Show Summary Details

Page of

PRINTED FROM OXFORD HANDBOOKS ONLINE (www.oxfordhandbooks.com). © Oxford University Press, 2018. All Rights Reserved. Under the terms of the licence agreement, an individual user may print out a PDF of a single chapter of a title in Oxford Handbooks Online for personal use (for details see Privacy Policy and Legal Notice).

date: 15 July 2019

Dendritic Targeting and Regulatory RNA Control of Local Neuronal Translation

Abstract and Keywords

This chapter reviews current developments in the area of translational control in neurons. It focuses on the activity-dependent translational modulation by neuronal regulatory RNAs, including underlying interactions with eukaryotic initiation factors (eIFs), and on the role of such modulation in locally controlled protein synthesis in synapto-dendritic domains. It highlights the role of dendritic RNA targeting as a key prerequisite of local translation at the synapse and discusses the significance of these mechanisms in the expression of higher brain functions, including learning, memory, and cognition. The chapter concludes with discussion of anticipated future work to continue to elucidate these mechanisms and provide advances in the area of translational regulation in neurons and our understanding of how translational dysregulation contributes to neurological and cognitive disorders.

Keywords: local protein synthesis, regulatory RNAs, synapses, translational control, translation initiation factors, RNA transport

Control of gene expression is essential for the temporal and spatial modulation of cellular form and function (Mathews, Sonenberg, & Hershey, 2007). Gene expression is regulated at the levels of transcription, RNA processing, translation, and post-translational modification. Translation of mRNAs is an important mechanism in the control of gene expression as regulation of protein synthesis directly and rapidly impacts cellular function (Van Der Kelen, Beyaert, Inze, & De Veylder, 2009). Translation proceeds in the three phases of initiation, elongation, and termination, and various translation factors cooperate with mRNAs, tRNAs, and ribosomal subunits in these phases. Translational initiation, which typically is rate-limiting, is often a site of regulation in the translation pathway.

Mechanism of Translation Initiation

Translation initiation unfolds in three steps: (i) formation of the 43S preinitiation complex (PIC), (ii) formation of the 48S initiation complex, and (iii) assembly of the 80S ribosome. In eukaryotes, translation initiation requires participation of 12 or more eIFs in the pathway that concludes with the formation of 80S ribosomes (Bourgeois, Mortreux, & Auboeuf, 2016; Costa-Mattioli, Sossin, Klann, & Sonenberg, 2009; Hinnebusch, 2017).

A ternary complex, consisting of eIF2, Met-tRNAiMet, and GTP, initially associates with the small 40S ribosomal subunit, together with eIFs 1, 1A, and 3, resulting in the formation of the 43S PIC (Jackson, Hellen, & Pestova, 2010). Higher-order structures in the 5′ untranslated region (UTR) of an mRNA are unwound by eIF4A, a factor that is in part integrated in eIF4F and operates in conjunction with eIF4B. A heterotrimeric complex, eIF4F consists of eIF4E (a cap-binding protein), eIF4A (a DEAD-box RNA helicase), and eIF4G (a scaffold protein interacting with eIF4E, eIF4A, eIF3, and poly(A)-binding protein (PABP)). eIF4A is an ATP-dependent RNA helicase which, at times assisted by RNA helicases Ddx3 and Dhx29, unwinds mRNA higher-order structures between the 5′ end and the initiator codon (Hinnebusch, 2017). eIF4B plays a dual role: it (i) stimulates the helicase activity of eIF4A and (ii) mediates recruitment of the 43S PIC to the mRNA. The latter is achieved by interactions with eIF3 and with 18S rRNA, the latter a component of the 40S ribosomal subunit. eIF4B contains two RNA-binding domains, an RNA recognition motif (RRM) located in the N-terminal region and two arginine-rich motifs (ARMs) located in the C-terminal region (Méthot, Pause, Hershey, & Sonenberg, 1994; Méthot, Pickett, Keene, & Sonenberg, 1996). eIF4B unspecifically binds mRNAs through the ARMs and specifically binds stem-loop structures in 18S rRNA through the RRM (Méthot et al., 1996). Thus, eIF4B plays a role as a bridge between the 5′ end of the mRNA and the 43S PIC (Méthot et al., 1996). In addition, PABP stimulates translation initiation by binding to the mRNA 3’ poly(A) tail and by simultaneously interacting with eIF4G, thus effectively circularizing the mRNA (Pestova, Lorsch, & Hellen, 2007).

Once the 43S PIC has attached to the mRNA, it translocates (“scans”) through the 5′ UTR until it recognizes a competent start codon, resulting in 48S initiation complex formation. Subsequently, the 80S ribosome is formed following factor release and joining of the 60S large ribosomal subunit.

RNA Helicases in Translation Initiation

Various RNA helicases participate in splicing, nuclear export, translation, cytoplasmic mRNA decay, miRNA-induced gene silencing, and RNA transport (Bourgeois et al., 2016). Here we will focus on RNA helicases associated with translation initiation.

The paramount RNA helicase operating in translation initiation is eIF4A. The eIF4A family consists of eIFs 4A1, 4A2, and 4A3 of which eIFs 4A1 and 4A2 share 95% amino acid identity whereas eIF4A3 shares 65% identity with the other two isoforms (Bourgeois et al., 2016; Yoder-Hill, Pause, Sonenberg, & Merrick, 1993). Structured 5′ UTRs interfere with the ability of the 43S PIC to bind to and move along the mRNA, and eIFs 4A1 and 4A2 promote 5′ UTR unwinding during 43S PIC recruitment and scanning (Pestova et al., 2007). While eIF4A3 is a component of exon junction complex, it also participates in the unwinding of structured 5′ UTRs (Choe et al., 2014).

Translation in Neurons

A CNS principal neuron typically entertains more than 1,000 synaptic connections with other neurons (Stiles & Jernigan, 2010). Synapses are regulated independently in an input-specific manner (Bartley, Huang, Huber, & Gibson, 2008). The term synaptic plasticity refers to the ability of synapses to strengthen or weaken in response to changes in the input they receive (Hughes, 1958). Long-lasting synaptic plasticity and long-term memory require new protein synthesis (Dahm, Kiebler, & Macchi, 2007; Kang & Schuman, 1996; Kindler, Wang, Richter, & Tiedge, 2005). Locally controlled translation allows select proteins to be synthesized at the synapse upon demand (Job & Eberwine, 2001). Regulators are therefore essential to control local translation at the synapse. The fragile X mental retardation protein (FMRP) (Bhakar, Dolen, & Bear, 2012), miRNAs (Fabian, Sonenberg, & Filipowicz, 2010) and brain cytoplasmic (BC) RNAs (Iacoangeli & Tiedge, 2013) have been identified as translational repressors in neurons in the basal default state. Mechanisms of translational control by FMRP and BC RNAs have been studied in depth and will be discussed in the following.

Fragile X syndrome (FXS), resulting from functional absence of FMRP, is a common cause of intellectual disability and autism (Bassell & Warren, 2008). Loss of FMRP is typically the consequence of transcriptional silencing induced by 200 or more CGG triplet repeats in the 5′ UTR of the FMR1 gene. Lack of FMRP results in impaired neuronal translational control, i.e. in inadequate translational repression of FMRP target mRNAs (Weiler et al., 1997). FMRP inhibits translation at the level of elongation by stalling translocation of ribosomes along the mRNA (Darnell et al., 2011). In addition, FMRP is associated with Dicer and Argonaute 2 (Ago2), components of the RNA-induced silencing complex (Chen & Joseph, 2015).

In Fmr1 KO animals, various proteins are expressed at elevated levels, including the α subunit of the Ca2+/calmodulin-dependent protein kinase II (CaMKIIα), striatal-enriched protein tyrosine phosphatase (STEP), potassium channels Kv3.1 and Kv4.2, microtubule-associated protein 1B, and PI3K enhancer (Goebel-Goody et al., 2012; Lee et al., 2011; Lu et al., 2004;Hou et al., 2006; Strumbos, Brown, Kronengold, Polley, & Kaczmarek, 2010). HITS-CLIP analysis (Darnell et al., 2011) identified 842 FMRP target mRNAs, including a subset encoding pre- and post-synaptic proteins. The data indicate that translation of selective mRNAs is regulated by FMRP to control expression of proteins associated with synaptic functions (Darnell & Klann, 2013). Lack of FMRP in Fmr1 KO mice results in increased susceptibility to audiogenic (sound-induced) seizures (Musumeci et al., 2000).

BC RNAs, constituting a subtype of non-protein-coding, small cytoplasmic RNAs (scRNAs), are neuronal regulatory RNAs that function as repressors of translation initiation in the basal default state (Eom, Berardi, Zhong, Risuleo, & Tiedge, 2011; Eom et al., 2014; Wang et al., 2002; Wang et al., 2005). BC RNAs are predominantly expressed in neurons (DeChiara & Brosius, 1987; Tiedge, Chen, & Brosius, 1993) as non-neuronal expression appears restricted to cells of the germ line (Muslimov et al., 2002) and subsets of cancer cells (Chen, Böcker, Brosius, & Tiedge, 1997; Iacoangeli et al., 2004).

Regulatory BC RNAs include rodent BC1 RNA and primate BC200 RNA. BC1 and BC200 RNAs are not orthologs as their evolutionary pedigrees are different. They are phylogenetically distinct (Martignetti & Brosius, 1993a): a common ancestor does not exist, with BC200 RNA being restricted to primates, BC1 RNA to rodents (Iacoangeli & Tiedge, 2013; Kim, Kass, & Deininger, 1995; Skryabin et al., 1998; Tiedge et al., 1993). Orthologs of either BC1 RNA or BC200 RNA have not been detected in other mammalian orders (Martignetti & Brosius, 1993a; 1993b). Despite the fact that BC1 and BC200 RNAs are evolutionary unrelated, the two RNAs are considered functional analogs as in all tests applied, their modes of action were found equivalent (Eom et al., 2011; Iacoangeli & Tiedge, 2013). BC1 and BC200 RNAs appear to have been independently but convergently recruited into their neuronal functional roles with the beginning of the mammalian radiation about 65 million years ago (Brosius, 2005; Iacoangeli & Tiedge, 2013). BC RNAs, in terms of their convergent evolutionary history, are thus comparable to animal wings. Wings are important for most birds, bats, and butterflies, but there is no common wing ancestor: animal wings are functionally analogous, not phylogenetically orthologous. We will further discuss RNA evolutionary mechanisms in the section “Activity-Dependent Transport.”

BC1 and BC200 RNAs are of limited sequence similarity but feature identical 3’ C-loop motifs that are critical for binding to eIF4B (Eom et al., 2011). BC RNAs repress protein synthesis by interacting with eIFs 4A and 4B and with PABP (Eom et al., 2011, 2014; Lin, Pestova, Hellen, & Tiedge, 2008; Wang et al., 2002; Wang et al., 2005). BC RNA translational repression is mediated mainly through interactions with eIFs 4A and 4B whereas interactions with PABP account for at most 20% of the repression mechanism (Eom et al., 2011; Lin et al., 2008). BC RNAs bind to eIF4A through their central A-rich regions and the 3’ stem-loop interfaces, causing inhibition of eIF4A helicase activity (Eom et al., 2011; Lin et al., 2008). They bind to eIF4B through their 3′ C-loop motifs in a high-affinity interaction that competitively inhibits binding of 18S rRNA to the factor and, as a consequence, prevents recruitment of the 43S PIC to the mRNA (Eom et al., 2011).

Phosphorylation Status in Translational Regulation

Phosphorylation and dephosphorylation of proteins are known to be among the most frequent posttranslational modification events and play important roles as molecular switches to regulate protein function. In response to various extracellular stimuli and intracellular messengers, signaling cascades regulate translation of mRNAs by modulating phosphorylation of components of the translational machinery (Roux & Topisirovic, 2012).

