Mechanisms of dendritic mRNA transport and its role in synaptic tagging
2011; Springer Nature; Volume: 30; Issue: 17 Linguagem: Inglês
10.1038/emboj.2011.278
ISSN1460-2075
AutoresMichael Doyle, Michael Kiebler,
Tópico(s)RNA and protein synthesis mechanisms
ResumoFocus Review31 August 2011free access Mechanisms of dendritic mRNA transport and its role in synaptic tagging Michael Doyle Michael Doyle Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria Search for more papers by this author Michael A Kiebler Corresponding Author Michael A Kiebler Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria Search for more papers by this author Michael Doyle Michael Doyle Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria Search for more papers by this author Michael A Kiebler Corresponding Author Michael A Kiebler Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria Search for more papers by this author Author Information Michael Doyle1 and Michael A Kiebler 1 1Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Vienna, Austria *Corresponding author. Department of Neuronal Cell Biology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Wien 1090, Austria. Tel.: +43 1 40160 34250; Fax: +43 1 40160 934253; E-mail: [email protected] The EMBO Journal (2011)30:3540-3552https://doi.org/10.1038/emboj.2011.278 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info The localization of RNAs critically contributes to many important cellular processes in an organism, such as the establishment of polarity, asymmetric division and migration during development. Moreover, in the central nervous system, the local translation of mRNAs is thought to induce plastic changes that occur at synapses triggered by learning and memory. Here, we will critically review the physiological functions of well-established dendritically localized mRNAs and their associated factors, which together form ribonucleoprotein particles (RNPs). Second, we will discuss the life of a localized transcript from transcription in the nucleus to translation at the synapse and introduce the concept of the ‘RNA signature’ that is characteristic for each transcript. Finally, we present the ‘sushi belt model’ of how localized RNAs within neuronal RNPs may dynamically patrol multiple synapses rather than being anchored at a single synapse. This new model integrates our current understanding of synaptic function ranging from synaptic tagging and capture to functional and structural reorganization of the synapse upon learning and memory. Introduction Memories are an essential part of our lives: some memories persist indefinitely whereas others gradually fade over time. Key to understanding these crucial differences is the identification of the molecular and cellular mechanisms underlying this process. It has been proposed that the physical substrate of ‘engrams’ or ‘traces’ for long-term memory (LTM) is the remarkable ability of neurons to alter the efficacy of individual synapses within a relevant neural network in an experience-dependent manner (Govindarajan et al, 2006; Redondo and Morris, 2011). It is now generally accepted that the hippocampus—part of the limbic system in mammals—has an important role in the formation of explicit/declarative memories. The ultimate storage of information, however, does not take place in the hippocampus, but has been proposed to occur in the temporal cortex. The hippocampus acts as a filter for the formation of new memories, and changes at glutamatergic excitatory synapses are key to this process (Redondo and Morris, 2011). In particular, two distinct mechanisms have been pinpointed that are important for this process: (1) the activation of gene expression in the nucleus and (2) local protein synthesis at the synapse (Kandel, 2001). These two events—when acting synergistically—are thought to alter individual synapses functionally as well as structurally. A typical highly polarized neuron, such as a pyramidal cell in the hippocampus, has a cell body, one extended axon and a distinct, fully differentiated dendritic tree. Translation in neurons primarily occurs in the soma, but it is thought that local protein synthesis at synapses far away from the cell body can be triggered by synaptic activation. Increasing evidence points to the presence of polyribosomes at the synapse allowing local translation of specific transcripts, which critically contributes to synaptic plasticity and memory consolidation (Steward and Levy, 1982; Kiebler and DesGroseillers, 2000). However, the regulated translation of synaptically localized mRNAs in the mature brain is not the only known functional contribution of mRNA localization in the central nervous system. Local translation of mRNAs in immature neurites, for example in axonal growth cones, critically contributes to the ability of neurons to respond to environmental cues and to guide its axon to the final destination in the brain (Lin and Holt, 2007). In order