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date: 22 October 2019

FMRP and MicroRNAs in Neuronal Protein Synthesis

Abstract and Keywords

New protein synthesis is critical for learning and memory. The discovery of ribosomes at synapses indicated the potential for local protein synthesis in response to stimulation. miRNAs play a key role in this process as evidenced by their role in normal neuronal development and function and in neurological disease. miRNA production is regulated and once bound by AGO2, the ensuing RISC complex is able to bind mRNAs and direct their translation suppression and degradation. However, other RNA binding proteins, including FMRP and MOV10, regulate AGO2 association with the miRNA recognition element (MRE) in target mRNAs. AGO2 itself is regulated by post-translational modifications, and neuronal activity controls post-translational modifications of FMRP and MOV10 that lead to their regulation and degradation. In addition, RNA localization at the synapse is a critical regulated event that depends on both cis sequences in the mRNA and the identity of the bound RNA binding proteins.

Keywords: AGO2, FMRP, miRNAs, MOV10, neurons, RNA binding proteins, translation


The critical role for new protein synthesis in learning and memory was first discovered through the use of protein synthesis inhibitors like puromycin to disrupt memory formation in mice during a specific behavioral task close to 60 years ago (Flexner, Flexner, Stellar, De La Haba, & Roberts, 1962; Flexner, Flexner, & Stellar, 1963). Since this seminal discovery, inhibition of neuronal protein synthesis with a wide variety of chemicals has been performed in many organisms from humans, birds, invertebrates such as Aplysia and even goldfish with striking results in the areas of learning and memory (reviewed in Sweatt, 2016). A key insight into the role of local translation came when Oswald Steward and colleagues discovered that ribosomes were present in the synapse (Steward & Levy, 1982). Localized protein synthesis allows for a rapid response upon stimulation and is considered indispensable for learning and memory. For protein synthesis at the synapse to take place there needs to be a system for organization, delivery and accurate regulation of the many factors involved: from localization of mRNAs, recruitment of RNA-protein-containing granules, accessory RNA binding proteins, polysome formation and miRNA-mediated regulation. We’ll begin our exploration of neuronal protein synthesis by discussing how this process is regulated.

miRNA Biogenesis and Its Consequences on mRNA Expression

Small ncRNAs represent an important subset of non-coding RNA transcripts. First discovered in 1993, they are loosely defined by their small size (typically less than 30 nucleotides), association with members of the Argonaute (AGO) family of proteins and their ability to regulate gene expression (Lee et al., 1993). This review will focus on miRNAs as a type of small non-coding RNA transcript that is now estimated to regulate over 50% of all human genes (Friedman, Burge, & Bartel, 2008).

Regulation of miRNAs can occur at the level of transcription as well as by the rate of cleavage or downstream processing (Gulyaeva & Kushlinskiy, 2016). Once fully processed, miRNAs are typically between 22 and 26 nucleotides. They form canonically when the primary transcript of a miRNA gene (pri-miRNA), a larger RNA precursor, is cleaved in the nucleus by the microprocessing complex DROSHA/DGCR8 into an approximately 70 nucleotide local hairpin structure called a precursor-miRNA (pre-miRNA) (Denli, Tops, Plasterk, Ketting, & Hannon, 2004; Gregory et al., 2004; Han, 2004; Lee, 2002, 2003; see Figure 1). After this cleavage, pre-miRNAs are exported into the cytoplasm and further processed by the RNAse III DICER to generate the final length miRNA, which is bound by AGO2 (Chendrimada et al., 2005; Lee, 2002; Lee et al., 2006).

FMRP and MicroRNAs in Neuronal Protein SynthesisClick to view larger

Figure 1. miRNA biogenesis and neuronal protein translation regulation of RNP-associated mRNAs. See text for explanations. Abbreviations: P, phosphorylation; UBQ, ubiquitination.

miRNAs regulate gene expression through binding of the seed sequence to the complementary target sequence in the mRNA called the miRNA Recognition Element (MRE). MREs are primarily in the 3′ untranslated region (UTR) but have also been reported in 5′UTRs and in coding regions (reviewed in Brodersen & Voinnet, 2009). In Drosophila and many plants, miRNA base pairing to target mRNAs is perfectly complementary whereas in other eukaryotes, the presence of a shorter seed sequence still allows for mRNA regulation upon miRNA binding (Bartel, 2009; Meister & Tuschl, 2004). Furthermore, although miRNAs can bind to any portion of the mRNA sequence that possesses a degree of complementarity, mRNAs with longer 3′ UTRs have been shown to contain a greater number of miRNA binding sites, and therefore have a higher potential for post-transcriptional regulation (Brummer & Hauser, 2014; Fang & Rawjeski, 2011; Kebaara & Atkin, 2009).

The most common mode of regulation is at the level of transcript stability when complete base pairing between the miRNA and its target mRNA leads to cleavage of the transcript by AGO2. The mRNA transcript itself can be degraded at differential rates, thereby reducing the amount of template available for protein translation (Bagga et al., 2005; Hutvagner, 2002; Nottrodd, Simard, & Richter, 2006). In the case of incomplete base pairing, translational suppression, followed ultimately by transcript degradation takes place (Béthune, Artus-Revel, & Filipowicz, 2012).

miRNA Biogenesis Factors

The importance of the miRNA pathway is underscored through the characterization of the knockout mice made of the individual components. Ablation of DGCR8, part of the nuclear microprocessor complex which generates pre-miRNAs (Figure 1), results in embryonic lethality at E6.5 (Wang, Medvid, Melton, Jaenisch, & Blelloch, 2007), establishing the importance of miRNA function in normal development. DROSHA, the ribonuclease III that forms the other half of the microprocessing complex, also leads to embryonic lethality when ablated in mice (Fan et al., 2013). DICER deficient mice are embryonic lethal at day E8.5 (Krill, Gurdziel, Heaton, Simon, & Hammer, 2013). Functional DICER is also crucial for maintaining neuronal integrity, as absence of DICER in brain leads to neurodegeneration, most notably cell shrinkage (Hebert et al., 2010).

Although AGO2 is one of four main Argonaute proteins in cells, when individual Argonautes are knocked out in mice, only loss of AGO2 causes embryonic lethality (Liu, 2004). The other AGO proteins are dispensable for animal development once again highlighting the importance of proper miRNA regulation of target mRNAs in embryonic tissue and organ development (Liu, 2004; Morita et al., 2007). AGO2 is also the only family member with mRNA slicing activity (Liu, 2004; Meister et al., 2005) making it the main effector of miRNA-mediated regulation.

The embryonic lethal phenotypes due to loss of miRNA biogenesis and effector components are not limited to this core group of proteins. Genetic studies have demonstrated that alterations in the levels of RISC accessory proteins and in the miRNAs themselves can lead to a wide variety of aberrant phenotypes both during development and post-embryonically (Bicker and Schratt, 2008; Edbauer et al., 2010; Schratt et al., 2006; Skariah et al., 2017). One example of this is AGO2-associated protein MOV10. Although more than one type of helicase can be found in the brain, MOV10 is particularly highly expressed embryonically and during early postnatal stages in mice, decreasing around P14, with a further drop in adulthood (Skariah et al., 2017). MOV10 ablation results in embryonic lethality before E9.5 (Skariah et al., 2017), and in Xenopus embryos it has been shown to be essential for completion of gastrulation (Skariah, Perry, Drnevich, Henry, & Ceman, 2018).

Regulation of AGO2 Function

Although miRNAs select their targets based on base pairing of their 2−7 nucleotide seed regions to the MRE in the target mRNA, the question remains of how a particular miRNA, which is vastly outnumbered by mRNAs in a given mammalian cell, is still able to functionally repress its targets? Recent CRISPR/Cas9 screenings have given insight by revealing novel regulators of miRNA-mediated silencing. Phosphorylation of AGO2 by CSNK1A1 triggers positive mRNA target engagement, which is then relieved upon dephosphorylation by the ANKRD52-PPP6C phosphatase. This cycle of phosphorylation/dephosphorylation is crucial for maintaining the global efficiency of miRNA-mediated repression because dephosphorylation of AGO2 allows it to engage new mRNA targets (Golden et al., 2017).

Other posttranslational modifications of AGO2 that influence miRNA-mediated silencing, include hydroxylation at residue 700 by the type I collagen prolyl-4-hydroxylase [C-P4H(I)] (Qi et al., 2008). Hydroxylation appears to enhance the stability of AGO2 as knockdown of C-P4H(I) reduces the translational suppression activity of RISC (Jee & Lai, 2014).

