Molecular Insights into mRNA Transport and Local Translation in the Mammalian Nervous System
2000; Cell Press; Volume: 25; Issue: 1 Linguagem: Inglês
10.1016/s0896-6273(00)80868-5
ISSN1097-4199
AutoresMichael Kiebler, Luc DesGroseillers,
Tópico(s)RNA Research and Splicing
ResumoIt is thought that remembering depends on the interaction between nerve cells. More precisely, it is thought that the change in the strength of synaptic connections allows for information storage. However, we are only beginning to know the actual molecular processes and mechanisms underlying the formation and storage of memories. For this reason, the finding that lasting changes in the efficacy of synaptic transmission as well as the acquisition of certain learning tasks depended on the synthesis of new protein was a landmark for the study of memory (45Goelet P Castellucci V.F Schacher S Kandel E.R The long and short of long-term memory—a molecular framework.Nature. 1986; 322: 419-422Crossref PubMed Scopus (794) Google Scholar). For a long time, it has been thought that this would exclusively occur in the cell body of the respective nerve cells. Recent evidence, however, suggests that targeting of certain messenger RNAs (mRNA) to synapses and subsequent local synthesis of proteins may represent another fundamental mechanism in generating lasting synaptic changes in the nervous system. In this review, we would like to elaborate on this exciting new hypothesis. First, we will critically review the experimental evidence for the existence of dendritic mRNA and its biological role in the CNS (see also 86Schuman E.M mRNA trafficking and local protein synthesis at the synapse.Neuron. 1999; 23: 645-648Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar). Second, we will present recent evidence on the first identified components of the mRNA transport machinery and its conservation in different systems and organisms. In particular, we will focus on the so-called trans-acting factors, RNA-binding proteins, with a special emphasis on Staufen and its involvement in the transport of mRNAs to dendrites. At the end, we would like to present a working model of how mRNA targeting could take place mechanistically in the CNS. Historically, the concept of RNA localization has developed by several quantum leaps. The first important step was the finding that polyribosomes were preferentially found near or even within postsynaptic spines (91Steward O Lewy W.B Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus.J. Neurosci. 1982; 2: 284-291Crossref PubMed Google Scholar). In later work, it became clear that these polyribosomes were found near tubular membranous structures most likely representing smooth endoplasmic reticulum (ER) (92Steward O Reeves T.M Protein synthetic machinery beneath postsynaptic sites on CNS neurons association between polyribosomes and other organelles at the synaptic site.J. Neurosci. 1988; 8: 176-184PubMed Google Scholar). The relevance of this finding gathered significantly more weight when 44Garner C.C Tucker R.P Matus A Selective localization of messenger RNA for cytoskeletal protein MAP2 in dendrites.Nature. 1988; 366: 674-677Crossref Scopus (428) Google Scholar found that the mRNA encoding the high molecular weight microtubule-associated protein (MAP2) was localized in mature dendrites. Subsequently, an increasing number of mRNAs have been reported to be selectively targeted to dendrites of CNS neurons (reviewed by 9Bashirullah A Cooperstock R.L Lipshitz H.D RNA localization in development.Annu. Rev. Biochem. 1998; 67: 335-394Crossref PubMed Scopus (283) Google Scholar, 60Kuhl D Skehel P Dendritic localization of mRNAs.Curr. Opin. Neurobiol. 1998; 8: 600-606Crossref PubMed Scopus (86) Google Scholar, 99Tiedge H Bloom F.E Richter D RNA, whither goest thou?.Science. 1999; 283: 186-187Crossref PubMed Scopus (81) Google Scholar). Interestingly, these code for cytoskeletal proteins (e.g., MAP2, Arc), kinases (e.g., the α subunit of Ca2+/CaM kinase II), Ca2+-binding proteins (e.g., dendrin, inositol 1,4,5-trisphosphate receptor type I), and even membrane-bound receptors (glycine receptors, glutamate receptors). Do these targeted mRNAs simply reach dendrites by a passive mechanism or is there an active sorting mechanism involved? First, recent work has clearly demonstrated that certain neuronal mRNAs (α subunit of CaMKII, MAP2, β-actin) contain dendritic targeting signals in their respective 3′-untranslated regions (3′-UTR) (54Kislauskis E.H Zhu X Singer R.H Sequences responsible for intracellular localization of beta-actin messenger RNA also affect cell phenotype.J. Cell Biol. 1994; 127: 441-451Crossref PubMed Scopus (405) Google Scholar, 70Mayford M Baranes D Podsypanina K Kandel E.R The 3′-untranslated region of α-CaMKII is a cis-acting signal for the localization and translation of mRNA in dendrites.Proc. 