to translate individual transcripts at activated synapses, the mRNAs need to be first selectively transported to these sites. Recently, a number of mechanisms have described how mRNAs can be localized in other experimental systems (from Drosophila to mammalian cells) ranging from active transport by motor proteins along the cytoskeleton to diffusion and trapping by a localized anchor as well as local protection from degradation (St Johnston, 2005; Palacios, 2007). In this review, we will focus on the different steps of mRNA localization describing how this process is currently mechanistically envisioned including (1) the presence of cis-acting localization elements (LEs) or zipcodes generally located in the 3′-untranslated region (3′-UTR) of localized transcripts, (2) the recognition of these signals by trans-acting RNA-binding proteins (RBPs), (3) the assembly of RBPs and their cargo RNAs into transport ribonucleoprotein particles (RNPs) as a functional complex, (4) the translocation of transport RNPs along the microtubule (MT) cytoskeleton to their final destination at synapses in a translationally repressed state, (5) the anchoring of these particles at or underneath activated synapses in a translationally repressed state and finally (6) the activation of translation of the localized mRNAs. While mRNA transport is important in many systems, here we will focus on dendritic mRNA localization, its underlying mechanisms and relationship to synaptic function. We will outline the latest experimental data, demonstrating that RBPs not only have important roles for synapse formation as well as morphogenesis, but also in synaptic plasticity. Finally, we will introduce a simple reductionist model termed ‘synaptic sushi belt’, which unifies cell body-initiated gene expression, dendritic mRNA localization and local protein synthesis at individual synapses with experience-dependent functional and structural remodelling of synapses during LTM. mRNA localization in nerve cells Regulated, localized mRNA translation is especially important in highly polarized cells such as differentiated neurons that may have up to 10 000 dendritic spines—the postsynaptic compartment of a synapse—and at least as many distinct excitatory inputs. It is important to note that the main pathway for protein delivery to synapses—be it the presynaptic or postsynaptic compartment—is via synthesis in the cell body and subsequently transport to either axons or dendrites (reviewed in Kennedy and Ehlers, 2006). However, mRNA localization also occurs during development in axonal growth cones of immature neurons as well as in dendrites of fully mature and polarized neurons. In the brain, mRNA localization is not only restricted to neurons, but also occurs in another type of nerve cell, the oligodendrocytes. Here, the mRNA encoding myelin basic protein (MBP) is selectively delivered into a distinct biochemical compartment in distal processes where myelination occurs (Ainger et al, 1993). It is becoming increasingly clear that local translation within the axon critically contributes to axon guidance. This topic has been recently covered in a series of reviews (Hengst and Jaffrey, 2007; Lin and Holt, 2007; Vuppalanchi et al, 2009) and therefore will not be discussed here. In the mature brain, mRNA localization into dendrites of fully polarized neurons serves a distinct function. The presence of a specific set of transcripts and the entire translational machinery at dendritic spines suggests that local translation could be regulated in an activity-dependent manner (Steward and Levy, 1982; reviewed in Sutton and Schuman, 2006). This in turn would allow an individual synapse of a given neuron to modify its function as well as its morphology, thereby providing a mechanism for synaptic plasticity and memory consolidation (Martin and Ephrussi, 2009). The advantages of mRNA localization as a key regulatory mechanism to fine-tune gene expression have been outlined in a series of recent reviews (St Johnston, 2005; Martin and Ephrussi, 2009; Cajigas et al, 2010). First, the localization of mRNA rather than its corresponding protein serves a dual function, since it targets the protein directly to the correct intracellular compartment while preventing its expression elsewhere. This is particularly important for those proteins that might be harmful to other parts of the cell, for example MBP in oligodendrocytes, or Tau and MT-associated protein 2 (MAP2) that could bind to all MTs in the cell. Second, it provides a synapse with the unique opportunity to spatially restrict gene expression with high temporal resolution. Therefore, an activated synapse could initiate local protein synthesis that in turn alters its function and morphology in its own microenvironment that is independent of the distant cell body. Third, it is more economic to reuse a given transcript several times for multiple rounds of translation instead of transporting each