Role of RNA Binding Proteins in miRNA-mediated Regulation

A growing body of research suggests that one of the key ways that the mRNA-miRNA interaction is regulated is through association of RNA binding proteins (RBPs) with the mRNA in the proximity of the MRE (Connerty, Ahadi, & Hutvagner, 2015; Kenny & Ceman, 2016; Loffreda, Rigamonti, Barabino, & Lenzken, 2015). Hundreds of RBPs have been discovered to play a key role in post-transcriptional regulation (Collins & Penny, 2009; Glisovic, Bachorik, Yong, & Dreyfuss, 2008; Keene, 2007; Mata, Marguerat, & Bähler, 2005) due to their unique ability to interact with RNA while forming protein-protein interactions with key players in the cell such as AGO2. RBPs are generally conserved between yeast and humans (Beckmann et al., 2015; Gerstberger, Hafner, Ascano, & Tuschl, 2014) yet can be functionally diverse and while many do not possess canonical RNA binding sequences, they still exert a great deal of control over their targets. We will focus now on RBPs that facilitate miRNA-mediated regulation.


One RNA binding protein that has emerged as a key interactor with the miRNA-mediated silencing pathway is the fragile X mental retardation protein (FMRP; Ashley, Wilkinson, Reines, & Warren, 1993). FMRP is the protein product of the FMR1 gene, whose loss leads to fragile X syndrome (FXS), a triplet-repeat expansion disease which is the leading cause of inherited cognitive impairment affecting 1:4000 males and 1:8000 females (Rajaratnam et al., 2017). Loss of FMRP leads to defects in synaptic plasticity and cognition (Bolduc, Bell, Cox, Broadie, & Tully, 2008; Kelleher & Bear, 2008; Liu-Yesucevitz et al., 2011).

FMRP is primarily a cytoplasmic protein although it does possess a nuclear localization signal (NLS; Devys, Lutz, Rouyer, Bellocq, & Mandel, 1993; Feng et al., 1997; Kim, Bellini, & Ceman, 2009; Vanderklish & Edelman, 2005; Willemsen, Oostra, Bassell, & Dictenberg, 2004). In mammals, FMRP possesses conserved functional domains, three of which are RNA binding domains (Siomi, Siomi, Nussbaum, & Dreyfuss, 1993). Two of the RNA-binding motifs are homology to hnRNP K (KH) domains and the third is an arginine-glycine-glycine (RGG) box, which is thought to bind G-rich secondary structures, such as G-quadraplexes (GQs; Darnell et al., 2001; Phan et al., 2011; Schaeffer, 2001). FMRP primarily binds within the coding sequence of its target mRNAs (Darnell et al., 2011) although it has also been shown to associate with the 3′UTR (Ascano et al., 2012; Ashley et al., 1993; Kenny et al., 2014).

Over 800 mRNA targets of FMRP have been identified, primarily in brain (Brown et al., 2001; Darnell et al., 2011; Miyashiro et al., 2003). FMRP functions in translational regulation and silencing of its mRNA targets, although recent research has shown in a small subset of mRNAs, along with other RNA binding proteins, FMRP promotes the opposite effect, leading to enhanced expression (Kenny et al., 2014).

FMRP was first implicated in miRNA-mediated regulation of transcript expression in two independent studies using its Drosophila homolog dFMR1 (Caudy, 2002; Ishizuka, 2002). In the first study, dFMRP was identified as co-purifying with AGO2. Knockdown of dFMR1 resulted in impaired RNA interference of a reporter, suggesting a functional association of dFMRP with RISC activity (Caudy, 2002). In the second study, dFMRP was also identified in an AGO2-containing messenger ribonucleoprotein particle (mRNP) that also contained ribosomal proteins L5 and L11. In contrast to the first study, though, dFMRP was not required for silencing of a reporter. One possible explanation for this difference is that FMRP may only be effective in silencing an mRNA when it also binds that mRNA, which may have occurred in the first study but not in the second study. These results were extended in mammalian cells when FMRP was shown to associate with endogenous miRNAs, DICER activity and AGO2 by co-immunoprecipitation (Jin et al., 2004). In 2010, miRNA-mediated regulation by FMRP was explored in brain when FMRP was shown to co-immunoprecipitate with a number of miRNAs important in neuronal function (Edbauer et al., 2010). Interestingly, this study made a case for AGO1 being the primary effector of the regulatory activity of miR-125b on the NR2A mRNA, which was also bound by FMRP. The participation of AGO2 was not examined in that work. The following year, FMRP was shown again to co-immunoprecipitate with AGO2 (Lee et al., 2010) in a study of regulation of the Amyloid Precursor Protein mRNA APP. Both FMRP and AGO1 and AGO2 were shown to bind APP and both were required for FMRP-mediated translation suppression of APP. These investigators also proposed that an FMRP-AGO complex competed with hnRNP C for APP binding and subsequent translational fate regulation where the former suppressed it and the latter activated it. Cross-linking immunoprecipitation (CLIP)-seq analysis of brain FMRP in 2011 showed that FMRP bound primarily in coding sequence (Darnell et al., 2011). However, another study the following year in HEK293 cells described the FMRP CLIP sites as being distributed between coding sequence and 3′UTR (Ascano, et al., 2012). FMRP was identified as interacting with the MID domain of AGO2 (Li, Tang, Zhang, & Zhang, 2014), which is interesting because that is the same domain that interacts with another RNA binding protein, fused in sarcoma (FUS). The authors speculate that by recruiting different RBPs through its MID domain, AGO2 could potentially enhance miRNA silencing of specific targets (Zhang et al., 2018).


The RNA helicase MOV10 was first implicated in the miRNA pathway in a mass spectrometry screen to identify proteins associated with AGO2. Importantly, knockdown of MOV10 eliminated miRNA-mediated suppression of a reporter construct, suggesting that this helicase played an important role in the miRNA pathway (Meister et al., 2005).

MOV10 possesses 5′–3′ helicase activity (Gregersen et al., 2014). The majority of MOV10 is localized to the cytoplasm and AGO2-containing cytoplasmic foci (Goodier, Cheung, & Kazazian, 2012; Messaoudi-Aubert et al., 2010), although MOV10 has been described in the nucleus in some cultured cell lines (Messaoudi-Aubert et al., 2010) and in early mouse hippocampal neurons, where it has been implicated in protection against retroviral elements such as LINE-1 (Skariah et al., 2017).

MOV10 is highly expressed in the murine brain, primarily in embryonic and early postnatal stages (Skariah et al., 2017). MOV10 is also required for the completion of gastrulation and for neural tube formation (Skariah et al., 2018). In the 3′UTR where MOV10 primarily binds its mRNA targets, it is found in G-C rich regions that include stable secondary structures such as GQs (Kenny et al., 2014). MOV10 has been implicated in the miRNA pathway as its activity-stimulated degradation leads to upregulation of bound targets (Banerjee, Neveu, & Kosik, 2009). MOV10 also colocalizes with FMRP and AGO2 in vivo in cultured neurons (Liu-Yesucevitz et al., 2011; Wulczyn et al., 2007). FMRP and MOV10 associate in brain and in cell lines in a partially RNA-dependent manner, while possessing a protein-protein interaction, as well, based on experiments with purified recombinant MOV10 and FMRP (Kenny et al., 2014).

In addition to its role in facilitating AGO2-mediated silencing, MOV10 is also able to block miRNA-mediated translational suppression in some mRNAs by directly interacting with FMRP on the same site in the mRNA. This is a significant observation because it suggests that the protein complex that assembles at an MRE can control AGO2 association (Kenny et al., 2014; Kenny & Ceman, 2016). In the absence of FMRP, MOV10 had reduced association with the subset of mRNAs that are shared between the two proteins (Kenny et al., 2014), suggesting that FMRP binds the mRNAs first and then recruits MOV10 to the mRNA. However, whether MOV10 serves as an agonist or antagonist in the miRNA pathway (Kenny et al., 2014) is directly related to its binding with FMRP in the 3′UTR. If FMRP and MOV10 bind the same 3′UTR at different sites, those mRNA targets are suppressed by AGO2. We hypothesize that this miRNA-mediated translational suppression occurs when MOV10 recruited by FMRP proceeds to remodel the 3′UTR landscape by unwinding secondary structures, potentially revealing embedded or previously inaccessible MREs for AGO2 recognition and binding. However, if FMRP and MOV10 bind the same site in the 3′ UTR, the direct proximity of these proteins leads to a protein-protein interaction that results in the MRE being protected from AGO2 association—likely by blocking AGO2 recognition of the MRE (Kenny et al., 2014; Kenny & Ceman, 2016; see Figure 2).

FMRP and MicroRNAs in Neuronal Protein SynthesisClick to view larger

Figure 2. Translational fate of an mRNA depends on its association with RNA binding proteins FMRP and MOV10 and where they are bound relative to an MRE within the mRNA. Top. FMRP and MOV10 bind in discrete, non-overlapping regions on the mRNA, which results in AGO2 access to the MRE, likely facilitated by MOV10-mediated unwinding. Bottom. FMRP and MOV10 bind the same site on the mRNA, which blocks AGO2 association.

