The Central Dogma Decentralized: New Perspectives on RNA Function and Local Translation in Neurons
Authors: Christine E. Holt, Erin M. Schuman
Journal: Neuron (2013)

The elaborate morphology of neurons together with the information processing that occurs in remote dendritic and axonal compartments makes the use of decentralized cell biological machines necessary. Recent years have witnessed a revolution in our understanding of signaling in neuronal compartments and the manifold functions of a variety of RNA molecules that regulate protein translation and other cellular functions. Here we discuss the view that mRNA localization and RNA-regulated and localized translation underlie many fundamental neuronal processes and highlight key issues for future experiments. The elaborate morphology of neurons together with the information processing that occurs in remote dendritic and axonal compartments makes the use of decentralized cell biological machines necessary. Recent years have witnessed a revolution in our understanding of signaling in neuronal compartments and the manifold functions of a variety of RNA molecules that regulate protein translation and other cellular functions. Here we discuss the view that mRNA localization and RNA-regulated and localized translation underlie many fundamental neuronal processes and highlight key issues for future experiments. It is now clear that individual neurons are highly compartmentalized with specific functions and/or signaling that occur in restricted subcellular domains. Extrinsic signals are often spatially localized such that they are "seen" by restricted parts of a neuron, such as synaptic input to a specific dendritic spine or a guidance cue encountered by a growth cone. Twenty-five years ago, when the first issue of Neuron was published, it was well appreciated that the neurons were capable of local information processing, but the potential cellular mechanisms that established and regulated local compartments were not well understood. Dendritic spines had been proposed as biochemical and/or electrical compartments (Harris and Kater, 1994Harris K.M. Kater S.B. Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function.Annu. Rev. Neurosci. 1994; 17: 341-371Crossref PubMed Google Scholar, Koch and Zador, 1993Koch C. Zador A. The function of dendritic spines: devices subserving biochemical rather than electrical compartmentalization.J. Neurosci. 1993; 13: 413-422PubMed Google Scholar), and polyribosomes had been identified at the base of spines (Steward and Levy, 1982Steward O. Levy 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). However, the view that dominated until nearly the end of the twentieth century was that the central dogma (DNA-RNA-protein) was carried out centrally—in the nuclei and somata of neurons. In that context, the localization of mRNA observed in some cells was thought to represent a specialized mechanism that operated in unique biological systems, such as egg cells, where storage of mRNAs is needed for subsequent patterning of the early embryo (see Martin and Ephrussi, 2009Martin K.C. Ephrussi A. mRNA localization: gene expression in the spatial dimension.Cell. 2009; 136: 719-730Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar for review). Evidence from a number of studies in the last decade, particularly in neurons, has led to a revolution in our thinking. Although the field is still young, it is becoming clear that RNA-based mechanisms provide a highly adaptable link between extrinsic signals in the environment and the functional responses of a neuron or parts of a neuron. This is accomplished by the localization of both protein-coding and noncoding RNA in neuronal processes and the subsequent regulated local translation of mRNA into protein. Here we discuss some of the key findings that lead us to the view that mRNA localization and RNA-regulated and localized translation underlie many fundamental cellular processes that are regulated by extrinsic signals in neurons, such as memory, dendrite and arbor branching, synapse formation, axon steering, survival, and likely proteostasis. The dynamic regulation of protein synthesis is essential for all cells, including neurons. Over 50 years ago, in vivo experiments (in a variety of species) established a clear functional link between protein synthesis and long-term memory (see Davis and Squire, 1984Davis H.P. Squire L.R. Protein synthesis and memory: a review.Psychol. Bull. 1984; 96: 518-559Crossref PubMed Scopus (896) Google Scholar for review), indicating that proteome remodeling underlies behavioral plasticity. These observations were paralleled by in vitro studies of synaptic plasticity demonstrating a clear requirement for newly synthesized proteins in the long-term modification of synaptic function (see Sutton and Schuman, 2006Sutton M.A. Schuman E.M. Dendritic protein synthesis, synaptic plasticity, and memory.Cell. 2006; 127: 49-58Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar for review; also, Tanaka et al., 2008Tanaka J. Horiike Y. Matsuzaki M. Miyazaki T. Ellis-Davies G.C. Kasai H. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines.Science. 2008; 319: 1683-1687Crossref PubMed Scopus (257) Google Scholar). This link between protein synthesis and long-term plasticity is most recently reinforced by studies showing that targeted genetic disruption of signaling molecules that regulate protein translation interfere with long-term synaptic or behavioral memories (Costa-Mattioli et al., 2009Costa-Mattioli M. Sossin W.S. Klann E. Sonenberg N. Translational control of long-lasting synaptic plasticity and memory.Neuron. 2009; 61: 10-26Abstract Full Text Full Text PDF PubMed Scopus (305) Google Scholar). The above studies, while indicating a requirement for protein synthesis, do not address the location. We now know dendrites and axons of neurons represent specialized cellular "outposts" that can function with a high degree of autonomy at long distances from the soma, as illustrated by the remarkable ability of growing axons to navigate correctly after soma removal (Harris et al., 1987Harris W.A. Holt C.E. Bonhoeffer F. 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. 1987; 101: 123-133PubMed Google Scholar) or isolated synapses to undergo plasticity (Kang and Schuman, 1996Kang H. Schuman E.M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity.Science. 1996; 273: 1402-1406Crossref PubMed Google Scholar, Vickers et al., 2005Vickers C.A. Dickson K.S. Wyllie D.J. Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones.J. 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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 (465) Google Scholar) and directly linked synaptic plasticity with local translation in dendrites (Aakalu et al., 2001Aakalu G. Smith W.B. Nguyen N. Jiang C. Schuman E.M. Dynamic visualization of local protein synthesis in hippocampal neurons.Neuron. 2001; 30: 489-502Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, Huber et al., 2000Huber K.M. Kayser M.S. Bear M.F. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression.Science. 2000; 288: 1254-1257Crossref PubMed Scopus (507) Google Scholar, Kang and Schuman, 1996Kang H. Schuman E.M. A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity.Science. 1996; 273: 1402-1406Crossref PubMed Google Scholar, Martin et al., 1997Martin K.C. Michael D. Rose J.C. Barad M. Casadio A. Zhu H. Kandel E.R. MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia.Neuron. 1997; 18: 899-912Abstract Full Text Full Text PDF PubMed Scopus (388) Google Scholar, Vickers et al., 2005Vickers C.A. Dickson K.S. Wyllie D.J. Induction and maintenance of late-phase long-term potentiation in isolated dendrites of rat hippocampal CA1 pyramidal neurones.J. Physiol. 2005; 568: 803-813Crossref PubMed Scopus (47) Google Scholar), providing definitive proof that dendrites are a source of protein during plasticity. In axons, the idea of local protein synthesis has been slower to find acceptance, no doubt hindered by the classical view of axons as information transmitters rather than receivers; so, why would local protein synthesis be required? Although ribosomes were identified in growth cones in early ultrastructural studies (Bunge, 1973Bunge M.B. Fine structure of nerve fibers and growth cones of isolated sympathetic neurons in culture.J. Cell Biol. 1973; 56: 713-735Crossref PubMed Google Scholar, Tennyson, 1970Tennyson V.M. The fine structure of the axon and growth cone of the dorsal root neuroblast of the rabbit embryo.J. Cell Biol. 1970; 44: 62-79Crossref PubMed Google Scholar), they were rarely observed in adult axons. It is now thought that at least part of the explanation for their apparent paucity lies in their localization close to the plasma membrane in axons (Sotelo-Silveira et al., 2008Sotelo-Silveira J. Crispino M. Puppo A. Sotelo J.R. Koenig E. Myelinated axons contain beta-actin mRNA and ZBP-1 in periaxoplasmic ribosomal plaques and depend on cyclic AMP and F-actin integrity for in vitro translation.J. Neurochem. 