protein or transcript individually to a distinct synapse. Interestingly, dendritic protein synthesis appears not to produce general housekeeping proteins, but rather to produce proteins with specialized synaptic functions, for example key kinases (CaMKIIα, PKMζ), cytoskeletal proteins (Arc, MAP2) and neurotransmitter receptors of the AMPA (GluR1 and 2) and NMDA (NR1) families (Bramham and Wells, 2007; Andreassi and Riccio, 2009; Wang et al, 2010). Cis-acting signals or zipcodes Thirty-one years ago, Blobel (1980) published his Nobel Prize winning signal peptide hypothesis, stating that proteins can be sorted to specific locations inside cells and that the relevant information ‘is encoded in discrete ‘topogenic’ sequences that constitute a permanent or transient part of the polypeptide chain.’ Since then, it has become increasingly apparent that other molecules, including mRNAs, contain molecular zipcodes that allow their targeting to distinct subcellular compartments in order to regulate gene expression with high temporal and spatial control. First experimental insights came from in situ hybridization (ISH) studies in oocytes, eggs or in asymmetric cells such as fibroblasts, oligodendrocytes and polarized neurons (Steward and Schuman, 2001). Given the unique morphology of highly polarized neurons with dendrites far away from the cell body, the detection of localized messages was straightforward due to physical distance. ISH on brain slices, where the dendrites are largely spatially segregated in the neuropil layer, or on cultured primary neurons is routinely used to assess dendritic mRNA localization. Such experiments allowed Oswald Steward and others to identify dendritically localized mRNAs that still serve as the ‘gold standard’, including mRNAs encoding for the activity-regulated cytoskeletal protein (Arc or Arg3.1), the α-subunit of the Ca2+/calmodulin kinase II (CaMKIIα) and MAP2. Whereas Arc mRNA is usually not detected in neurons under basal conditions, since it is a product of an immediate early gene (Plath et al, 2006), CaMKIIα and MAP2 mRNAs are routinely detected in dendrites, but in a distinct pattern from each other (Garner et al, 1988; Burgin et al, 1990). Since these early analyses, many other mRNAs have now been reported to localize to neuronal dendrites (Bramham and Wells, 2007; Andreassi and Riccio, 2009). Of particular interest for both immature and mature neurons is the β-actin transcript. It is found in neuronal growth cones but also localizes to synapses in fully mature neurons (Tiruchinapalli et al, 2003). Another mRNA that has recently received attention in the context of maintaining molecular memory is PKMζ mRNA. It encodes a constitutively active isoform of protein kinase C, which is exclusively expressed in neural tissue (Sacktor, 2011). Its mRNA has been found in dendrites of hippocampal neurons (Muslimov et al, 2004). Once translated locally at activated synapses, high levels of this kinase yield increased numbers of AMPA receptors at postsynaptic sites, potentiating synaptic transmission (Sacktor, 2011). Many experimental approaches have been applied in neurons to analyse the localization of particular mRNAs in detail. Chimeric constructs consisting of a reporter gene fused to putative LEs were used to visually identify cis-acting sequences that direct mRNAs to their destination in dendrites near synapses (Chartrand et al, 2001; Martin and Ephrussi, 2009). These experiments convincingly proved the existence of similar ‘topogenic’ sequences that Blobel (1980) discovered in proteins. These cis-acting elements are now commonly referred to as ‘LEs’ or ‘zipcodes’ and are often located in the 3′-UTR of the transcript. However, in contrast to the protein zipcodes, these elements can be very heterogeneous in size and structure. They range from 5–6 nts up to very complex secondary structures that can be as much as 1 kb or more in length. An example of a short, well-defined LE is found in MBP mRNA. It contains two partially overlapping 11 nt cis-acting RNA sequences in its 3′-UTR that have since been termed the heterogeneous nuclear ribonucleoprotein (hnRNP) A2 response element (A2RE) as they are recognized by hnRNP A2 (Gao et al, 2008). The more complex LEs often contain one or several distinct stem loops and are referred to as RNA folds. Because of the complexity of RNA secondary structure, it is challenging to delineate these localization sequences and deduce a clear consensus, either at the level of sequence or structure. In Drosophila, Bullock et al (2010) were able to identify the first conserved LEs in developmentally important transcripts. These in turn recruit two-core components of a selective dynein motor complex, Egalitarian (Egl) and Bicaudal D (BicD), driving transcript localization in a variety of tissues. A recent comparison of mRNA localization in oligodendrocytes and neurons revealed that three dendritically localized mRNAs, CaMKIIα, neurogranin and Arc, appear to assemble into the same hnRNP A2 granules. They are targeted by the same A2RE, which also mediates targeting of MBP RNA by the hnRNP A2 pathway in oligodendrocytes (Gao et al, 2008). It is tempting to speculate that such conserved signals are recognized by a common group of conserved RBPs that decipher a complex ‘RNA signature’ on a given transcript (Schnapp, 1999; Bullock and Ish-Horowicz, 2001; Gao et al, 2008). It is important to note that, aside from LEs, regulatory elements found within both the 5′- and 3′-UTR of transcripts can regulate other stages of posttranscriptional control (Andreassi and Riccio, 2009). Interestingly, in the 5′-UTR they appear to be primarily involved in translational control, whereas those in the 3′-UTR can affect various stages, including quality control, nuclear export, localization in the cytoplasm, trafficking to specific intracellular compartments, translational control and mRNA stability (Moore, 2005). Also important to note is that 3′-UTRs often contain binding sites for miRNAs that can trigger the translation repression and/or degradation of an mRNA via the RNA interference (RNAi) pathway. Several studies have reported the presence of miRNAs at the synapse, suggesting that the RNAi pathway locally contributes to synaptic function (Kosik, 2006). Furthermore, it has been hypothesized that mRNA binding of certain RBPs, for example Pumilio2, GW182, Ago and HuR proteins, might either positively or negatively affect miRNA binding and subsequent function (Filipowicz et al, 2008; Jacobsen et al, 2010). It is likely that localized transcripts contain more than one copy of a dendritic LE as well as combinations of different zipcodes mediating distinct steps in localization. Complexity can be further increased if these signals (partially) overlap and are recognized by different RBPs. For example, it has been surprisingly difficult to distinguish LEs from other elements regulating translational control. Because of the complexity and the variability of the localization sequences identified to date, it has not yet been possible to unambiguously identify LEs by computational prediction or even to deduce common sequence and structural motifs. In conclusion, a large volume of data on putative LEs within localized transcripts has been collected that now needs to be rigorously validated in its physiological context. Ultimately, RNA signatures for each localized transcript have to be determined experimentally. To this end, the development of new experimental approaches that allow high-resolution imaging of mRNA localization in living neurons will undoubtedly yield new mechanistic insight in the underlying process of mRNA localization. In addition, both loss-of-function as well as gain-of-function experiments must be applied in vivo to selectively interfere with either the LEs of the RNA to be studied or the RBP(s) that selectively bind(s) to the LE. Analysis of the process of mRNA localization in neurons would then show whether localization is selectively impaired or whether other aspects of mRNA metabolism are also affected. We would like to highlight two key studies (Miller et al, 2002; Lionnet et al, 2011) that investigated the localization of the prominently dendritically localized mRNAs, CaMKIIα and β-actin, in their physiological context at the activated synapse. For CaMKIIα mRNA, there are conflicting studies defining its LE(s). Mori et al (2000) identified a 94-nt long element in the 3′-UTR of the CaMKIIα transcript that proved to be sufficient to target a GFP reporter construct to dendrites. They further identified a larger element downstream of the first that exhibited a dominant-negative effect on RNA localization. Using a similar reporter assay, Kindler and coworkers identified a distinct LE in the middle of the 3′-UTR of CaMKIIα mRNA (Blichenberg et al, 2001). These experiments clearly demonstrate how difficult it is to interpret the results of deletion and overexpression studies. Mayford and colleagues went on to investigate the in vivo role of the CaMKIIα 3′-UTR at the synapse by generating a mutant mouse that was lacking most of the 3′-UTR (Miller et al, 2002). However, the 94-nt ‘Mori element’ was still present. ISH analyses of brains from these mice showed that the mutant CaMKIIα mRNA containing the entire 5′-UTR, coding region and the ‘Mori element’ failed to localize to dendrites. This confirms in vivo that CaMKIIα 3′-UTR is necessary for dendritic targeting and that the Mori element alone is not sufficient. Very recently, Moine and colleagues have described a G-quadruplex RNA structure in the CaMKIIα 3′-UTR that directs the RNA into cortical neurites (Subramanian et al, 2011). Consequently, the localization of the CaMKIIα mRNA appears to depend on multiple LEs, and further work is needed to delineate which are indeed necessary and sufficient in vivo and which may act synergistically. Most importantly, late-phase long-term potentiation (L-LTP) was reduced in the 3′-UTR mutant mice, providing the strongest evidence to date for a functional contribution of dendritic mRNA localization to the stabilization of synaptic plasticity and memory consolidation. Furthermore, spatial memory, associative fear conditioning and object recognition memory were also impaired (Miller et al, 2002). To date, no similar mutant mice for other well-known dendritically localized transcripts are available. Such mouse models will substantially increase our understanding of mRNA localization in the nervous system and its contributions to synaptic function and learning and memory. Recently, a novel approach to study the dynamics of mRNA localization ex vivo was published by Singer and colleagues (Lionnet et al, 2011). This is based on the bacteriophage MS2 imaging system they previously established, where an RNA of interest is tagged with MS2-binding sites (MBS) that are recognized by the MS2 coat protein (MCP), which in turn is fused to a fluorescent protein. The RNA and the MCP are expressed from different plasmids that are cotransfected in the same cell, thus allowing visualization of the overexpressed MCP bound to the MBS on RNA. A careful comparison of the localization pattern of the overexpressed transcript with the endogenous RNA is required to ensure that the insertion of multiple MBS reflects the normal physiological localization. In mammalian cells, this system has previously only been used in transiently transfected cells. Singer and colleagues now applied the system in vivo by generating a transgenic mouse where they inserted an MBS cassette into the endogenous β-actin locus, in the 3′-UTR, which still contains its normal LE. Using primary hippocampal neurons derived from these mice, the authors studied the transport of the endogenous β-actin mRNA ex vivo. When they coexpressed an MCP-YFP reporter in these neurons, they were able to track single endogenous labelled β-actin mRNA particles on their way into dendrites. It is important to note that the MBS cassette did not interfere with the dendritic targeting of the β-actin transcript. This is a crucial technological advancement, since it now allows the visualization of an endogenously expressed mRNA at normal expression levels in contrast to reporter constructs that often yield overexpression artefacts. Therefore, the β-actin-MBS mouse provides a powerful tool for many future experiments: (1) for live cell imaging of an endogenous localized transcript in brain tissue in vivo, for (2) biochemical isolation of β-actin-RNPs in order to unravel its binding partners in the brain and for (3) crossing these mice with other mouse models to assess the roles of other factors involved in mRNA localization (e.g. RBPs—see below) (Lionnet et al, 2011). Trans-acting factors or RBPs In a simplistic model of mRNA localization, a single LE could be recognized by a single RBP. Up-to-now, only one mRNA appears to fall into this category: the MBP mRNA containing the A2RE, which is specifically recognized by hnRNP A2. It is both necessary and sufficient to direct MBP mRNA towards oligodendrocyte processes (Hoek et al, 1998; Munro et al, 1999). All other well-characterized mRNAs that localize to dendrites contain LEs that are more complex, often folding into higher-order secondary structures. These mRNAs might contain multiple elements that are (at least) partially redundant or exert related regulatory functions. Consequently, it is necessary to investigate the trans-acting factors that bind the cis-acting elements to link an mRNA to the localization machinery and achieve its targeting to the activated synapse. A likely scenario is that RBPs or associated proteins provide the link to the molecular motor involved in this process (Dictenberg et al, 2008). There are three possible mechanisms by which RBPs are recruited to regulatory elements that might promote localization (Palacios, 2007): (1) active and direct transport of the transcript via molecular motor proteins and the neuronal cytoskeleton; (2) facilitated diffusion and subsequent trapping of the transcript by a localized anchor and (3) protection from degradation only at the site of localization. Over the last 20 years, a large number of RBPs have been implicated in mRNA localization in various organisms. Most of these were either identified in genetic screens involved in mRNA localization or in biochemical and proteomic approaches (Kiebler and DesGroseillers, 2000; Bassell and Kelic, 2004; St Johnston, 2005; Bramham and Wells, 2007; Holt and Bullock, 2009; Martin and Ephrussi, 2009). A careful comparison of these factors showed that some of them belong to large, well-conserved families of RBPs (Schnapp, 1999; Bullock and Ish-Horowicz, 2001). RBPs that were characterized for their contribution to dendritic mRNA localization include ZBP1, the Staufen proteins, fragile × mental retardation protein (FMRP), the cytoplasmic polyadenylation element-binding protein (CPEB) and the hnRNP A2 protein. However, very few of the identified RBPs have been assigned specific roles during the multi-step process of mRNA localization (see Figure 1). Figure 1.RNA signature. mRNAs—as depicted in the centre of the figure—contain multiple regulatory elements at both the primary sequence and structural levels that are recognized by certain trans-acting factors or RBPs. These can bind either single-stranded (simple line) or double-stranded (hairpin structures) RNA. In addition, some of them can also interact with other proteins as shown on the right. Consequently, each transcript has its own unique ‘RNA signature’, which determines the fate and function of an mRNA including its stability, localization, translational control and whether it undergoes local protein synthesis (functions listed in the outer panels). As every mRNA can contain various combinations of regulatory elements and bind different RBPs, this not only increases the functionality of a transcript, but also offers unique ways to regulate the fate of the RNA. ARE, AU-rich element; Cap, 7-methylguanosine; CPE, cytoplasmic polyadenylation element; CPEB, cytoplasmic polyadenylation element-binding protein; EJC, exon junction complex; LE, localization element; miRNA, microRNA bound to its miRNA-binding site; mRNPs, messenger RNA-containing RNPs; TLC, translation control element. Download figure Download PowerPoint ZBP1 protein is one of the best-studied neuronal trans-acting factors, with its expression peaking during brain development. In developing neurons, ZBP1 binds to the zipcode of β-actin mRNA in axonal growth cones and critically contributes to growth cone navigation by regulating the stimulus-induced local translation of β-actin (Lin and Holt, 2007). During later development, ZBP1 contributes to proper dendritic branching (Perycz et al, 2011). In fully polarized neurons, a ZBP1 β-actin mRNA complex selectively trafficks into dendritic spines upon synaptic stimulation (Tiruchinapalli et al, 2003). The essential role of ZBP1 in promoting β-actin localization is the inhibition of β-actin mRNA translation. This is abrogated upon phosphorylation of ZBP1 by Src kinase, resulting in the release of β-actin mRNA from mRNPs and the activation of mRNA at the site of high actin dynamics, for instance exploratory growth cones (Hüttelmaier et al, 2005). Interestingly, Bassell and colleagues provided detailed insight into the role of tyrosine phosphorylation of ZBP1 in neurons. They showed that phosphorylation of ZBP1 at Y396 within growth cones regulates local protein synthesis and growth cone turning (Sasaki et al, 2010). The Staufen proteins are some of the best-known proteins involved in mRNA localization in many species. Staufen orthologues have been implicated in mRNA transport in Drosophila, the sea mollusc Aplysia and vertebrates (St Johnston, 2005). Staufen proteins belong to the family of double-stranded RBPs (St Johnston et al, 1992). In mammals, two Staufen proteins exist: a ubiquitously expressed Staufen 1 (Stau1) that has been implicated in mRNA localization and decay (Vessey et al, 2008; Gong and Maquat, 2011) and Staufen 2 (Stau2), which is preferentially expressed in the brain. Because of alternative splicing, four major Stau2 isoforms are expressed in the mammalian brain (Mallardo et al, 2003; Monshausen et al, 2004). Domain organization of the longest Stau2 isoform, Stau262, is most similar to Drosophila Staufen (Duchaine et al, 2002). Interestingly, Stau262 is a nucleocytoplasmic shuttling protein (Macchi et al, 2004; Miki et al, 2005) and was therefore proposed to transport RNAs from the nucleus into neuronal dendrites, keeping them in a translationally repressed state until synaptic activity relieves the translational block (Goetze et al, 2006). The first evidence that Staufen proteins are directly involved in synaptic plasticity came from Lacaille and colleagues. They showed that Stau1 is required for the late phase of LTP (Lebeau et al, 2008). In contrast, Stau2 downregulation appears to affect only metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) (Lebeau et al, 2011). These studies clearly demonstrate that RBPs, in this case Staufen proteins, critically contribute to synaptic plasticity. Moreover, the two Staufen proteins appear to have specific roles in separate physiological processes, arguing for their distinct functions at the synapse. Another important trans-acting factor involved in dendritic mRNA localization is FMRP, which is abundant in the brain, where it is thought to regulate many different mRNAs (Zalfa et al, 2006; Bassell and Warren, 2008). FMRP binds to several localized transcripts, including CaMKIIα, MAP1b, PSD-95 as well as its own mRNA. Recent evidence suggests that FMRP regulates mRNA transport in dendrites (Dictenberg et al, 2008). In this study, Bassell and cowo
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