In brain, a 50% reduction in MOV10 such as in heterozygous mice has been shown to have a dramatic impact on proper neuronal morphology, with MOV10-deficient hippocampal neurons exhibiting reduced dendritic arborization (Skariah et al., 2017).

Other important RNA binding proteins that participate in miRNA-mediated translational regulation include but are not limited to polypyrimidine tract-binding protein (PTB), human antigen R (HuR), Pumilio (PUM1), dead end 1 (DND1), FUS, and coding region determinant-binding protein (CRD-BP).

PTB was originally described as a repressor of nervous system-specific splicing (Black, 2003; Sharma, Falick, & Black, 2005; Spellman & Smith, 2006; Wagner & Garcia-Blanco, 2001). Suppression of PTB by miR-124 led to neuronal differentiation (Boutz et al., 2007; Makeyev, Zhang, Carrasco, & Maniatis, 2007; Xue et al., 2013; Zheng et al., 2012). To understand how PTB mediates its effect, the PTB binding sites in regulated RNAs were examined to reveal that PTB binding could block miRNA association in the 3′UTR. However, in other target mRNAs, PTB binding facilitated miRNA association. By carefully examining the secondary structure of PTB-bound mRNAs, the authors found that modulation of RNA secondary structure by PTB may enhance or shield miRNA target sites in adjacent regions, thus affecting RNA stability in both directions. This was confirmed by AGO2-CLIP seq in the presence or absence of PTB (Xue et al., 2013).

HUR, a member of the ELAVL protein family possesses three RNA-binding domains (Ma, Cheng, Campbell, Wright, & Furneaux, 1996) and has been implicated in the regulation of stability and translation of over one hundred mRNAs in mammalian cells (Abdelmohsen et al., 2007; Brennan & Steitz, 2001; Cherry et al., 2006; Meisner et al., 2004). Binding of HUR may suppress the inhibitory effect of miRNAs interacting with regulatory regions such as the 3′UTR and instead help to lift repression by facilitating mRNA association with polysomes for active translation (Meisner & Filipowicz, 2010).

Pumilio proteins PUM1 and PUM2 also regulate miRNA-dependent gene silencing. PUM2 induces a conformational switch in the 3′ UTR region of p27 mRNA, which leads to miRNA-mediated repression of this cell-cycle regulator in rapidly proliferating cells through miR-121 and 122 (Kedde et al., 2010). PUM1 and PUM2 have also been shown to bind the 3′ UTR of E2F protein 3 (E2F3) and enhance the activity miRNAs targeting E2F3 (Miles, Tschop, Herr, Ji, & Dyson, 2012).

Dead end 1 (DND1) is found in germ cells and functions as a negative regulator of miRNA-induced silencing (Kedde et al., 2007; Kouwenhove, Kedde, & Agami, 2011). It binds to uridine-rich regions in the 3′UTR through its N-terminal RNA-binding domain and blocks AGO2 association by either physically associating with an mRNA to block AGO2 or by displacing AGO2 to relieve translational suppression.

FUS is a dual DNA/RNA binding protein linked to amyotrophic lateral sclerosis (ALS). FUS was recently shown to associate with miRISC components AGO2, miRNAs and their target transcripts (Zhang et al., 2018). FUS and AGO2 bind approximately 85% of the same mRNA targets and both are localized to approximately the same locations in the 3′ UTR (Zhang et al., 2018).

Coding region determinant-binding protein (CRD-BP) is an RRM and KH-domain-containing RNA-binding protein primarily expressed in fetal tissues and primary tumors (Ioannidis et al., 2003). CRD-BP binds to the 5′UTR of the c-Myc mRNA, and protects it from repression (Noubissi et al., 2006). It also binds in the coding region of βTrCP1 mRNA and protects it from miR-183-induced degradation (Elcheva, Goswami, Noubissi, & Spiegelman, 2009; Noubissi et al., 2006). Regulation of c-Myc and βTrCP1 mRNA by CDB-BP is induced in response to β-catenin signaling (Noubissi et al., 2006). Dysregulation in CDB-BP levels leads to changes in c-Myc expression, which is widely considered a factor for the development of 75% of primary tumors (Ioannidis et al., 2003).

In summary, RBPs are important for and can facilitate AGO2-mediated regulation. RBPs that block AGO2 function may do so through one of three possible ways: (1) RBP binding to the MRE directly competes with miRNA binding to that same site; (2) RBPs may bind in proximity to the MRE in such a way that alters the mRNA structure to either facilitate or decrease access to the MRE; (3) the RBP may directly interact with AGO2 to either recruit AGO2 to the MRE or to prevent AGO2 association with the MRE.

Role of miRNAs in Nervous System Development

The first miRNA found to directly regulate dendritic spine morphology was miR-134 (Schratt et al., 2006). Overexpression of miR-134 in rat hippocampal neurons reduces the size of dendritic spines by mediating the translational suppression of Lim-domain containing protein kinase 1 (LIMK1) at the synapse (Bicker & Schratt, 2008; Schratt et al., 2006). Translational suppression of LIMK1 could be relieved by addition of brain derived neurotrophic factor (BDNF). miR-134 also regulates synaptic plasticity when overexpressed in mouse hippocampus, impairing long-term potentiation (LTP) and long-term memory formation in a contextual-fear conditioning paradigm (Gao et al., 2010).

Another miRNA of high importance in neurons is miR-132, which is a positive regulator of dendritic outgrowth that has been shown both in vitro and in vivo to translationally suppress Rho GTPase activating protein p250GAP (Vo et al., 2005). miR-132 also decreases spine density upon overexpression (Cheng et al., 2007; Hotulainen & Hoogenraad, 2010; Vo et al., 2005; Wayman et al., 2008). A different miRNA, miR-125b yields a similar phenotype consisting of long and thin spines upon overexpression. Importantly, both miR-132 and miR-125b interact with FMRP—probably in a complex that includes AGO2 (Lee et al., 2010), as there is no evidence to date that FMRP directly binds miRNAs. Upon short-hairpin RNA (shRNA)–mediated knockdown of FMRP, the spine phenotype is reversed (Edbauer et al., 2010).

FMRP, through its association with molecular motors as part of an RNP, mediates axonal delivery of miR-181d (Wang et al., 2015). Specifically, this study demonstrates that FMRP is required to transport the Map1b mRNA into the axon from the cell body. Loss of FMRP expression results in decreased protein levels of MAP1B in the axons, but not in the cell bodies, thus supporting FMRP’s role in mRNA localization and subsequent translation regulation. During the long distance axonal delivery of RNPs, FMRP is proposed to have dual roles wherein it anchors Map1b and Calm1 to cytoskeletal motors and functions in miR-181d-mediated RISC assembly to repress gene translation. Upon stimulation with NGF (Nerve Growth Factor), Map1b and Calm1 are released from FMRP granules and made available for local translation. The authors hypothesize that the NGF stimulation leads to reorganization of the granule to mediate this effect. There is precedent for translation repression by miRNAs without immediate degradation (Béthune et al., 2012). This would be particularly important in neurons where localized translation occurs in response to stimulation, requiring that target mRNAs are repressed translationally without major mRNA decay (Bhattacharyya, Habermacher, Martine, Closs, & Filipowicz, 2006; Muddashetty et al., 2011; Schratt et al., 2006).

Control of mRNA Localization for Proper Neuronal Protein Synthesis

Some mRNAs are specifically enriched at the synapse, dendrites or in the distal axon. A number of studies have yielded important insights into how mRNAs are targeted to the synapse for local translation regulation (Cohen, Lee, Chen, Li, & Fields, 2011; Corbin, Olsson-Carter, & Slack, 2009; Fu, Shah, & Baraban, 2016; Kiebler & Bassell, 2006; Liegro, Schiera, & Liegro, 2014; Mahmoudi & Cairns, 2016; Schratt, 2011; Wang, Martin, & Zukin, 2010; Ye, Xu, Su, & He, 2016). While the majority of mRNA translation in neurons takes place in the cell body, a subset of mRNAs upon being exported from the nucleus are coated with RNA binding proteins to form RNPs which are packaged into RNP granules. Neuronal granules typically consist of one mRNA and a large composition of RNA binding proteins (Batish, Bogaard, Kramer, & Tyagi, 2012). mRNAs in neurons are packaged into granules to transport them to sites of local protein translation (Krichevsky & Kosik, 2001). Granules are trafficked along microtubule and actin filament tracks via motor proteins to distinct localizations both in axons and along dendrites (Hirokawa, Niwa, & Tanaka, 2010). During travel, the neuronal granules contain translationally silent mRNAs. To achieve translational suppression during transport, associated RNA binding proteins contact the mRNA, essentially preventing it from associating with pro-translation factors that are located within the same RNP. In addition, RNA granules are not translationally competent because they do not include eIF4E, 4G and tRNAs (Krichevsky & Kosik, 2001).