FMRP Phosphorylation Status

Phosphorylation of FMRP occurs primarily at serine 499 (S499), and FMRP thus phosphorylated associates with stalled ribosomes (Ceman et al., 2003), that is, is linked to reduced translation elongation. In addition, phosphorylation of FMRP promotes formation of Ago2-miRNA inhibitory complexes on target mRNAs, causing translational repression (Muddashetty et al., 2011). S499-phosphorylated FMRP thus acts as a negative translational regulator in the basal state. Upon stimulation of group I metabotropic glutamate receptors (mGluRs), protein phosphatase 2A (PP2A) is rapidly activated to dephosphorylate FMRP at S499. This dephosphorylation enhances translation of FMRP target mRNAs as dephosphorylated FMRP does not stall polyribosomes and does not promote formation of miRNA inhibitory complexes (Muddashetty et al., 2011; Narayanan et al., 2007; 2008; Niere, Wilkerson, & Huber, 2012). Thus, phosphorylation and dephosphorylation of FMRP are key regulatory events in the activity-dependent control of neuronal protein synthesis (Figure 1).

Dendritic Targeting and Regulatory RNA Control of Local Neuronal TranslationClick to view larger

Figure 1. Phosphorylation status in translational control.

BC RNAs and FMRP repress translation of their target mRNAs at the levels of initiation and elongation, respectively. During initiation, binding of BC RNAs to eIF4B competitively inhibits binding of 18S rRNA (and, consequently, the 43S PIC) to the factor, thus repressing translation initiation. FMRP stalls translocation of ribosomes along mRNAs in the elongation phase of translation. As a result, the two translational control systems (BC RNAs and FMRP) repress translation of a subset of mRNAs at the synapse in the basal state. Upon neuronal stimulation via group I mGluR signaling, PP2A is rapidly activated to dephosphorylate eIF4B at S406 and FMRP at S499. Dephosphorylation of eIF4B at S406 decreases its binding affinity for BC RNAs, releasing BC RNAs from the eIF4B-BC RNA complex (Eom et al., 2014). eIF4B engages with the 40S small ribosomal subunit in the 43S PIC to initiate translation. Dephosphorylation of FMRP ends polyribosome stalling, thus allowing elongation to resume.

eIF4B Phosphorylation Status

Serine 406 (S406) and serine 422 (S422) are known phosphorylation sites on eIF4B (Raught et al., 2004; van Gorp et al., 2009). Phosphorylation of eIF4B at S422 enhances its affinity for the eIF3 complex and stimulates the helicase activity of eIF4A (Shahbazian et al., 2006). Several kinases phosphorylate eIF4B at S422, including S6 kinase (S6K), a downstream target of PI3K/mTOR signaling (Raught et al., 2004), p90 ribosomal protein S6 kinase (RSK), a downstream target of ERK1/2 MAPK signaling (Shahbazian et al., 2006), and protein kinase B (PKB), a component of the PI3K-mTOR pathway (van Gorp et al., 2009). In contrast, the significance of S406 eIF4B phosphorylation in translational control has remained poorly understood until recently.

Phosphorylation of eIF4B at S406 significantly increases the factor’s affinity for BC RNAs (whereas phosphorylation at S422 does not), with the result that it is higher for BC RNAs than it is for 18S rRNA (Eom et al., 2014). S406 dephosphorylation reduces the factor’s affinity for BC RNAs by almost two orders of magnitude. In neurons, such dephosphorylation occurs rapidly, within 1 min, following stimulation of group I mGluRs and activation of PP2A. As a result, the eIF4B-BC RNA complex dissociates, enabling recruitment of the 43S PIC and thus translation initiation. PP2A is subsequently deactivated (beginning after 2 min) and eIF4B is rephosphorylated at S406 (within 10 min of initial mGluR activation) (Eom et al., 2014; Narayanan et al., 2007). As a result, BC RNA translational control switches back from permissive to repressive (Figure 1). This mechanism establishes an activity-dependent window of opportunity for the synaptic synthesis of select proteins, effectively controlling the amount of protein that can be produced following one round of receptor activation. Tight control of local protein synthesis is essential, as excessive production may give rise to adverse phenotypic consequences (see the next section).

Which kinase is responsible for the rephosphorylation of eIF4B at S406? Maternal and embryonic leucine zipper kinase (MELK) phosphorylates eIF4B at S406 (but not at S422) in cancer cells (Wang et al., 2016). Synthesis of myeloid cell leukemia 1 protein, an anti-apoptotic protein important for cancer cell survival during cell division, is associated with phosphorylation of eIF4B by MELK (Wang et al., 2016). The eIF4B phosphorylation status may differentially impact translation in different cell types, owing to cell-type specific availability of additional interacting factors.

The dual phosphorylation status of eIF4B, at S406 and S422, is a determinant of the reversible, activity-dependent switch between repressive and permissive states of translation initiation in neurons (Eom et al., 2014). The available evidence is in support of the following scenario. In the repressive state, S406 is phosphorylated, allowing high-affinity binding of BC RNAs and thus disallowing interactions with the 43S PIC, as a consequence repressing translation initiation. At the same time, S422 is dephosphorylated, and binding to eIF3 is not enabled. Conversely, in the permissive state, S406 is PP2A-dephosphorylated, enabling eIF4B interactions with the 43S PIC, whereas S422 is phosphorylated, enabling interactions with eIF3. As a result, translation is initiated.

Translational Dysregulation: Phenotypic Consequences

Absence of regulatory BC1 RNA in the BC1 KO animal model results in exaggerated protein synthesis that is dependent on group I mGluR activation and MEK-ERK signaling (Zhong et al., 2009). Thus, in the basal neuronal default state, BC1 RNA negatively regulates neuronal translation, acting as a break downstream of translational stimulation mediated by activation of group I mGluRs (Chuang et al., 2005; Huber, Kayser, & Bear, 2000; Zhong et al., 2009). Absence of this break gives rise to excessive cortical gamma oscillations, prolonged epileptiform discharges in hippocampal CA3 pyramidal cells, and convulsive seizures upon auditory stimulation in vivo (Zhong et al., 2009).

As cortical gamma oscillations have been implicated in prefrontal cortical mechanisms of perception and cognition (Cho, Konecky, & Carter, 2006; Cho et al., 2015), dysregulation of such oscillations in BC1 KO animals raised the question whether these animals are cognitively impaired. Recent work (Iacoangeli, Dosunmu, Eom, Stefanov, & Tiedge, 2017) indicates that this is indeed the case. BC1 KO animals excessively self-groom, an activity associated with autism-like behavior in rodents (Kalueff et al., 2016; McFarlane et al., 2008; Silverman, Tolu, Barkan, & Crawley, 2010). Furthermore, behavioral analysis using a modified Attentional Set Shift Task assay has shown that while learning and memory per se appear normal, BC1 KO animals are impaired in the cognitive control of acquired memories. When presented with a novel situation that conflicts with previously stored information, BC1 KO animals (but not corresponding WT animals) continue to operate in the framework of the older but now superseded memory. The cognitive errors are of the regressive type (Iacoangeli et al., 2017): a BC1 KO animal will, even after having made a serendipitously correct choice and having been rewarded for it, revert to making a series of consecutive incorrect decisions. The previously stored but now irrelevant information has remained dominant over subsequently acquired relevant but conflicting information (Figure 2). Thus, the animals display lack of behavioral flexibility as supervisory cognitive control is defective (Iacoangeli et al., 2017).

Dendritic Targeting and Regulatory RNA Control of Local Neuronal TranslationClick to view larger

Figure 2. BC RNA control in animal cognition. (A) BC1 KO and WT animals perform equally well in discrimination learning. They learn and memorize that a scent of sage, but not of cinnamon, is predicting a reward (a cheerio). (B) BC1 KO animals are significantly impaired in cognitive flexibility. In conflict learning sessions, WT animals rapidly adjust their retrieval strategy as they learn and memorize that the reward-predicting odor has been switched from sage to cinnamon. BC1 KO animals, in contrast, operate on the basis of the earlier acquired information and continue to search for a reward in the sage-scented bowl even when confronted with repeated negative feedback. Thus, in the absence of BC RNA translational control, cognitive flexibility is impaired as animal behavior is dominated by previously established but now outdated outcome expectancies (Iacoangeli et al., 2017).

Adapted from Iacoangeli et al. (2017).

In addition, Briz et al. (2017) recently reported that BC1 KO animals exhibited impaired texture recognition and social interactions, similar to what has been observed with animal models of FXS and autism spectrum disorder (ASD) (Pasciuto et al., 2015; Santos, Kanellopoulos, & Bagni, 2014). The novel object recognition test (NORT), using visual NORT (vNORT) and texture NORT (tNORT), was applied to examine whether visual or sensory experience is associated with learning. BC1 KO animals preferred a novel object over a familiar one in the vNORT, but had no preference for a novel object in the tNORT (Briz et al., 2017). In a three-chamber test, BC1 KO animals showed deficits in sociability but not in social memory (Briz et al., 2017).

The question arises how BC1 RNA impacts animal behavior. BC1 RNA represses synthesis of a subset of synaptic proteins (including PSD-95, NR2B and mGluR5) in postsynaptic microdomains (Briz et al., 2017; Zhong et al., 2009). In BC1 KO mice, elevated levels of such proteins lead to increased spine density and decreased dendritic complexity, similar to what has been observed in Fmr1 KO mice, an FXS animal model (Restivo et al., 2005; De Rubeis, Fernandez, Buzzi, Di Marino, & Bagni, 2012)). Elevated PSD-95 levels cause increased postsynaptic clustering and stabilization of spines, and increase the number and size of spines along dendrites (De Roo, Klauser, Mendez, Poglia, & Muller, 2008; El-Husseini, Schnell, Chetkovich, Nicoll, & Bredt, 2000). In BC1 KO animals, significantly elevated levels of PSD-95 are associated with spine abnormalities, including enlarged spine heads and PSDs (Briz et al., 2017; Zhong et al., 2009). Such abnormalities may skew synaptic excitation-repression equilibria, causing neuronal hyperexcitability which, in BC1 KO animals, has been observed in the form of an increased propensity for prolonged epileptiform discharges and a susceptibility to audiogenic seizures (Zhong et al., 2009; Iacoangeli & Tiedge, 2013; Zhong et al., 2009).

In addition, excessive cortical gamma frequency oscillations are a hallmark of BC1 KO mice (Zhong et al., 2009). Gamma frequency band activity has been implicated in cortical mechanisms of cognitive processing (Fries, 2009), specifically as it relates to prefrontal cortical network functionality and cognitive flexibility (Cho et al., 2006; 2015). Impaired gamma synchrony may cause discoordination of network connectivity and reduced cognitive flexibility, thus contributing to autism spectrum disorder (ASD) phenotypes (D’Cruz et al., 2013; Uhlhaas & Singer, 2012. In summary, recent work (Briz et al., 2017; Iacoangeli et al., 2017) is in support of the notion that impaired neuronal translational control may give rise to cognitive phenotypes that resemble ASD manifestations (Aguilar-Valles et al., 2015; Gkogkas et al., 2013; Santini et al., 2013).

Strain type may constitute a confound in the phenotypic analysis of mice. Iacoangeli et al (2017) found that cognitive competence in the C57BL/6J strain is generally lower than that in a C57BL/6J and 129X1/SvJ mixed-background strain. Translational control may potentially be impacted in C57BL/6J mice as a result of a mutation in a CNS-specific tRNA gene which, in the presence of a second, interacting mutation, may cause ribosome stalling (Ishimura et al., 2014). Possible deleterious consequences of such an epistatic tRNA gene mutation may thus affect the readout of other mutations (Ishimura et al., 2014). This is directly relevant in cases where such other mutations impact neuronal translational control pathways, in particular considering the possibility that tRNA mutation-induced potential ribosome stalling may be exacerbated under conditions when rapid or local synthesis of proteins is required in the brain (Darnell, 2014). In conclusion, any mutation impacting neuronal translation in a mouse-model on the C57BL/6J background may potentially face phenotypic interactions with that strain’s tRNA mutation. Caution is therefore advisable when performing translational control phenotypic work with mutant model mice on the C57BL/6J background (Darnell, 2014).

Dendritic RNA Targeting

Dendritic RNAs

Once a neuron is fully differentiated, distal dendritic domains can be several hundred micrometers away from the nucleus. Dendritic arborizations of mature neurons may feature thousands of dendritic spines (Loew & Hell, 2013), micro-protrusions each of which typically forms a synapse with a presynaptic terminal.