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In contrast to the latter finding, a 21-nucleotide sequence termed the RNA transport signal (RTS) has been identified in the myelin basic protein (MBP) mRNA in oligodendrocytes (2Ainger K Avossa D Diana A.S Barry C Barbarese E Carson J.H Transport and localization elements in myelin basic protein mRNA.J. Cell Biol. 1997; 138: 1077-1087Crossref PubMed Scopus (249) Google Scholar). Remarkably, RTS-like motifs have been found in the 3′-UTR of other dendritically localized mRNAs such as MAP2, neurogranin, and glial fibrillary acidic protein. This motif, however, also exists in numerous mRNAs that are not targeted to dendrites (M. A. K. and T. Dandekar, unpublished data). Further analysis of general RTS will certainly yield more complex targeting motifs. Second, synaptic activity and/or application of neurotrophins or cAMP analogs have been shown to modulate the transport of different mRNAs or RNA-containing granules in dendrites (56Knowles R.B Kosik K.S Neurotrophin-3 signals redistribute RNA in neurons.Proc. Natl. Acad. Sci USA. 1997; 94: 14804-14808Crossref PubMed Scopus (57) Google Scholar, 100Tongiorgi E Righi M Cattaneo A Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons.J. Neurosci. 1997; 17: 9492-9505Crossref PubMed Google Scholar, 10Bassell G.J Zhang H.L Byrd A.L Femino A.M Singer R.H Taneja K.L Lifshitz L.M Herman I.M Kosik K.S Sorting of β-actin mRNA and protein to neurites and growth cones in culture.J. Neurosci. 1998; 18: 251-265Crossref PubMed Google Scholar, 74Muslimov I.A Banker G Brosius J Tiedge H Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture.J. 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USA. 1995; 92: 5734-5738Crossref PubMed Scopus (543) Google Scholar, 65Lyford G.L Yamagata K Kaufmann W.E Barnes C.A Sanders L.K Copeland N.G Gilbert D.J Jenkins N.A Lanahan A.A Worley P.F Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites.Neuron. 1995; 14: 433-445Abstract Full Text PDF PubMed Scopus (945) Google Scholar), whose constitutive expression is low in the hippocampus, several paradigms of synaptic activity led to a strong induction of gene expression in the hippocampal granule cells. Upon closer examination, both Arc mRNA and protein were found to be enriched in synapse-activated dendrites (93Steward O Wallace C.S Lyford G.L Worley P.F Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites.Neuron. 1998; 21: 741-751Abstract Full Text Full Text PDF PubMed Scopus (636) Google Scholar). Likewise, induction of long-term potentiation (LTP) also caused an increase in the level of CaMKII transcript in distal dendrites (98Thomas K.L Laroche S Errington M.L Bliss T.V Hunt S.P Spatial and temporal changes in signal transduction pathways during LTP.Neuron. 1994; 13: 737-745Abstract Full Text PDF PubMed Scopus (163) Google Scholar). Third, differential sorting of multiple mRNAs coding for cytosolic and membrane-bound proteins relied on different motor proteins (87Severt W.L Biber T.U.L Wu X.-Q Hecht N.B DeLorenzo R.J Jakoi E.R The suppression of testis-brain binding protein and kinesin heavy chain disrupts mRNA sorting in dendrites.J. Cell Sci. 1999; 112: 3691-3702PubMed Google Scholar). Taken together, the evidence presented here supported the view that RNAs are actively targeted to the cell periphery. Novel experimental approaches have tried to tackle the dynamics of this process in dendrites. Bassell and Kosik labeled RNA in neurons with the cell-permeant fluorescent dye SYTO14 and found two different types of granules moving in the cytoplasm and dendrites of cortical neurons. They identified one of the structures as mitochondria (they contain their own RNA) and proposed that the others represented RNA-containing granules (57Knowles R.B Sabry J.H Martone M.E Deerinck T.F Ellisman M.H Bassell G.J Kosik K.S Translocation of RNA granules in living neurons.J. Neurosci. 1996; 16: 7812-7820Crossref PubMed Google Scholar), which may potentially move along microtubules. The dendritic delivery rate was found to be ∼6 μm/min. The same granular appearance has been reported for several dendritic mRNAs by high-resolution in situ hybridization techniques (80Racca C Gardiol A Triller A Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs.J. 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These authors were the first to observe the formation of granules within minutes and followed their subsequent transport down the processes to the cell periphery. This microinjection experiment has now also been performed in neurons by Muslimov and Tiedge who microinjected sympathetic neurons with radiolabeled BC1 RNA. They determined the dendritic delivery rate by autoradiography (73Muslimov I.A Santi E Homel P Perini S Higgins D Tiedge H RNA transport in dendrites a cis-acting targeting element is contained within neuronal BC1 RNA.J. Neurosci. 1997; 17: 4722-4733PubMed Google Scholar) to be ∼4 μm/min. Based on the landmark findings by Ainger and Carson, a compelling hypothetical framework was put forward on how mRNA localization could be achieved in an ordered, multistep pathway (107Wilhelm J.E Vale R.D RNA on the move the mRNA localization pathway.J. Cell Biol. 1993; 123: 269-274Crossref PubMed Scopus (298) Google Scholar). It predicted (1) the formation of ribonucleoprotein particles (RNP) as a functional complex, (2) the translocation of these particles to their destinations, (3) the anchoring of the particles to the local cytoskeleton, and (4) the translation of the localized mRNAs. This model gained significant support by the finding that such RNA-containing granules have been visualized in systems as diverse as fibroblasts (97Sundell C.L Singer R.H Actin mRNA localizes in the absence of protein synthesis.J. Cell Biol. 1990; 111: 2397-2403Crossref PubMed Scopus (85) Google Scholar), neurons (57Knowles R.B Sabry J.H Martone M.E Deerinck T.F Ellisman M.H Bassell G.J Kosik K.S Translocation of RNA granules in living neurons.J. 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Early evidence for local protein synthesis in dendrites came from experiments using subcellular fractions enriched in isolated pre- and postsynaptic nerve endings (alternatively called synaptosomes, synaptodendrosomes, or synaptoneurosomes) (7Autilio L.A Appel S.H Pettis P Gambetti P Biochemical studies of synapses in vitro 1. Protein synthesis.Biochemistry. 1968; 7: 2615-2622Crossref PubMed Scopus (163) Google Scholar). Subsequent work revealed that the synthesis primarily occurred in the dendritic fragments and contaminating cell bodies (40Gambetti P Autilio-Gambetti L.A Gonatas N.K Shafer B Protein synthesis in synaptosomal fractions ultrastructural radioautographic study.J. Cell Biol. 1972; 52: 526-535Crossref PubMed Scopus (60) Google Scholar). This suggested that localized mRNAs could be locally translated into active proteins, thus changing the composition of synaptic components in response to specific physiological conditions (104Weiler I.J Greenough W.T Metabotropic glutamate receptors trigger postsynaptic protein synthesis.Proc. Natl. Acad. Sci. USA. 1993; 90: 7168-7171Crossref PubMed Scopus (205) Google Scholar). Indeed, expression of exogenous mRNAs in severed dendrites, growth cones, and/or neurites in culture resulted in local translation of the RNAs (26Crino P.B Eberwine J Molecular characterization of the dendritic growth cone regulated mRNA transport and local protein synthesis.Neuron. 1996; 17: 1173-1187Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar, 101van Minnen J Bergman J.J Van Kesteren E.R Smit A.B Geraerts W.P Lukowiak K Hasan S.U Syed N.I De novo protein synthesis in isolated axons of identified neurons.Neuroscience. 1997; 80: 1-7Crossref PubMed Scopus (73) Google Scholar). Next, 33Feig S Lipton P Pairing the cholinergic agonist carbachol with patterned Schaffer collateral stimulation initiates protein synthesis in hippocampal CA1 pyramidal cell dendrites via a muscarinic, NMDA-dependent mechanism.J. Neurosci. 1993; 13: 1010-1021Crossref PubMed Google Scholar studied the effects of afferent stimulation paired with the cholinergic agonist carbachol on protein synthesis in hippocampal slices. Whereas there was no detectable extramitochondrial protein synthesis in dendrites in the resting slice, the paired stimulation protocol yielded a rapid, increased incorporation of labeled amino acids in dendritic laminae. The assumption that local protein synthesis might somehow be involved in synaptic plasticity was further validated by 50Kang H Schuman E.M A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity.Science. 1996; 273: 1402-1406Crossref PubMed Scopus (726) Google Scholar, who showed that application of the neurotrophic factors brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) to hippocampal slices caused a long-lasting synaptic potentiation that was critically dependent on the rapid synthesis of new proteins. Indeed, there is suggestive evidence that CaMKII (78Ouyang Y Kantor D Harris K.M Schuman E.M Kennedy M.B Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus.J. 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Neurosci. 1999; 19: 7834-7845Crossref PubMed Google Scholar), and even CREB (27Crino P Khodakhah K Becker K Ginsberg S Hemby S Eberwine J Presence and phosphorylation of transcription factors in developing dendrites.Proc. Natl. Acad. Sci. USA. 1998; 95: 2313-2318Crossref PubMed Scopus (127) Google Scholar) may be locally synthesized in dendrites. This body of experimental evidence, however, did not shed any light on the biological role of dendritic mRNA transport and subsequent local translation. By using hippocampal LTP, a widely studied synaptic model for memory, 38Frey U Morris R.G.M Synaptic tagging and long-term potentiation.Nature. 1997; 385: 533-536Crossref PubMed Scopus (1193) Google Scholar were the first to study the influence of newly made proteins in the cell body on synapse-specific LTP. Their work showed that a weak tetanus that normally induces the early, protein synthesis–independent phase of LTP can elicit its late, protein synthesis–dependent phase if a strong tetanus had previously been applied to a separate synaptic input. This finding suggested the generation of a short-living neuron-wide "synaptic tag," which seizes the molecules necessary to induce late LTP upon subsequent activation. The formation of this postulated synaptic tag, however, was found to be independent of new protein synthesis. In an independent and parallel set of studies, Kelsey Martin, Eric Kandel, and their coworkers used an elegant three-cell culture system (a single bifurcated sensory neuron making synapses with two spatially separated motor neurons) derived from Aplysia neurons. With this new experimental system, the authors convincingly demonstrated that local protein synthesis is required to allow synapse-specific long-term facilitation (LTF) in the presynaptic (note, however, that it is postsynaptic to the serotonin-releasing neuron) sensory neuron (69Martin K.C Casadio A Zhu H E Y Rose J.C Chen M Bailey C.H Kandel E.R Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses a function for local protein synthesis in memory storage.Cell. 1997; 91: 927-938Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar). Subsequent work from the same laboratory then suggested that local protein synthesis may serve (at least) two different functions (20Casadio A Martin K.C Giustetto M Zhu H Chen M Bartsch D Bailey C.H Kandel E.R A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis.Cell. 1999; 99: 221-237Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar): first, the generation of a retrograde signal at the site of initiation of LTF in order to induce CREB-mediated transcription; second, the marking of a particular synapse for persistence of long-term functional and structural changes at the activated synapse. Most interestingly, these two events seem to operate through different molecular pathways: whereas the first one is rapamycin resistant, the second one is rapamycin sensitive (20Casadio A Martin K.C Giustetto M Zhu H Chen M Bartsch D Bailey C.H Kandel E.R A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis.Cell. 1999; 99: 221-237Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar). Further experiments are clearly needed to identify the molecular nature of both the retrograde signal and the synaptic tag. In conclusion, all the work presented so far suggests that mRNA transport and local translation in neuronal processes may indeed represent an important aspect of synaptic plasticity and be potentially relevant for memory storage. Whether this phenomenon represents an essential or a complementary step as compared to protein targeting at synapses needs to be further evaluated. We still do not know the molecular machinery involved in dendritic mRNA targeting. Similarly, the mechanisms that potentially repress mRNA translation during transport and/or regulate local translation at the synapse are still unknown. Recently, progress has been made in identifying several families of trans-acting factors, involved in localization of mRNA in oocytes, embryos and fibroblasts. Among the growing list of RNA-binding proteins, members of three different families have emerged: heterogeneous nuclear ribonucleoproteins (hnRNPs), zipcode binding proteins (ZBP, Vera, or Vg1 RBP) and double-stranded RNA-binding proteins (especially Staufen). The striking (and surprising) outcome that homologs of the same trans-acting factors interact with different, unrelated mRNAs in distinct species and cell types provided the first compelling evidence that the mRNA localization machinery might be evolutionarily conserved (76Oleynikov Y Singer R.H RNA localization different zipcodes, same postman?.Trends Cell Biol. 1998; 8: 381-383Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 85Schnapp B.J RNA localization a glimpse of the machinery.Curr. Biol. 1999; 9: R725-R727Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). 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