2008; 104: 545-557PubMed Google Scholar) where ribosomal subunits can associate directly with surface receptors (Tcherkezian et al., 2010Tcherkezian J. Brittis P.A. Thomas F. Roux P.P. Flanagan J.G. Transmembrane receptor DCC associates with protein synthesis machinery and regulates translation.Cell. 2010; 141: 632-644Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). In addition, evidence indicates that myelinated axons can tap into an external supply of ribosomes by the translocation of ribosomal proteins from Schwann cells (Court et al., 2011Court F.A. Midha R. Cisterna B.A. Grochmal J. Shakhbazau A. Hendriks W.T. Van Minnen J. Morphological evidence for a transport of ribosomes from Schwann cells to regenerating axons.Glia. 2011; 59: 1529-1539Crossref PubMed Scopus (29) Google Scholar). Growing and navigating axons are clearly information receivers, like dendrites, since their growth cones steer using extrinsic signals. Indeed, the first functional evidence for local protein synthesis in axons came from studies that showed that cue-induced directional steering is abolished by inhibitors of protein synthesis, including rapamycin, in surgically isolated axons (Campbell and Holt, 2001Campbell D.S. Holt C.E. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation.Neuron. 2001; 32: 1013-1026Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar). Subsequent studies confirmed this result in different neurons (Wu et al., 2005Wu K.Y. Hengst U. Cox L.J. Macosko E.Z. Jeromin A. Urquhart E.R. Jaffrey S.R. Local translation of RhoA regulates growth cone collapse.Nature. 2005; 436: 1020-1024Crossref PubMed Scopus (213) Google Scholar, Yao et al., 2006Yao J. Sasaki Y. Wen Z. Bassell G.J. Zheng J.Q. An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance.Nat. 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Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration.J. Neurosci. 2005; 25: 331-342Crossref PubMed Scopus (196) Google Scholar, Yoon et al., 2012Yoon B.C. Jung H. Dwivedy A. O'Hare C.M. Zivraj K.H. Holt C.E. Local translation of extranuclear lamin B promotes axon maintenance.Cell. 2012; 148: 752-764Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, Zheng et al., 2001Zheng J.Q. Kelly T.K. Chang B. Ryazantsev S. Rajasekaran A.K. Martin K.C. Twiss J.L. A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons.J. Neurosci. 2001; 21: 9291-9303Crossref PubMed Google Scholar). Neuronal function is highly dependent on spatially precise signaling. Increasing evidence indicates that the complex morphology of neurons has created biological compartments that subdivide the neuron into spatially distinct signaling domains important for neuronal function (Hanus and Schuman, 2013Hanus C. Schuman E.M. Proteostasis in complex dendrites.Nat. Rev. Neurosci. 2013; 14: 638-648Crossref PubMed Scopus (8) Google Scholar). Dendritic spines represent a specialized ("classical") cellular compartment in which subsets of specific proteins (e.g. receptors, channels, signaling molecules, and scaffolds) are collected together with a common function for receiving and processing electrical and chemical input. Spines have a distinct structural morphology and, as such, are easy to classify as a compartment. Although spines are small (∼1 μm3), they can still be subdivided into further functional compartments (see Chen and Sabatini, 2012Chen Y. Sabatini B.L. Signaling in dendritic spines and spine microdomains.Curr. Opin. Neurobiol. 2012; 22: 389-396Crossref PubMed Scopus (16) Google Scholar for review) with multiple microdomains, raising the question of how a compartment is defined. For example, a recent superresolution imaging study demonstrated that, within synapses, AMPA receptors are clustered into small nanodomains (∼70 nm in diameter) that contain on average ∼20 receptors (Nair et al., 2013Nair D. Hosy E. Petersen J.D. Constals A. Giannone G. Choquet D. Sibarita J.B. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95.J. Neurosci. 2013; 33: 13204-13224Crossref PubMed Scopus (28) Google Scholar). These nanodomains are dynamic in both their shape and position and may have a limited lifetime. Anatomically and functionally distinct compartments also exist in axons, such as the growth cone, the axon initial segment, and terminal arbor. Equally, there are examples of compartments that exhibit no obvious "anatomical" specializations. In axons, for example, some membrane proteins are localized to restricted segments of the axon (Fasciclins, Tag1/L1, Robo) (Bastiani et al., 1987Bastiani M.J. Harrelson A.L. Snow P.M. Goodman C.S. Expression of fasciclin I and II glycoproteins on subsets of axon pathways during neuronal development in the grasshopper.Cell. 1987; 48: 745-755Abstract Full Text PDF PubMed Scopus (175) Google Scholar, Dodd et al., 1988Dodd J. Morton S.B. Karagogeos D. Yamamoto M. Jessell T.M. Spatial regulation of axonal glycoprotein expression on subsets of embryonic spinal neurons.Neuron. 1988; 1: 105-116Abstract Full Text PDF PubMed Scopus (446) Google Scholar, Katsuki et al., 2009Katsuki T. Ailani D. Hiramoto M. Hiromi Y. Intra-axonal patterning: intrinsic compartmentalization of the axonal membrane in Drosophila neurons.Neuron. 2009; 64: 188-199Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Rajagopalan et al., 2000Rajagopalan S. Nicolas E. Vivancos V. Berger J. Dickson B.J. 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Ultimately, a neuron must integrate the information received from multiple compartments. As such, future experiments aimed at understanding how different compartments emerge and what mechanisms generate such spatially precise intracellular patterning will be very informative. Compartmentalized signaling presents several challenges to the cell, a prime one being the localization of its component parts. Specific molecules must be transported and delivered to the appropriate subcellular destinations. One of the remarkable features of RNA is its ability to be spatially localized and, therefore, potentially contribute to neuronal compartmentalization. Historically, localized mRNAs have been studied during development (see Martin and Ephrussi, 2009Martin K.C. Ephrussi A. mRNA localization: gene expression in the spatial dimension.Cell. 2009; 136: 719-730Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar). That localized RNA is more often the rule than the exception is spectacularly illustrated by the finding that 71% of the Drosophila embryo transcriptome is localized to specific subcellular compartments (Lécuyer et al., 2007Lécuyer E. Yoshida H. Parthasarathy N. Alm C. Babak T. Cerovina T. Hughes T.R. Tomancak P. Krause H.M. Global analysis of mRNA localization reveals a prominent role in organizing cellular architecture and function.Cell. 2007; 131: 174-187Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). The proteins encoded by localized mRNAs are also concentrated at the site suggesting that mRNA localization and the ensuing local translation plays an important role in positioning proteins for cellular functions. A general function of mRNA localization is the generation of asymmetry. mRNAs tend to be abundantly localized to the peripheral domains and motile parts of neurons where they are optimally positioned for the arrival of external signals, e.g., in dendrites (synaptic activation) and growth cones. Subcellular asymmetry can lead to highly polarized dynamics and cell morphology that can operate on a remarkably fine scale. To navigate, growth cones must be able to make directional turns, which demands asymmetry. In retinal growth cones, for example, which are only 5 μm in diameter, a polarized external gradient of netrin-1 triggers increases in both the transport and translation of β-actin mRNA on the gradient near side (Leung et al., 2006Leung K.M. van Horck F.P. Lin A.C. Allison R. Standart N. Holt C.E. Asymmetrical beta-actin mRNA translation in growth cones mediates attractive turning to netrin-1.Nat. Neurosci. 2006; 9: 1247-1256Crossref PubMed Scopus (193) Google Scholar, Yao et al., 2006Yao J. Sasaki Y. Wen Z. Bassell G.J. Zheng J.Q. An essential role for beta-actin mRNA localization and translation in Ca2+-dependent growth cone guidance.Nat. Neurosci. 2006; 9: 1265-1273Crossref PubMed Scopus (167) Google Scholar). This polarized translation leads to a rapid (5 min) polarized increase in β-actin protein that helps to drive axon turning towards the gradient source. Interestingly, different cues show specificity in their effects on mRNA transport and translation. Different growth factors, for example, trigger the transport of a specific repertoire of mRNAs in axons (Willis et al., 2005Willis D. Li K.W. Zheng J.Q. Chang J.H. Smit A.B. Kelly T. Merianda T.T. Sylvester J. van Minnen J. Twiss J.L. Differential transport and local translation of cytoskeletal, injury-response, and neurodegeneration protein mRNAs in axons.J. 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Neurosci. 2006; 9: 1265-1273Crossref PubMed Scopus (167) Google Scholar). β-actin mRNA translation is triggered by netrin-1 but not Sema3A, whereas RhoA and cofilin mRNA translation is induced by Sema3A but not netrin-1. This has given rise to the differential translation model suggesting that translation-dependent repulsive and attractive turning in growth cones depends on the differential translation of mRNAs involved in assembly or disassembly of the actin cytoskeleton (Lin and Holt, 2007Lin A.C. Holt C.E. Local translation and directional steering in axons.EMBO J. 2007; 26: 3729-3736Crossref PubMed Scopus (102) Google Scholar). Several aspects of this translation-driven cue-induced turning remain to be understood, such as how receptor activation signals mRNA recruitment and, critically, how specific subsets of mRNA are translated. Navigating growth cones encounter a series of patterned molecular cues along the pathway from which they must read out their spatial position. Although there are several examples of stimulus-induced local translation in axons in vitro (Shigeoka et al., 2013Shigeoka T. Lu B. Holt C.E. Cell biology in neuroscience: RNA-based mechanisms underlying axon guidance.J. Cell Biol. 2013; 202: 991-999Crossref PubMed Scopus (4) Google Scholar), it has only recently become possible to investigate translation in neuronal compartments in vivo. Early studies by Flanagan and colleagues showing compartmentalized expression of EphA2, recapitulated by a translation reporter, in the post-midline crossing segment of commissural spinal cord axons introduced the idea that the growing tip of the axon is stimulated by a regionally expressed cue (e.g., at the midline) that triggers the region-specific translation of proteins needed for pathfinding (Brittis et al., 2002Brittis P.A. Lu Q. Flanagan J.G. Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target.Cell. 2002; 110: 223-235Abstract Full Text Full Text PDF PubMed Scopus (280) Google Scholar). A recent study provides direct evidence for this type of mechanism in the control of Robo expression and midline guidance (Colak et al., 2013Colak D. Ji S.J. Porse B.T. Jaffrey S.R. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay.Cell. 2013; 153: 1252-1265Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Two Robo3 receptor isoforms have opposing roles in guiding axons to and away from the midline, and their expression is compartmentalized in pre-crossing (Robo3.1) and postcrossing (Robo3.2) axonal segments (Chen et al., 2008Chen Z. Gore B.B. Long H. Ma L. Tessier-Lavigne M. Alternative splicing of the Robo3 axon guidance receptor governs the midline switch from attraction to repulsion.Neuron. 2008; 58: 325-332Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). The switch to Robo3.2 expression at the midline (the transcript of which contains a premature termination codon) is controlled by midline-induced axonal protein synthesis coupled with nonsense-mediated mRNA decay. This provides an elegant mechanism for turning on synthesis time linked to the crossing event (Colak et al., 2013Colak D. Ji S.J. Porse B.T. Jaffrey S.R. Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay.Cell. 2013; 153: 1252-1265Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). It was not previously technically possible to inhibit translation of a specific transcript in a compartment-specific manner. Recently, however, new tools have been developed that allow separate manipulation of specific neuronal compartments in vivo such as targeted delivery of siRNAs or antisense morpholinos and conditional targeting of 3′UTRs (Perry et al., 2012Perry R.B. Doron-Mandel E. Iavnilovitch E. Rishal I. Dagan S.Y. Tsoory M. Coppola G. McDonald M.K. Gomes C. Geschwind D.H. et al.Subcellular knockout of importin β1 perturbs axonal retrograde signaling.Neuron. 2012; 75: 294-305Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Yoon et al., 2012Yoon B.C. Jung H. Dwivedy A. O'Hare C.M. Zivraj K.H. Holt C.E. Local translation of extranuclear lamin B promotes axon maintenance.Cell. 2012; 148: 752-764Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). These subcellular-directed approaches are beginning to yield information suggesting that local translation is involved in regulating multiple aspects of axonal and dendritic biology. Guidance cues induce immediate steering responses in growth cones via classical signaling pathways that involve receptor activation and phosphorylation of downstream signaling molecules (Bashaw and Klein, 2010Bashaw G.J. Klein R. Signaling from axon guidance receptors.Cold Spring Harb. Perspect. Bio