Antar LN, Singer RH, Bassell GJ (2003) Localization of a beta-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses. J Neurosci 23:10433–10444PubMedGoogle Scholar
  22. Gallo G, Letourneau PC (2004) Regulation of growth cone actin filaments by guidance cues. J Neurobiol 58:92–102PubMedCrossRefGoogle Scholar
  23. Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963PubMedCrossRefGoogle Scholar
  24. Giuditta A, Chun JT, Eyman M, Cefaliello C, Bruno AP, Crispino M (2008) Local gene expression in axons and nerve endings: the glia-neuron unit. Physiol Rev 88:515–555PubMedCrossRefGoogle Scholar
  25. Gu W, Pan F, Zhang H, Bassell GJ, Singer RH (2002) A predominantly nuclear protein affecting cytoplasmic localization of beta-actin mRNA in fibroblasts and neurons. J Cell Biol 156:41–51PubMedCrossRefGoogle Scholar
  26. Guirland C, Buck KB, Gibney JA, DiCicco-Bloom E, Zheng JQ (2003) Direct cAMP signaling through G-protein-coupled receptors mediates growth cone attraction induced by pituitary adenylate cyclase-activating polypeptide. J Neurosci 23:2274–2283Google Scholar
  27. Hachet O, Ephrussi A (2004) Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428:959–963PubMedCrossRefGoogle Scholar
  28. Harris WA, Holt CE, Bonhoeffer F (1987) 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 101:123–133PubMedGoogle Scholar
  29. Hengst U, Cox LJ, Macosko EZ, Jaffrey SR (2006) Functional and selective RNA interference in developing axons and growth cones. J Neurosci 26:5727–5732PubMedCrossRefGoogle Scholar
  30. Hirokawa N (2006) mRNA transport in dendrites: RNA granules, motors, and tracks. J Neurosci 26:7139–7142PubMedCrossRefGoogle Scholar
  31. Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6:201–214PubMedCrossRefGoogle Scholar
  32. Huang YS, Carson JH, Barbarese E, Richter JD (2003) Facilitation of dendritic mRNA transport by CPEB. Genes Dev 17:638–653PubMedCrossRefGoogle Scholar
  33. Huff T, Muller CS, Otto AM, Netzker R, Hannappel E (2001) beta-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol 33:205–220PubMedCrossRefGoogle Scholar
  34. Huttelmaier S, Zenklusen D, Lederer M, Dictenberg J, Lorenz M, Meng X, Bassell GJ, Condeelis J, Singer RH (2005) Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1. Nature 438:512–515PubMedCrossRefGoogle Scholar
  35. Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, Fisher AS, Berliocchi L, Sivasubramaniam AK, Sheasby A, Lumb BM, Hunt SP (2008) Local translation in primary afferent fibers regulates nociception. PLoS ONE 3:e1961PubMedCrossRefGoogle Scholar
  36. Jin P, Zarnescu DC, Ceman S, Nakamoto M, Mowrey J, Jongens TA, Nelson DL, Moses K, Warren ST (2004) Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat Neurosci 7:113–117PubMedCrossRefGoogle Scholar
  37. Jirikowski GF, Sanna PP, Bloom FE (1990) mRNA coding for oxytocin is present in axons of the hypothalamo-neurohypophysial tract. Proc Natl Acad Sci USA 87:7400–7404PubMedCrossRefGoogle Scholar
  38. Kanai Y, Dohmae N, Hirokawa N (2004) Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43:513–525PubMedCrossRefGoogle Scholar
  39. Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM, Ruvkun G (2004) Identification of many microRNAs that copurify with polyribosomes in mammalian neurons. Proc Natl Acad Sci USA 101:360–365PubMedCrossRefGoogle Scholar
  40. Kindler S, Wang H, Richter D, Tiedge H (2005) RNA transport and local control of translation. Annu Rev Cell Dev Biol 21:223–245PubMedCrossRefGoogle Scholar
  41. Kislauskis EH, Zhu X, Singer RH (1994) Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. J Cell Biol 127:441–451PubMedCrossRefGoogle Scholar
  42. Knowles RB, Sabry JH, Martone ME, Deerinck TJ, Ellisman MH, Bassell GJ, Kosik KS (1996) Translocation of RNA granules in living neurons. J Neurosci 16:7812–7820PubMedGoogle Scholar
  43. Koenig E (1967) Synthetic mechanisms in the axon. IV. In vitro incorporation of [3H]precursors into axonal protein and RNA. J Neurochem 14:437–446PubMedCrossRefGoogle Scholar
  44. Koenig E, Adams P (1982) Local protein synthesizing activity in axonal fields regenerating in vitro. J Neurochem 39:386–400PubMedCrossRefGoogle Scholar
  45. Koenig E, Giuditta A (1999) Protein-synthesizing machinery in the axon compartment. Neuroscience 89:5–15PubMedCrossRefGoogle Scholar
  46. Koenig E, Koelle GB (1960) Acetylcholinesterase regeneration in peripheral nerve after irreversible inactivation. Science 132:1249–1250PubMedCrossRefGoogle Scholar
  47. Koenig E, Martin R (1996) Cortical plaque-like structures identify ribosome-containing domains in the Mauthner cell axon. J Neurosci 16:1400–1411PubMedGoogle Scholar
  48. Koenig E, Martin R, Titmus M, Sotelo-Silveira JR (2000) Cryptic peripheral ribosomal domains distributed intermittently along mammalian myelinated axons. J Neurosci 20:8390–8400PubMedGoogle Scholar
  49. Kress TL, Yoon YJ, Mowry KL (2004) Nuclear RNP complex assembly initiates cytoplasmic RNA localization. J Cell Biol 165:203–211PubMedCrossRefGoogle Scholar
  50. Krichevsky AM, Kosik KS (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32:683–696PubMedCrossRefGoogle Scholar
  51. Kye MJ, Liu T, Levy SF, Xu NL, Groves BB, Bonneau R, Lao K, Kosik KS (2007) Somatodendritic microRNAs identified by laser capture and multiplex RT-PCR. Rna 13:1224–1234PubMedCrossRefGoogle Scholar
  52. Lee SK, Hollenbeck PJ (2003) Organization and translation of mRNA in sympathetic axons. J Cell Sci 116:4467–4478PubMedCrossRefGoogle Scholar
  53. Leung KM, Holt CE (2008) Live visualization of protein synthesis in axonal growth cones by microinjection of photoconvertible Kaede into Xenopus embryos. Nat Protoc 3:1318–1327PubMedCrossRefGoogle Scholar
  54. Leung KM, van Horck FP, Lin AC, Allison R, Standart N, Holt CE (2006) Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1. Nat Neurosci 9:1247–1256PubMedCrossRefGoogle Scholar
  55. Lin AC, Holt CE (2008) Function and regulation of local axonal translation. Curr Opin Neurobiol 18:60–68PubMedCrossRefGoogle Scholar
  56. Litman P, Barg J, Rindzoonski L, Ginzburg I (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: implications for neuronal polarity. Neuron 10:627–638PubMedCrossRefGoogle Scholar
  57. Mann F, Miranda E, Weinl C, Harmer E, Holt CE (2003) B-type Eph receptors and ephrins induce growth cone collapse through distinct intracellular pathways. J. Neurobiology 57:323–336.CrossRefGoogle Scholar
  58. Merianda TT, Lin A, Lam J, Vuppalanchi D, Willis DE, Karin N, Holt CE, Twiss JL (2009) A functional equivalent of endoplasmic reticulum and Golgi in axons for secretion of locally synthesized proteins. Mol Cell Neurosci 40:128–142PubMedCrossRefGoogle Scholar
  59. Min H, Turck CW, Nikolic JM, Black DL (1997) A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. Genes Dev 11:1023–1036PubMedCrossRefGoogle Scholar
  60. Ming GL, Wong ST, Henley J, Yuan XB, Song HJ, Spitzer NC, Poo MM (2002) Adaptation in the chemotactic guidance of nerve growth cones. Nature 417:411–418PubMedCrossRefGoogle Scholar
  61. Olink-Coux M, Hollenbeck PJ (1996) Localization and active transport of mRNA in axons of sympathetic neurons in culture. J Neurosci 16:1346–1358PubMedGoogle Scholar
  62. Palacios IM, St. Johnston D (2001) Getting the message across: the intracellular localization of mRNAs in higher eukaryotes. Annu Rev Cell Dev Biol 17:569–614PubMedCrossRefGoogle Scholar
  63. Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, Leung KM, Cogill E, Holt C (2006) Signaling mechanisms underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49:215–228PubMedCrossRefGoogle Scholar
  64. Piper M, Salih S, Weinl C, Holt CE, Harris WA (2005) Endocytosis-dependent desensitization and protein synthesis-dependent resensitization in retinal growth cone adaptation. Nat Neurosci 8:179–186PubMedCrossRefGoogle Scholar
  65. Rehbein M, Wege K, Buck F, Schweizer M, Richter D, Kindler S (2002) Molecular characterization of MARTA1, a protein interacting with the dendritic targeting element of MAP2 mRNAs. J Neurochem 82:1039–1046PubMedCrossRefGoogle Scholar
  66. Richter JD (1999) Cytoplasmic polyadenylation in development and beyond. Microbiol Mol Biol Rev 63:446–456PubMedGoogle Scholar
  67. Rosoff WJ, Urbach JS, Esrick MA, McAllister RG, Richards LJ, Goodhill GJ (2004) A new chemotaxis assay shows the extreme sensitivity of axons to molecular gradients. Nat Neurosci 7:678–682PubMedCrossRefGoogle Scholar
  68. Ross AF, Oleynikov Y, Kislauskis EH, Taneja KL, Singer RH (1997) Characterization of a beta-actin mRNA zipcode-binding protein. Mol Cell Biol 17:2158–2165PubMedGoogle Scholar
  69. Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289PubMedCrossRefGoogle Scholar
  70. Sossin WS, DesGroseillers L (2006) Intracellular trafficking of RNA in neurons. Traffic 7:1581–1589PubMedCrossRefGoogle Scholar
  71. Sotelo-Silveira JR, Calliari A, Kun A, Benech JC, Sanguinetti C, Chalar C, Sotelo JR (2000) Neurofilament mRNAs are present and translated in the normal and severed sciatic nerve. J Neurosci Res 62:65–74PubMedCrossRefGoogle Scholar
  72. Stein E, Tessier-Lavigne M (2001) Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 291:1928–1938PubMedCrossRefGoogle Scholar
  73. Steward O, Levy WB (1982) Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. J Neurosci 2:284–291PubMedGoogle Scholar
  74. Tennyson VM (1970) The fine structure of the axon and growth cone of the dorsal root neuroblast of the rabbit embryo. J Cell Biol 44:62–79PubMedCrossRefGoogle Scholar
  75. Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274:1123–1133PubMedCrossRefGoogle Scholar
  76. Tohda C, Sasaki M, Konemura T, Sasamura T, Itoh M, Kuraishi Y (2001) Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity. J Neurochem 76:1628–1635PubMedCrossRefGoogle Scholar
  77. Trembleau A, Morales M, Bloom FE (1996) Differential compartmentalization of vasopressin messenger RNA and neuropeptide within the rat hypothalamo-neurohypophysial axonal tracts: light and electron microscopic evidence. Neuroscience 70:113–125PubMedCrossRefGoogle Scholar
  78. van Kesteren RE, Carter C, Dissel HM, van Minnen J, Gouwenberg Y, Syed NI, Spencer GE, Smit AB (2006) Local synthesis of actin-binding protein beta-thymosin regulates neurite outgrowth. J Neurosci 26:152–157PubMedCrossRefGoogle Scholar
  79. Weiner OD, Zorn AM, Krieg PA, Bittner GD (1996) Medium weight neurofilament mRNA in goldfish Mauthner axoplasm. Neurosci Lett 213:83–86PubMedCrossRefGoogle Scholar
  80. Wensley CH, Stone DM, Baker H, Kauer JS, Margolis FL, Chikaraishi DM (1995) Olfactory marker protein mRNA is found in axons of olfactory receptor neurons. J Neurosci 15:4827–4837PubMedGoogle Scholar
  81. Willis D, Li KW, Zheng JQ, Chang JH, Smit A, Kelly T, Merianda TT, Sylvester J, van Minnen J, Twiss JL (2005) Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons. J Neurosci 25:778–791PubMedCrossRefGoogle Scholar
  82. Willis DE, van Niekerk EA, Sasaki Y, Mesngon M, Merianda TT, Williams GG, Kendall M, Smith DS, Bassell GJ, Twiss JL (2007) Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs. J Cell Biol 178:965–980PubMedCrossRefGoogle Scholar
  83. Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR (2005) Local translation of RhoA regulates growth cone collapse. Nature 436:1020–1024PubMedCrossRefGoogle Scholar
  84. Yamada KM, Spooner BS, Wessells NK (1971) Ultrastructure and function of growth cones and axons of cultured nerve cells. J Cell Biol 49:614–635PubMedCrossRefGoogle Scholar
  85. Yao J, Sasaki Y, Wen Z, Bassell GJ, Zheng JQ (2006) An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance. Nat Neurosci 9:1265–1273PubMedCrossRefGoogle Scholar
  86. Zalfa F, Achsel T, Bagni C (2006) mRNPs, polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol 16:265–269PubMedCrossRefGoogle Scholar
  87. Zelenà J (1970) Ribosome-like particles in myelinated axons of the rat. Brain Res 24:359–363PubMedCrossRefGoogle Scholar
  88. Zhang HL, Eom T, Oleynikov Y, Shenoy SM, Liebelt DA, Dictenberg JB, Singer RH, Bassell GJ (2001) Neurotrophin-induced transport of a beta-actin mRNP complex increases beta-actin levels and stimulates growth cone motility. Neuron 31:261–275PubMedCrossRefGoogle Scholar
  89. Zhang HL, Singer RH, Bassell GJ (1999) Neurotrophin regulation of beta-actin mRNA and protein localization within growth cones. J Cell Biol 147:59–70PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Byung C. Yoon
    • 1
  • Krishna H. Zivraj
    • 1
  • Christine E. Holt
    • 1
    Email author
  1. 1.Department of Physiology, Development and NeuroscienceUniversity of CambridgeCambridgeUK

Personalised recommendations