Once an RNP has reached its target destination, translation initiation factors such as eIF4E and eIF2A promote assembly of polysomes on the mRNA (Krichevsky & Kosik, 2001; Smart, Edelman, & Vanderklish, 2003). RNA-binding proteins such as STAUFEN and FMRP have been shown to stall polysomes on a given mRNA (Darnell et al., 2011; Thomas, Tosar, Desbats, Leishman, & Boccaccio, 2009) and the RISC complex itself can also associate with polysomes and lead to ribosomal pausing (Maroney, Yu, Fisher, & Nilsen, 2006; Nottrodd et al., 2006; Petersen, Bordeleau, Pelletier, & Sharp, 2006). The first study describing miRNAs and their regulatory role showed that they were on polysomes (Lee et al., 1993). Barman and Bhattacharyya showed that mRNAs are recruited to the ER membrane where they are translated and then AGO2/miRNA is recruited for repression and degradation (Barman & Bhattacharyya, 2015). Although there is evidence that miRNAs block elongation (Petersen et al., 2006), including in the first description of small RNA-mediated translation regulation (Lee et al., 1993), in the majority of cases, miRNAs seem to block translation at initiation through AGO2 association with GW182, which binds eukaryotic initiation factors (Gu & Kay, 2010).

Cis-sequences within the mRNA itself may direct its transport such as with the β-actin mRNA which expresses a “zipcode” in its 3′ UTR that is recognized by the KH domains of the RNA binding protein zipcode binding protein 1 (ZBP1), allowing it to be translocated to specific regions within the cell (Driesche & Martin, 2018; Jambhekar & Derisi, 2007; Kindler, Wang, Richter, & Tiedge, 2005). When β-actin transcripts reach the periphery of the cell, Src-dependent phosphorylation of ZBP1 releases the mRNA and allows the synthesis of β-actin protein (Huttelmaier et al., 2005).

FMRP is also crucial for the proper localization of mRNA cargo to various regions along the axon and dendrites of neurons by binding to cis-factors within its target mRNAs. Intramolecular G-quadruplexes (GQs) have been implicated in mRNA targeting (Subramanian et al., 2011). FMRP binds to RNA in vitro with high affinity to kissing complex RNA secondary structure and GQs through its KH2 and RGG-binding domains, respectively (Darnell et al., 2005; Menon, Mader, & Mihailescu, 2008). GQs in mRNAs seem to be involved with the assembly of the FMRP/MOV10 complex that blocks AGO2 association (Kenny et al., 2014) and importantly all of these components such as FMRP and MOV10 are in found in neuronal granules (Fritzsche et al., 2013; Kiebler & Bassell, 2006). FMRP also has a protein-protein interaction with kinesin motors within neurons, and it serves as a linker between the motor proteins along the dendrites and the RNP carrying the mRNA cargo itself, along with other RNA regulatory factors (Davidovic et al., 2007; Dictenberg, Antar, Singer, & Bassell, 2008; Ling, Fahrner, Greenough, & Gelfand, 2004).

Activity-Dependent Translation Regulation in the Nervous System

Local regulation of miRNAs at the synapse is believed to depend on whether the synapse is undergoing chemical or electrical stimulation. DICER generates the final functional miRNA from pre-miRNAs and can be dendritically and synaptically localized (Bicker et al., 2013; Mikl, Vendra, Doyle, & Kiebler, 2010), suggesting a mechanism in place for rapid control of miRNA synthesis upon signal stimulation. An example is when miRNA biogenesis factor DICER is upregulated in dendrites upon synaptic stimulation leading to an increase in miRNA production and the eventual local regulation of CamKII (Sambandan et al., 2017).

In the unstimulated state, synaptically localized miRNA is associated with AGO2. AGO2-mediated regulation has been particularly well studied in the synaptically localized translation of PSD-95 (Miyoshi, Okada, Siomi, & Siomi, 2009; Muddashetty et al., 2011; Okamura, 2004; Pratt & Macrae, 2009) and involves the rapid phosphorylation and dephosphorylation of FMRP. Dephosphorylation of FMRP leads to the release of AGO2 upon group 1 metabotropic glutamate receptor (mGluR) stimulation, thus, leading to the release of suppression of the cobound PSD-95 mRNA. There is also evidence that stimulation of the NDMA receptor leads to ubiquitination of MOV10, which leads to degradation, releasing its bound mRNAs for translation (Banerjee et al., 2009; Fu et al., 2016).

Interestingly, the FMR1 mRNA is itself dendritically localized and its translation regulated by group 1 mGluR signaling (Bassell & Warren, 2008). Stimulation of the group 1 mGluRs leads to a transient increase in FMRP followed by its rapid degradation by the ubiquitin proteasome pathway and release of mRNAs for translation (Figure 2; Hou et al., 2006).

FMRP blocks translation through ribosome stalling, which takes place during the elongation phase (Ceman et al., 2003; Darnell et al., 2011). FMRP blocks mRNA translation by binding to the translation machinery itself (Chen, Sharma, Shi, Agrawal, & Joseph, 2014). Upon receipt of a signal, ribosome stalling can be relieved—perhaps by dephosphorylation of FMRP (Ceman et al., 2003; Narayanan et al., 2007), and local protein translation can take place. Moreover, it is hypothesized that the presence of stalled ribosomes on a given mRNA during the transport process may actually decrease the likelihood of the mRNA being degraded as it is essentially being protected by the presence of the ribosomes.


Local protein translation is required for learning and memory by altering the synapse after stimulation. RNA binding proteins like FMRP dynamically control protein translation by facilitating mRNA localization, by being locally translated and degraded by stimulation and finally by modulating mRNA stability and translation through the miRNA pathway.

Future Directions

  1. 1. What is the identity of individual proteins that form a complex on an MRE?

  2. 2. What is the identity of cis sequences and/or the secondary structures in the mRNA that recruit RBPs in proximity to MREs?

  3. 3. How is assembly of the RBP complex on the MRE regulated?

  4. 4. Which post-translational modifications regulate assembly and disassembly of this complex?

  5. 5. How are the enzymes that mediate the post-translational modifications regulated?

  6. 6. How is the RNP assembled in the nucleus and cell body that is ultimately targeted to the dendritic spines?

  7. 7. How are activated spines “tagged” or recognized by transport granules?

  8. 8. How do activated synapses communicate with the cell body and nucleus?


Grants NIH/NIMH MH093661 (to SC) and Kiwanis Neuroscience Research Foundation (to SC)


Abdelmohsen, K., Pullman, R., Lal, A., Kim, H. H., Galban, S., Yang, X., Blethrow, J. D., … Gorospe, M. (2007). Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Molecular Cell, 23(25), 543–557.Find this resource:

Ascano, M., Mukherjee, N., Bandaru, P., Miller, J. B., Nusbaum, J. D., Corcoran, D. L., & Tuschl, T. (2012). FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature, 492(7429), 382–386.Find this resource:

Ashley, C., Wilkinson, K., Reines, D., & Warren, S. (1993). FMR1 protein: Conserved RNP family domains and selective RNA binding. Science, 262(5133), 563–566.Find this resource:

Bagga, S., Bracht, J., Hunter, S., Massirer, K., Holtz, J., Eachus, R., & Pasquinelli, A. E. (2005). Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation. Cell, 122(4), 553–563.Find this resource:

Banerjee, S., Neveu, P., & Kosik, K. S. (2009). A coordinated local translational control point at the synapse involving relief from silencing and MOV10 degradation. Neuron, 64(6), 871–884.Find this resource:

Barbee, S. A., Estes, P. S., Cziko, A., Hillebrand, J., Luedeman, R. A., Coller, J. M., & Ramaswami, M. (2006). Staufen- and FMRP-containing neuronal RNPs are structurally and functionally related to somatic p bodies. Neuron, 52(6), 997–1009.Find this resource:

Barman, B., & Bhattacharyya, S. N. (2015). MRNA targeting to endoplasmic reticulum precedes ago protein interaction and microRNA (miRNA)-mediated translation repression in mammalian cells. Journal of Biological Chemistry, 290(41), 24650–24656.Find this resource:

Bartel, D. P. (2009). MicroRNAs: Target recognition and regulatory functions. Cell, 136(2), 215–233.Find this resource:

Bassell, G. J., & Warren, S. T. (2008). Fragile X syndrome: Loss of local mRNA regulation alters synaptic development and function. Neuron, 60(2), 201–214.Find this resource:

Batish, M., Bogaard, P. V., Kramer, F. R., & Tyagi, S. (2012). Neuronal mRNAs travel singly into dendrites. Proceedings of the National Academy of Sciences, 109(12), 4645–4650.Find this resource:

Beckmann, B. M., Horos, R., Fischer, B., Castello, A., Eichelbaum, K., Alleaume, A. M., …. Hentze, M. W. (2015). The RNA-binding proteomes from yeast to man harbor conserved enigmRBPs. Nature Communications, 3(6), 10127.Find this resource:

Béthune, J., Artus-Revel, C. G., & Filipowicz, W. (2012). Kinetic analysis reveals successive steps leading to miRNA-mediated silencing in mammalian cells. EMBO Reports, 13(8), 716–723.Find this resource:

Bhattacharyya, S. N., Habermacher, R., Martine, U., Closs, E. I., & Filipowicz, W. (2006). Relief of microRNA-mediated translational repression in human cells subjected to stress. Cell, 125(6), 1111–1124.Find this resource:

Bicker, S., Khudayberdiev, S., Weiss, K., Zocher, K., Baumeister, S., & Schratt, G. (2013). The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134. Genes & Development, 27(9), 991–996.Find this resource:

Bicker, S., & Schratt, G. (2008). MicroRNAs: Tiny regulators of synapse function in development and disease. Journal of Cellular and Molecular Medicine, 12(5a), 1466–1476.Find this resource:

Black, D. L. (2003). Mechanisms of Alternative Pre-Messenger RNA Splicing. Annual Review of Biochemistry, 72, 291–336.Find this resource:

Bolduc, F. V., Bell, K., Cox, H., Broadie, K. S., & Tully, T. (2008). Excess protein synthesis in Drosophila fragile X mutants impairs long-term memory. Nature Neuroscience, 11(10), 1143–1145.Find this resource:

Boutz, P. L., Stoilov, P., Li, Q., Lin, C., Chawla, G., Ostrow, K., & Black, D. L. (2007). A post-transcriptional regulatory switch in polypyrimidine tract-binding proteins reprograms alternative splicing in developing neurons. Genes & Development, 21(13), 1636–1652.Find this resource:

Bramhan, C. R., & Wells, D. G. (2010). Dendritic mRNA: Transport, translation and function. Nature Reviews Neuroscience, 8(10), 776–789.Find this resource:

Brennan, C. M., & Steitz, J. A. (2001). HuR and mRNA stability. Cellular and Molecular Life Sciences, 58(2), 266–277.Find this resource:

Brodersen, P., & Voinnet, O. (2009). Revisiting the principles of microRNA target recognition and mode of action. Nature Reviews Molecular Cell Biology, 10(2), 141–148.Find this resource:

Brown, V., Jin, P., Ceman, S., Darnell, J. C., Odonnell, W. T., Tenenbaum, S. A., & Warren, S. T. (2001). Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell, 107(4), 477–487.Find this resource:

Brummer A., & Hausser, J. (2014). MicroRNA binding sites in the coding region of mRNAs: Extending the repertoire of post-transcriptional gene regulation. Bioessays, 36(6), 617–626.Find this resource:

Caudy, A. A. (2002). Fragile X-related protein and VIG associate with the RNA interference machinery. Genes & Development, 16(19), 2491–2496.Find this resource:

Ceman, S., Odonnell, W. T., Reed, M., Patton, S., Pohl, J., & Warren, S. T. (2003). Phosphorylation influences the translation state of FMRP-associated polyribosomes. Human Molecular Genetics, 12(24), 3295–3305.Find this resource:

Chen, E., Sharma, M., Shi, X., Agrawal, R., & Joseph, S. (2014). Fragile X mental retardation protein regulates translation by binding directly to the ribosome. Molecular Cell, 54(3), 407–417.Find this resource:

Chendrimada, T. P., Gregory, R. I., Kumaraswamy, E., Norman, J., Cooch, N., Nishikura, K., & Shiekhattar, R. (2005). TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature, 436(7051), 740–744.Find this resource:

Cheng, H. M., Papp, J. W., Varlamova, O., Dziema, H., Russell, B., Curfman, J. P., & Obrietan, K. (2007). MicroRNA modulation of circadian-clock period and entrainment. Neuron, 54(5), 813–829.Find this resource:

Cherry, S., Kunte, A., Wang, H., Coyne, C., Rawson, R. B., & Perrimon, N. (2006). COPI activity coupled with fatty acid biosynthesis is required for viral replication. PLoS Pathogens, 2(10), e102.Find this resource:

Cohen, J. E., Lee, P. R., Chen, S., Li, W., & Fields, R. D. (2011). MicroRNA regulation of homeostatic synaptic plasticity. Proceedings of the National Academy of Sciences, 108(28), 11650–11655.Find this resource:

Collins, L. J., & Penny, D. (2009). The RNA infrastructure: Dark matter of the eukaryotic cell? Trends in Genetics, 25(3), 120–128.Find this resource:

Connerty, P., Ahadi, A., & Hutvagner, G. (2015). RNA binding proteins in the miRNA pathway. International Journal of Molecular Sciences, 17(1), pii: E31.Find this resource:

Corbin, R., Olsson-Carter, K., & Slack, F. (2009). The role of microRNAs in synaptic development and function. BMB Reports, 42(3), 131–135.Find this resource:

Coyne, A. N., Yamada, S. B., Siddegowda, B. B., Estes, P. S., Zaepfel, B. L., Johannesmeyer, J. S., & Zarnescu, D. C. (2015). Fragile X protein mitigates TDP-43 toxicity by remodeling RNA granules and restoring translation. Human Molecular Genetics, 24(24), 6886–6898.Find this resource:

Darnell, J. C., Fraser, E. C., Mostovetsky, O., Stefani, G., Jones, T. A., Eddy, S. R., & Darnell, R. B. (2005). Kissing complex RNAs mediate interaction between the Fragile-X mental retardation protein KH2 domain and brain polyribosomes. Genes & Development, 19(8), 903–918.Find this resource:

Darnell, J. C., Jensen, K. B., Jin, P., Brown, V., Warren, S. T., & Darnell, R. B. (2001). Fragile X mental retardation protein targets g quartet mRNAs important for neuronal function. Cell, 107(4), 489–499.Find this resource:

Darnell, J., Van Driesche, S., Zhang, C., Hung, K., Mele, A., Fraser, C., & Darnell, R. (2011). FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell, 146(2), 247–261.Find this resource:

Davidovic, L., Jaglin, X. H., Lepagnol-Bestel, A., Tremblay, S., Simonneau, M., Bardoni, B., & Khandjian, E. W. (2007). The fragile X mental retardation protein is a molecular adaptor between the neurospecific KIF3C kinesin and dendritic RNA granules. Human Molecular Genetics, 16(24), 3047–3058.Find this resource:

Denli, A. M., Tops, B. B., Plasterk, R. H., Ketting, R. F., & Hannon, G. J. (2004). Processing of primary microRNAs by the Microprocessor complex. Nature, 432(7014), 231–235.Find this resource:

Devys, D., Lutz, Y., Rouyer, N., Bellocq, J., & Mandel, J. (1993). The FMR–1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature Genetics, 4(4), 335–340.Find this resource:

Dictenberg, J., Antar, L., Singer, R., & Bassell, G. (2008). A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. International Journal of Developmental Neuroscience, 26(8), 831.Find this resource:

Driesche, S. J., & Martin, K. C. (2018). New frontiers in RNA transport and local translation in neurons. Developmental Neurobiology, 78(3), 331–339.Find this resource:

Edbauer, D., Neilson, J. R., Foster, K. A., Wang, C., Seeburg, D. P., Batterton, M. N., & Sheng, M. (2010). Regulation of synaptic structure and function by FMRP-Associated MicroRNAs miR-125b and miR-132. Neuron, 65(3), 373–384.Find this resource:

Elcheva, I., Goswami, S., Noubissi, F. K., & Spiegelman, V. S. (2009). CRD-BP protects the coding region of βTrCP1 mRNA from miR-183-mediated degradation. Molecular Cell, 35(2), 240–246.Find this resource:

El-Shami, M., Pontier, D., Lahmy, S., Braun, L., Picart, C., Vega, D., & Lagrange, T. (2007). Reiterated WG/GW motifs form functionally and evolutionarily conserved ARGONAUTE-binding platforms in RNAi-related components. Genes & Development, 21(20), 2539–2544.Find this resource:

Fan, P., Chen, Z., Tian, P., Liu, W., Jiao, Y., Xue, Y., & Yue, J. (2013). MiRNA biogenesis enzyme drosha is required for vascular smooth muscle cell survival. PLoS One, 8(4), e60888.Find this resource:

Fang, Z., & Rajewsky, N. (2011). The impact of miRNA target sites in coding sequences and in 3′UTRs. PLoS One, 6(3), e18067.Find this resource:

Feng, Y., Gutekunst, C. A., Eberhart, D. E., Yi, H., Warren, S. T., & Hersch, S. M. (1997). Fragile X mental retardation protein: Nucleocytoplasmic shuttling and association with somatodendritic ribosomes. Journal of Neuroscience, 17(5),1539–1547.Find this resource:

Filipowicz, W., Bhattacharyya, S. N., & Sonenberg, N. (2008). Mechanisms of post-transcriptional regulation by microRNAs: Are the answers in sight? Nature Reviews Genetics, 9(2), 102–114.Find this resource:

Flexner, J. B., Flexner, L. B., Stellar, E., De La Haba, G., & Roberts, R. B. 1962. Inhibition of protein synthesis in brain and learning and memory following puromycin. Journal of Neurochemistry, 9, 595–605.Find this resource:

Flexner, L. B., Flexner, J. B., & Stellar, E. 1963. Memory in mice as affected by intracerebral puromycin. Science, 141(3575), 57–59.Find this resource:

Friedman, R. C., Farh, K. K., Burge, C. B., & Bartel, D. P. (2008). Most mammalian mRNAs are conserved targets of microRNAs. Genome Research, 19(1), 92–105.Find this resource:

Fritzsche, R., Karra, D., Bennett, K., Ang, F., Heraud-Farlow, J., Tolino, M., & Kiebler, M. (2013). Interactome of two diverse RNA granules links mRNA localization to translational repression in neurons. Cell Reports, 5(6), 1749–1762.Find this resource:

Fu, X., Shah, A., & Baraban, J. M. (2016). Rapid reversal of translational silencing: Emerging role of microRNA degradation pathways in neuronal plasticity. Neurobiology of Learning and Memory, 133, 225–232.Find this resource:

Fusco, D., Accornero, N., Lavoie, B., Shenoy, S. M., Blanchard, J., Singer, R. H., & Bertrand, E. (2003). Single mRNA molecules demonstrate probabilistic movement in living mammalian cells. Current Biology, 13(2), 161–167.Find this resource:

Gao, J., Wang, W., Mao, Y., Gräff, J., Guan, J., Pan, L., & Tsai, L. (2010). A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature, 466(7310), 1105–1109.Find this resource:

Gerstberger, S., Hafner, M., Ascano, M., & Tuschl, T. (2014). Evolutionary conservation and expression of human RNA-binding proteins and their role in human genetic disease. Systems Biology of RNA Binding Proteins, 825, 1–55.Find this resource:

Gibbings, D. J., Ciaudo, C., Erhardt, M., & Voinnet, O. (2009). Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nature Cell Biology, 11(9), 1143–1149.Find this resource:

Glisovic, T., Bachorik, J. L., Yong, J., & Dreyfuss, G. (2008). RNA-binding proteins and post-transcriptional gene regulation. FEBS Letters, 582(14), 1977–1986.Find this resource:

Golden, R. J., Chen, B., Li, T., Braun, J., Manjunath, H., Chen, X., & Mendell, J. T. (2017). An Argonaute phosphorylation cycle promotes microRNA-mediated silencing. Nature, 542(7640), 197–202.Find this resource:

Goodier, J. L., Cheung, L. E., & Kazazian, H. H. (2012). MOV10 RNA Helicase is a potent inhibitor of retrotransposition in cells. PLoS Genetics, 8(10), e100294.Find this resource:

Gregersen, L., Schueler, M., Munschauer, M., Mastrobuoni, G., Chen, W., Kempa, S., & Landthaler, M. (2014). MOV10 Is a 5′ to 3′ RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3′ UTRs. Molecular Cell, 54(4), 573–585.Find this resource:

Gregory, R. I., Yan, K., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N., & Shiekhattar, R. (2004). The microprocessor complex mediates the genesis of microRNAs. Nature, 432(7014), 235–240.Find this resource:

Gu, S., & Kay, M. A. (2010). How do miRNAs mediate translational repression? Silence, 1(1), 11.Find this resource:

Gulyaeva, L. F., & Kushlinskiy, N. E. (2016). Regulatory mechanisms of microRNA expression. Journal of Translational Medicine, 14(1), 143.Find this resource:

Han, J. (2004). The Drosha-DGCR8 complex in primary microRNA processing. Genes & Development, 18(24), 3016–3027.Find this resource:

Hebert, S. S., Papadopoulou, A. S., Smith, P., Galas, M. C., Planel, E., Silahtaroglu, A. N., … De Strooper, B. (2010). Genetic ablation of Dicer in adult forebrain neurons results in abnormal tau hyperphosphorylation and neurodegeneration. Human Molecular Genetics, 19(20), 3959–3969.Find this resource:

Hirokawa, N., Niwa, S., & Tanaka, Y. (2010). Molecular motors in neurons: Transport mechanisms and roles in brain function, development, and disease. Neuron, 68(4), 610–638.Find this resource:

Hotulainen, P., & Hoogenraad, C. C. (2010). Actin in dendritic spines: Connecting dynamics to function. The Journal of Cell Biology, 189(4), 619–629.Find this resource:

Hou, L., Antion, M. D., Hu, D., Spencer, C. M., Paylor, R., & Klann, E. (2006). Dynamic translational and proteasomal regulation of fragile x mental retardation protein controls mGluR-dependent long-term depression. Neuron, 51(4), 441–454.Find this resource:

Huttelmaier, S., Zenklusen, D., Lederer, M., Dictenberg, J., Lorenz, M., Meng, X., … Singer, R. H. (2005). Spatial regulation of beta-actin translation by Src-dependent phosphorylation of ZBP1. Nature, 438(7067), 512–515.Find this resource:

Hutvagner, G. (2002). A microRNA in a multiple-turnover RNAi enzyme complex. Science, 297(5589), 2056–2060.Find this resource:

Ioannidis, P., Mahaira, L., Papadopoulou, A., Teixeira, M. R., Heim, S., Andersen, J. A. Evangelou, E., … Trangas, T. (2003). CDB-BP: A c-Myc mRNA stabilizing protein with an oncofetal pattern of expression. Anticancer Research, 23(3A), 2179–2183.Find this resource:

Ishizuka, A. (2002). A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes & Development, 16(19), 2497–2508.Find this resource:

Jambhekar, A., & Derisi, J. L. (2007). Cis-acting determinnants of asymmetric, cytoplasmic RNA transport. RNA, 13(5), 625–642.Find this resource:

Jee, D., & Lai, E. C. (2014). Alteration of miRNA activity via context-specific modifications of Argonaute proteins. Trends in Cell Biology, 24(9), 546–553.Find this resource:

Jin, P., Zarnescu, D. C., Ceman, S., Nakamoto, M., Mowrey, J., Jongens, T. A., & Warren, S. T. (2004). Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neuroscience, 7(2), 113–117.Find this resource:

Kebaara, B. W., & Atkin, A. L. (2009). Long 3’-UTRs target wild-type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae. Nucleic Acids Research, 37(9), 2771–2778.Find this resource:

Kedde, M., Kouwenhove, M. V., Zwart, W., Vrielink, J. A., Elkon, R., & Agami, R. (2010). A Pumilio-induced RNA structure switch in p27-3′ UTR controls miR-221 and miR-222 accessibility. Nature Cell Biology, 12(10), 1014–1020.Find this resource:

Kedde, M., Strasser, M. J., Boldajipour, B., Vrielink, J. A., Slanchev, K., Sage, C. L., & Agami, R. (2007). RNA-binding protein Dnd1 inhibits MicroRNA access to target mRNA. Cell, 131(7), 1273–1286.Find this resource:

Keene, J. D. (2007). RNA regulons: Coordination of post-transcriptional events. Nature Reviews Genetics, 8(7), 533–543.Find this resource:

Kelleher, R. J., & Bear, M. F. (2008). The autistic neuron: Troubled translation? Cell, 135(3), 401–406.Find this resource:

Kenny, P., & Ceman, S. (2016). RNA secondary structure modulates FMRP’s bi-functional role in the MicroRNA pathway. International Journal of Molecular Sciences, 17(12), 985.Find this resource:

Kenny, P., Zhou, H., Kim, M., Skariah, G., Khetani, R., Drnevich, J., & Ceman, S. (2014). MOV10 and FMRP regulate AGO2 association with microrna recognition elements. Cell Reports, 9(5), 1729–1741.Find this resource:

Kiebler, M. A., & Bassell, G. J. (2006). Neuronal RNA granules: Movers and makers. Neuron, 51(6), 685–690.Find this resource:

Kim, M, Bellini, M., & Ceman S. (2009). Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. Molecular and Cellular Biology, 29(1), 214–228.Find this resource:

Kindler, S., Wang, H., Richter, D., & Tiedge, H. (2005). RNA transport and local control of translation. Annual Review of Cell and Developmental Biology, 21, 223–245.Find this resource:

Korb, E., & Finkbeiner, S. (2011). Arc in synaptic plasticity: From gene to behavior. Trends in Neurosciences, 34(11), 591–598.Find this resource:

Kouwenhove, M. V., Kedde, M., & Agami, R. (2011). MicroRNA regulation by RNA-binding proteins and its implications for cancer. Nature Reviews Cancer, 11(9), 644–656.Find this resource:

Krichevsky, A. M., & Kosik, K. M. (2001). Neuronal RNA granules: A link between RNA localization and stimulation-dependent translation. Neuron 32(4), 693–696.Find this resource:

Krill, K. T., Gurdziel, K., Heaton, J. H., Simon, D. P., & Hammer, G. D. (2013). Dicer deficiency reveals microRNAs predicted to control gene expression in the developing adrenal cortex. Molecular Endocrinology, 27(5), 754–768.Find this resource:

Lee, E. K., Kim, H. J., Kuwano, Y., Abdelmohsen, K., Srikantan, S., Subaran, S. S., … Gorospe, M. (2010). hnRNP C promotes APP translation by competing with FMRP for APP mRNA recruitment to P bodies. Nature Structural & Molecular Biology, 17(6): 732–739.Find this resource:

Lee, R. C., Feinbaum, R. L., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell, 75(5), 843–854.Find this resource:

Lee, Y. (2002). MicroRNA maturation: Stepwise processing and subcellular localization. The EMBO Journal, 21(17), 4663–4670.Find this resource:

Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., & Kim, V. N. (2003). The nuclear RNase III Drosha initiates microRNA processing. Nature, 425(6956), 415–419.Find this resource:

Lee, Y., Hur, I., Park, S., Kim, Y., Suh, M. R., & Kim, V. N. (2006). The role of PACT in the RNA silencing pathway. The EMBO Journal, 25(3), 522–532.Find this resource:

Li, Y., Tang, W., Zhang, L.-R., & Zhang, C.-Y. (2014). FMRP regulates miR196a-mediated repression of HOXB8 via interaction with the AGO2 MID domain. Molecular BioSystems 10(7), 1757–1764.Find this resource:

Liegro, C. M., Schiera, G., & Liegro, I. D. (2014). Regulation of mRNA transport, localization and translation in the nervous system of mammals (Review). International Journal of Molecular Medicine, 33(4), 747–762.Find this resource:

Ling, S., Fahrner, P. S., Greenough, W. T., & Gelfand, V. I. (2004). Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein. Proceedings of the National Academy of Sciences, 101(50), 17428–17433.Find this resource:

Liu, J. (2004). Argonaute2 is the catalytic engine of mammalian RNAi. Science, 305(5689), 1437–1441.Find this resource:

Liu-Yesucevitz, L., Bassell, G. J., Gitler, A. D., Hart, A. C., Klann, E., Richter, J. D., & Wolozin, B. (2011). Local RNA translation at the synapse and in disease. Journal of Neuroscience, 31(45), 16086–16093.Find this resource:

Loffreda, A., Rigamonti, A., Barabino, S., & Lenzken, S. (2015). RNA-binding proteins in the regulation of miRNA activity: A focus on neuronal functions. Biomolecules, 5(4), 2363–2387.Find this resource:

Ma, W., Cheng, S., Campbell, C., Wright, A., & Furneaux, H. (1996). Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. Journal of Biological Chemistry, 271(14), 8144–8151.Find this resource:

Mahmoudi, E., & Cairns, M. J. (2016). MiR-137: An important player in neural development and neoplastic transformation. Molecular Psychiatry, 22(1), 44–55.Find this resource:

Makeyev, E. V., Zhang, J., Carrasco, M. A., & Maniatis, T. (2007). The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Molecular Cell, 27(3), 435–448.Find this resource:

Maroney, P. A., Yu, Y., Fisher, J., & Nilsen, T. W. (2006). Evidence that microRNAs are associated with translating messenger RNAs in human cells. Nature Structural & Molecular Biology, 13(12), 1102–1107.Find this resource:

Mata, J., Marguerat, S., & Bähler, J. (2005). Post-transcriptional control of gene expression: A genome-wide perspective. Trends in Biochemical Sciences, 30(9), 506–514.Find this resource:

Meisner, N., & Filipowicz, W. (2010). Properties of the regulatory RNA-binding protein HuR and its role in controlling miRNA repression. Advances in Experimental Medicine and Biology Regulation of MicroRNAs, 700, 106–123. (Abstract)Find this resource:

Meisner, N. C., Hackermuller, J., Uhl, V., Aszodi, A., Jaritz, M., & Auer, M. (2004). mRNA openers and closers: Modulating AU-rich element-controlled mRNA stability by a molecular switch in mRNA secondary structure. Chembiochem, 5(10), 1432–1447.Find this resource:

Meister, G., Landthaler, M., Peters, L., Chen, P. Y., Urlaub, H., Luhrmann, R., & Tuschl, T. (2005). Identification of novel argonautre-associated proteins. Current Biology, 15(23), 2149–2155.Find this resource:

Meister, G., & Tuschl, T. (2004). Mechanisms of gene silencing by double-stranded RNA. Nature, 431(7006), 343–349.Find this resource:

Menon, L., Mader, S. A., & Mihailescu, M. (2008). Fragile X mental retardation protein interactions with the microtubule associated protein 1B RNA. RNA, 14(8), 1644–1655.Find this resource:

Messaoudi-Aubert, S. E., Nicholls, J., Maertens, G. N., Brookes, S., Bernstein, E., & Peters, G. (2010). Role for the MOV10 RNA helicase in Polycomb-mediated repression of the INK4a tumor suppressor. Nature Structural & Molecular Biology, 17(7), 862–868.Find this resource:

Mikl, M., Vendra, G., Doyle, M., & Kiebler, M. A. (2010). RNA localization in neurite morphogenesis and synaptic regulation: Current evidence and novel approaches. Journal of Comparative Physiology A, 196(5), 321–334.Find this resource:

Miles, W. O., Tschop, K., Herr, A., Ji, J., & Dyson, N. J. (2012). Pumilio facilitates miRNA regulation of the E2F3 oncogene. Genes & Development, 26(4), 356–368.Find this resource:

Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T., Becker, K. G., Barret, T., Liu, L., & Eberwine, J. (2003). RNA cargoes associating with FMRP Reveal deficits in cellular functioning in Fmr1 null mice. Neuron, 37(3), 417–431.Find this resource:

Miyoshi, K., Okada, T. N., Siomi, H., & Siomi, M. C. (2009). Characterization of the miRNA-RISC loading complex and miRNA-RISC formed in the Drosophila miRNA pathway. RNA, 15(7), 1282–1291.Find this resource:

Morita, S., Horii, T., Kimura, M., Goto, Y., Ochiya, T., & Hatada, I. (2007). One Argonaute family member, Eif2c2 (Ago2), is essential for development and appears not to be involved in DNA methylation. Genomics, 89(6), 687–696.Find this resource:

Muddashetty, R., Nalavadi, V., Gross, C., Yao, X., Xing, L., Laur, O., … Bassell, G. (2011). Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Molecular Cell, 42(5), 673–688.Find this resource:

Nalavadi, V. C., Muddashetty, R. S., Gross, C., & Bassell, G. J. (2012). Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: A role in immediate early mGluR-stimulated translation. Journal of Neuroscience, 32(8), 2582–2587.Find this resource:

Narayanan, U., Nalavadi, V., Nakamoto, M., Pallas, D. C., Ceman, S., Bassell, G. J., & Warren, S. T. (2007). FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. Journal of Neuroscience, 27(52), 14349–14357.Find this resource:

Noubissi, F. K., Elcheva, I., Bhatia, N., Shakoori, A., Ougolkov, A., Liu, J., & Spiegelman, V. S. (2006). CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling. Nature, 441(7095), 898–901.Find this resource:

Nottrodd, S., Simard, M. J., & Richter, J. D. (2006). Human let-7a miRNA blocks protein production on actively translating polyribosomes. Nature Structural & Molecular Biology, 13(12), 1108–1114.Find this resource:

Okamura, K. (2004). Distinct roles for Argonaute proteins in small RNA-directed RNA cleavage pathways. Genes & Development, 18(14), 1655–1666.Find this resource:

Pastuzyn, E. D., Day, C. E., Kearns, R. B., Kyrke-Smith, M., Taibi, A. V., Mccormick, J., … Shepherd, J. D. (2018). The neuronal gene arc encodes a repurposed retrotransposon gag protein that mediates intercellular RNA transfer. Cell, 173(1), 275.Find this resource:

Petersen, C. P., Bordeleau, M., Pelletier, J., & Sharp, P. A. (2006). Short RNAs repress translation after initiation in mammalian cells. Molecular Cell, 21(4), 533–542.Find this resource:

Phan, A. T., Kuryavyi, V., Darnell, J. C., Serganov, A., Majumdar, A., Ilin, S., & Patel, D. J. (2011). Structure-function studies of FMRP RGG peptide recognition of an RNA duplex-quadruplex junction. Nature Structural & Molecular Biology, 18(7), 796–804.Find this resource:

Pratt, A. J., & Macrae, I. J. (2009). The RNA-induced silencing complex: A versatile gene-silencing machine. Journal of Biological Chemistry, 284(27), 17897–17901.Find this resource:

Qi, H. H., Ongusaha, P. P., Myllyharju, J., Cheng, D., Pakkanen, O., Shi, Y., & Shi, Y. (2008). Prolyl 4-hydroxylation regulates Argonaute 2 stability. Nature, 455(7211), 421–424.Find this resource:

Rajaratnam, A., Shergill, J., Salcedo-Arellano, M., Saldarriaga, W., Duan, X., & Hagerman, R. (2017). Fragile X syndrome and fragile X-associated disorders. F1000Research, 6, 2112.Find this resource:

Sambandan, S., Akbalik, G., Kochen, L., Rinne, J., Kahlstatt, J., Glock, C., & Schuman, E. M. (2017). Activity-dependent spatially localized miRNA maturation in neuronal dendrites. Science, 355(6325), 634–637.Find this resource:

Schaeffer, C. (2001). The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif. The EMBO Journal, 20(17), 4803–4813.Find this resource:

Schratt, G. (2011). MicroRNAs at the synapse. Nature Reviews Neuroscience, 10(12), 842–849.Find this resource:

Schratt, G. M., Tuebing, F., Nigh, E. A., Kane, C. G., Sabatini, M. E., Kiebler, M., & Greenberg, M. E. (2006). A brain-specific microRNA regulates dendritic spine development. Nature, 439(7074), 283–289.Find this resource:

Schubert, M., Soule, J., Tiron, A., & Wibrand, K. (2010). The Arc of synaptic memory. Experimental Brain Research, 200(2), 125–140.Find this resource:

Sharma, S., Falick, A. M., & Black, D. L. (2005). Polypyrimidine tract binding protein blocks the 5′ splice site-dependent assembly of U2AF and the prespliceosomal E complex. Molecular Cell, 19(4), 485–496.Find this resource:

Siomi, H., Siomi, M. C., Nussbaum, R. L., & Dreyfuss, G. (1993). The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell, 74(2), 291–298.Find this resource:

Skariah, G., Perry, K. J., Drnevich, J., Henry, J. J., & Ceman, S. (2018). RNA helicase Mov10 is essential for gastrulation and central nervous system development. Developmental Dynamics, 247(4), 660–671.Find this resource:

Skariah, G., Seimetz, J., Norsworthy, M., Lannom, M. C., Kenny, P. J., Elrakhawy, M., & Ceman, S. (2017). Mov10 suppresses retroelements and regulates neuronal development and function in the developing brain. BMC Biology, 15(1), 54.Find this resource:

Smart, F. M., Edelman, G. M., & Vanderklish, P. W. (2003). BDNF induces translocation of initiation factor 4E to mRNA granules: Evidence for a role of synaptic microfilaments and integrins. Proceedings of the National Academy of Sciences of the United States of America, 100(24), 14403–14408.Find this resource:

Spellman, R., & Smith, C. W. (2006). Novel modes of splicing repression by PTB. Trends in Biochemical Sciences, 31(2), 73–76.Find this resource:

Steward, O., & Levy, W. B. (1982). Preferential localization of polyribosomes under the base of dendritic spines in granule cells of the dentate gyrus. Journal of Neuroscience, 2(3), 284–291.Find this resource:

Subramanian, M., Rage, F., Tabet, R., Flatter, E., Mandel, J., & Moine, H. (2011). G–quadruplex RNA structure as a signal for neurite mRNA targeting. EMBO Reports, 12(7), 697–704.Find this resource:

Sweatt, J. D. (2016). Neural plasticity and behavior—sixty years of conceptual advances. Journal of Neurochemistry, 139(2), 179–199.Find this resource:

Thomas, M. G., Tosar, L. J., Desbats, M. A., Leishman, C. C., & Boccaccio, G. L. (2009). Mammalian Staufen 1 is recruited to stress granules and impairs their assembly. Journal of Cell Science, 122 (4), 563–573.Find this resource:

Vanderklish, P. W., & Edelman, G. M. (2005). Differential translation and fragile X syndrome. Genes, Brain and Behavior, 4(6), 360–384.Find this resource:

Vo, N., Klein, M. E., Varlamova, O., Keller, D. M., Yamamoto, T., Goodman, R. H., & Impey, S. (2005). From the cover: A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proceedings of the National Academy of Sciences, 102(45), 16426–16431.Find this resource:

Wagner, E. J., & Garcia-Blanco, M. A. (2001). Polypyrimidine tract binding protein antagonizes exon definition. Molecular and Cellular Biology, 21(10), 3281–3288.Find this resource:

Wang, B., Pan, L., Wei, M., Wang, Q., Liu, W., Wang, N., & Bao, L. (2015). FMRP-mediated axonal delivery of miR-181d regulates axon elongation by locally targeting Map1b and calm1. Cell Reports, 13(12), 2794–2807.Find this resource:

Wang, D. O., Martin, K. C., & Zukin, R. S. (2010). Spatially restricting gene expression by local translation at synapses. Trends in Neurosciences, 33(4), 173–182.Find this resource:

Wang, K., & Chang, H. (2011). Molecular mechanisms of long noncoding RNAs. Molecular Cell, 43(6), 904–914.Find this resource:

Wang, Y., Medvid, R., Melton, C., Jaenisch, R., & Blelloch, R. (2007). DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genetics, 39(3), 380–385.Find this resource:

Wayman, G. A., Davare, M., Ando, H., Fortin, D., Varlamova, O., Cheng, H. M., & Impey, S. (2008). An activity-regulated microRNA controls dendritic plasticity by down-regulating p250GAP. Proceedings of the National Academy of Sciences, 105(26), 9093–9098.Find this resource:

Willemsen, R., Oostra, B. A., Bassell, G. J., & Dictenberg, J. (2004). The fragile X syndrome: From molecular genetics to neurobiology. Mental Retardation and Developmental Disabilities Research Reviews, 10(1), 60–67.Find this resource:

Wulczyn, F. G., Smirnova, L., Rybak, A., Brandt, C., Kwidzinski, E., Ninnemann, O., & Nitsch, R. (2007). Post-transcriptional regulation of the let-7 microRNA during neural cell specification. The FASEB Journal, 21(2), 415–426.Find this resource:

Xu, J., Zhang, R., Shen, Y., Liu, G., Lu, X., & Wu, C. (2013). The evolution of evolvability in microRNA target sites in vertebrates. Genome Research, 23(11), 1810–1816.Find this resource:

Xue, Y., Ouyang, K., Huang, J., Zhou, Y., Ouyang, H., Li, H., & Fu, X. (2013). Direct conversion of fibroblasts to neurons by reprogramming PTB-regulated MicroRNA circuits. Cell, 152(1–2), 82–96.Find this resource:

Ye, Y., Xu, H., Su, X., & He, X. (2016). Role of MicroRNA in governing synaptic plasticity. Neural Plasticity, 2016, 1–13.Find this resource:

Zekri, L., Huntzinger, E., Heimstadt, S., & Izaurralde, E. (2009). The silencing domain of GW182 Interacts with PABPC1 to promote translational repression and degradation of MicroRNA targets and is required for target release. Molecular and Cellular Biology, 29(23), 6220–6231.Find this resource:

Zhang, T., Wu, Y.-C., Mullane, P., Ji, Y. J., Liu, H., He, L., Arora, A., … Wang, J. (2018). FUS regulates activity of MicroRNA-mediated gene silencing. Molecular Cell, 69(5), 787–801, e788.Find this resource:

Zhang, Y. Q., Bailey, A. M., Matthies, H. J., Renden, R. B., Smith, M. A., Speese, S. D., & Broadie, K. (2001). Drosophila fragile x-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell, 107(5), 591–603.Find this resource:

Zheng, S., Gray, E. E., Chawla, G., Porse, B. T., Odell, T. J., & Black, D. L. (2012). PSD-95 is post-transcriptionally repressed during early neural development by PTBP1 and PTBP2. Nature Neuroscience, 15(3), 381–388.Find this resource:

Zhou, F., Zhou, J., Dedhar, S., Wu, Y., & Snider, W. D. (2004). NGF-induced axon growth is mediated by localized inactivation of GSK-3β and functions of the microtubule plus end binding protein APC. Neuron, 42(6), 897–912.Find this resource: