Skip to main content

Local Translation and mRNA Trafficking in Axon Pathfinding

  • Chapter
  • First Online:
Cell Biology of the Axon

Part of the book series: Results and Problems in Cell Differentiation ((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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • 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 62:1–62

    Article  PubMed  CAS  Google Scholar 

  • 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 99:12651–12656

    Article  PubMed  CAS  Google Scholar 

  • 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 32:37–48

    Article  PubMed  CAS  Google Scholar 

  • Aronov S, Marx R, Ginzburg I (1999) Identification of 3′UTR region implicated in tau mRNA stabilization in neuronal cells. J Mol Neurosci 12:131–145

    Article  PubMed  CAS  Google Scholar 

  • 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 28:12581–12590

    Article  PubMed  CAS  Google Scholar 

  • 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 85:8335–8339

    Article  PubMed  CAS  Google Scholar 

  • Bassell GJ, Kelic S (2004) Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological disease. Curr Opin Neurobiol 14:574–581

    Article  PubMed  CAS  Google Scholar 

  • 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 18:251–265

    PubMed  CAS  Google Scholar 

  • 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 103:19919–19924

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8:776–789

    Article  PubMed  CAS  Google Scholar 

  • Brittis PA, Lu Q, Flanagan JG (2002) Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 110:223–235

    Article  PubMed  CAS  Google Scholar 

  • 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 438:94–98

    Article  PubMed  CAS  Google Scholar 

  • Campbell DS, Holt CE (2001) Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron 32:1013–1026

    Article  PubMed  CAS  Google Scholar 

  • Campbell DS, Holt CE (2003) Apoptotic pathway and MAPKs differentially regulate chemotropic responses of retinal growth cones. Neuron 37:939–952

    Article  PubMed  CAS  Google Scholar 

  • Chang L, Karin M (2001) Mammalian MAP kinase signalling cascades. Nature 410:37–40

    Article  PubMed  CAS  Google Scholar 

  • Cox LJ, Hengst U, Gurskaya NG, Lukyanov KA, Jaffrey SR (2008) Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival. Nat Cell Biol

    Google Scholar 

  • Dickson BJ (2002) Molecular mechanisms of axon guidance. Science 298:1959–1964

    Article  PubMed  CAS  Google Scholar 

  • Dodd J, Morton SB, Karagogeos D, Yamamoto M, Jessell TM (1988) Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons. Neuron 1:105–116

    Article  PubMed  CAS  Google Scholar 

  • 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 19:1–9

    PubMed  CAS  Google Scholar 

  • 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 23:10433–10444

    PubMed  CAS  Google Scholar 

  • Gallo G, Letourneau PC (2004) Regulation of growth cone actin filaments by guidance cues. J Neurobiol 58:92–102

    Article  PubMed  CAS  Google Scholar 

  • Gingras AC, Raught B, Sonenberg N (1999) eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu Rev Biochem 68:913–963

    Article  PubMed  CAS  Google Scholar 

  • 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 88:515–555

    Article  PubMed  CAS  Google Scholar 

  • 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 156:41–51

    Article  PubMed  CAS  Google Scholar 

  • 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 23:2274–2283

    Google Scholar 

  • Hachet O, Ephrussi A (2004) Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428:959–963

    Article  PubMed  CAS  Google Scholar 

  • 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 101:123–133

    PubMed  CAS  Google Scholar 

  • Hengst U, Cox LJ, Macosko EZ, Jaffrey SR (2006) Functional and selective RNA interference in developing axons and growth cones. J Neurosci 26:5727–5732

    Article  PubMed  CAS  Google Scholar 

  • Hirokawa N (2006) mRNA transport in dendrites: RNA granules, motors, and tracks. J Neurosci 26:7139–7142

    Article  PubMed  CAS  Google Scholar 

  • Hirokawa N, Takemura R (2005) Molecular motors and mechanisms of directional transport in neurons. Nat Rev Neurosci 6:201–214

    Article  PubMed  CAS  Google Scholar 

  • Huang YS, Carson JH, Barbarese E, Richter JD (2003) Facilitation of dendritic mRNA transport by CPEB. Genes Dev 17:638–653

    Article  PubMed  CAS  Google Scholar 

  • Huff T, Muller CS, Otto AM, Netzker R, Hannappel E (2001) beta-Thymosins, small acidic peptides with multiple functions. Int J Biochem Cell Biol 33:205–220

    Article  PubMed  CAS  Google Scholar 

  • 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 438:512–515

    Article  PubMed  Google Scholar 

  • 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:e1961

    Article  PubMed  Google Scholar 

  • 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 7:113–117

    Article  PubMed  CAS  Google Scholar 

  • 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 87:7400–7404

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 101:360–365

    Article  PubMed  CAS  Google Scholar 

  • Kindler S, Wang H, Richter D, Tiedge H (2005) RNA transport and local control of translation. Annu Rev Cell Dev Biol 21:223–245

    Article  PubMed  CAS  Google Scholar 

  • Kislauskis EH, Zhu X, Singer RH (1994) Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype. J Cell Biol 127:441–451

    Article  PubMed  CAS  Google Scholar 

  • Knowles RB, Sabry JH, Martone ME, Deerinck TJ, Ellisman MH, Bassell GJ, Kosik KS (1996) Translocation of RNA granules in living neurons. J Neurosci 16:7812–7820

    PubMed  CAS  Google Scholar 

  • Koenig E (1967) Synthetic mechanisms in the axon. IV. In vitro incorporation of [3H]precursors into axonal protein and RNA. J Neurochem 14:437–446

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Koenig E, Giuditta A (1999) Protein-synthesizing machinery in the axon compartment. Neuroscience 89:5–15

    Article  PubMed  CAS  Google Scholar 

  • Koenig E, Koelle GB (1960) Acetylcholinesterase regeneration in peripheral nerve after irreversible inactivation. Science 132:1249–1250

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Kress TL, Yoon YJ, Mowry KL (2004) Nuclear RNP complex assembly initiates cytoplasmic RNA localization. J Cell Biol 165:203–211

    Article  PubMed  CAS  Google Scholar 

  • Krichevsky AM, Kosik KS (2001) Neuronal RNA granules: a link between RNA localization and stimulation-dependent translation. Neuron 32:683–696

    Article  PubMed  CAS  Google Scholar 

  • 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 13:1224–1234

    Article  PubMed  CAS  Google Scholar 

  • Lee SK, Hollenbeck PJ (2003) Organization and translation of mRNA in sympathetic axons. J Cell Sci 116:4467–4478

    Article  PubMed  CAS  Google Scholar 

  • Leung KM, Holt CE (2008) Live visualization of protein synthesis in axonal growth cones by microinjection of photoconvertible Kaede into Xenopus embryos. Nat Protoc 3:1318–1327

    Article  PubMed  CAS  Google Scholar 

  • 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 9:1247–1256

    Article  PubMed  CAS  Google Scholar 

  • Lin AC, Holt CE (2008) Function and regulation of local axonal translation. Curr Opin Neurobiol 18:60–68

    Article  PubMed  CAS  Google Scholar 

  • Litman P, Barg J, Rindzoonski L, Ginzburg I (1993) Subcellular localization of tau mRNA in differentiating neuronal cell culture: implications for neuronal polarity. Neuron 10:627–638

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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 40:128–142

    Article  PubMed  CAS  Google Scholar 

  • Min H, Turck CW, Nikolic JM, Black DL (1997) A new regulatory protein, KSRP, mediates exon inclusion through an intronic splicing enhancer. Genes Dev 11:1023–1036

    Article  PubMed  CAS  Google Scholar 

  • 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 417:411–418

    Article  PubMed  CAS  Google Scholar 

  • Olink-Coux M, Hollenbeck PJ (1996) Localization and active transport of mRNA in axons of sympathetic neurons in culture. J Neurosci 16:1346–1358

    PubMed  CAS  Google Scholar 

  • Palacios IM, St. Johnston D (2001) Getting the message across: the intracellular localization of mRNAs in higher eukaryotes. Annu Rev Cell Dev Biol 17:569–614

    Article  PubMed  CAS  Google Scholar 

  • 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 49:215–228

    Article  PubMed  CAS  Google Scholar 

  • 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 8:179–186

    Article  PubMed  CAS  Google Scholar 

  • 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 82:1039–1046

    Article  PubMed  CAS  Google Scholar 

  • Richter JD (1999) Cytoplasmic polyadenylation in development and beyond. Microbiol Mol Biol Rev 63:446–456

    PubMed  CAS  Google Scholar 

  • 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 7:678–682

    Article  PubMed  CAS  Google Scholar 

  • Ross AF, Oleynikov Y, Kislauskis EH, Taneja KL, Singer RH (1997) Characterization of a beta-actin mRNA zipcode-binding protein. Mol Cell Biol 17:2158–2165

    PubMed  CAS  Google Scholar 

  • Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, Greenberg ME (2006) A brain-specific microRNA regulates dendritic spine development. Nature 439:283–289

    Article  PubMed  CAS  Google Scholar 

  • Sossin WS, DesGroseillers L (2006) Intracellular trafficking of RNA in neurons. Traffic 7:1581–1589

    Article  PubMed  CAS  Google Scholar 

  • 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 62:65–74

    Article  PubMed  CAS  Google Scholar 

  • Stein E, Tessier-Lavigne M (2001) Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 291:1928–1938

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Tennyson VM (1970) The fine structure of the axon and growth cone of the dorsal root neuroblast of the rabbit embryo. J Cell Biol 44:62–79

    Article  PubMed  CAS  Google Scholar 

  • Tessier-Lavigne M, Goodman CS (1996) The molecular biology of axon guidance. Science 274:1123–1133

    Article  PubMed  CAS  Google Scholar 

  • 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 76:1628–1635

    Article  PubMed  CAS  Google Scholar 

  • 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 70:113–125

    Article  PubMed  CAS  Google Scholar 

  • 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 26:152–157

    Article  PubMed  CAS  Google Scholar 

  • Weiner OD, Zorn AM, Krieg PA, Bittner GD (1996) Medium weight neurofilament mRNA in goldfish Mauthner axoplasm. Neurosci Lett 213:83–86

    Article  PubMed  CAS  Google Scholar 

  • 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 15:4827–4837

    PubMed  CAS  Google Scholar 

  • 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 25:778–791

    Article  PubMed  CAS  Google Scholar 

  • 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 178:965–980

    Article  PubMed  CAS  Google Scholar 

  • Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR (2005) Local translation of RhoA regulates growth cone collapse. Nature 436:1020–1024

    Article  PubMed  CAS  Google Scholar 

  • Yamada KM, Spooner BS, Wessells NK (1971) Ultrastructure and function of growth cones and axons of cultured nerve cells. J Cell Biol 49:614–635

    Article  PubMed  CAS  Google Scholar 

  • 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 9:1265–1273

    Article  PubMed  CAS  Google Scholar 

  • Zalfa F, Achsel T, Bagni C (2006) mRNPs, polysomes or granules: FMRP in neuronal protein synthesis. Curr Opin Neurobiol 16:265–269

    Article  PubMed  CAS  Google Scholar 

  • Zelenà J (1970) Ribosome-like particles in myelinated axons of the rat. Brain Res 24:359–363

    Article  PubMed  Google Scholar 

  • 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 31:261–275

    Article  PubMed  CAS  Google Scholar 

  • Zhang HL, Singer RH, Bassell GJ (1999) Neurotrophin regulation of beta-actin mRNA and protein localization within growth cones. J Cell Biol 147:59–70

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christine E. Holt .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2009 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Yoon, B.C., Zivraj, K.H., Holt, C.E. (2009). Local Translation and mRNA Trafficking in Axon Pathfinding. In: Koenig, E. (eds) Cell Biology of the Axon. Results and Problems in Cell Differentiation, vol 48. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_2009_5

Download citation

Publish with us

Policies and ethics