The discovery of RNAs, ribosomes and translation factors in dendrites and dendritic spines suggested that synapse form and function can be modulated directly through regulation of local protein synthesis (Steward & Levy, 1982; Sutton & Schuman, 2006; Tiedge & Brosius, 1996). Today we know that RNA transport serves as an important cellular protein-sorting and distribution mechanism, and that mRNAs are locally translated in neurons as well as in other eukaryotic cell types (Grossman, Aldridge, Weiler, & Greenough, 2006; Martin & Zukin, 2006; Pfeiffer & Huber, 2006; Schuman, Dynes, & Steward, 2006; Wells, 2006). Through this mechanism, neurons acquire spatial and temporal control of mRNA translation in synapto-dendritic domains. Neurons are thus enabled to rapidly produce proteins at individual dendritic branches or even at single synapses in response to local stimulation (Besse & Ephrussi, 2008). Thus, RNA transport is requisite for rapid translational responses that are independent of transcription in the nucleus or translation in the cell body (Shav-Tal & Singer, 2005).

Local translation occurs during development in processes of immature neurons as well as in dendrites of fully differentiated neurons (Kennedy & Ehlers, 2006). The first step for such regulation is the selective transport of a specific set of RNAs (including mRNAs, tRNAs, and regulatory RNAs) to dendritic destination sites. Well-established dendritically localized mRNAs include those encoding microtubule-associated protein 2 (MAP2) (Garner, Tucker, & Matus, 1988), the α subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) (Burgin et al., 1990), inositol 1,4,5-triphosphate receptor type 1 (Furuichi et al., 1993), neurogranin (Landry, Watson, Kashima, & Campagnoni, 1994), activity-regulated cytoskeleton-associated protein (Arc, arg3.1) (Link et al., 1995; Lyford et al., 1995), dendrin (Herb et al., 1997), cAMP response element binding protein (CREB) (Crino et al., 1998), β-actin (Eom, Antar, Singer, & Bassell, 2003), and protein kinase M-zeta (PKMζ) (Muslimov et al., 2004). In addition, the synapto-dendritic presence of rRNAs, tRNAs and regulatory BC RNAs has been documented (Kleiman, Banker, & Steward, 1993; Tiedge et al., 1993; Tiedge & Brosius, 1996; Tiedge, Fremeau, Weinstock, Arancio, & Brosius, 1991). These discoveries raised questions concerning mechanisms of RNA transport and the nature of spatial determinants that specify RNA delivery to dendritic destination sites.

Cis-Acting Targeting Elements and Trans-Acting Transport Factors

Neuronal RNAs located in synapto-dendritic domains contain cis-acting dendritic targeting elements (DTEs). Deletion of a DTE impairs dendritic localization of the RNA (Blichenberg et al., 1999; Mori, Imaizumi, Katayama, Yoneda, & Tohyama, 2000; Muslimov et al., 1997; Muslimov et al., 2004). In dendritic mRNAs, DTEs are found within UTRs as well as in protein-coding regions (Andreassi & Riccio, 2009; Moore, 2005; Muslimov et al., 2004). It is likely that localized neuronal RNAs use more than one type of DTE as combinations of different DTEs can mediate distinct steps in transport and localization (Blichenberg et al., 1999; Muslimov et al., 2004; Muslimov, Iacoangeli, Brosius, & Tiedge, 2006; Subramanian et al., 2011). Localization of BC RNAs and CaMKIIα mRNA appears to depend on multiple DTEs (Gao, Tatavarty, Korza, Levin, & Carson, 2008; Mori et al., 2000; Muslimov et al., 2004; 2006; Subramanian et al., 2011).

RNA transport is mediated by trans-acting RNA-binding proteins (RBPs) which recognize DTEs and specify RNA delivery (Gao et al., 2008; Huang, Jung, Sarkissian, & Richter, 2002; Kwon et al., 2002; Muslimov et al., 2006). RNAs with multiple DTEs can be recognized by different RBPs, further increasing the complexity of neuronal RNA targeting mechanisms (Bassell & Kelic, 2004; Bullock, Ringel, Ish-Horowicz, & Lukavsky, 2010). Dendritically localized RNAs and their cognate transport factors associate to form ribonucleoprotein (RNP) complexes. These complexes engage, directly or indirectly, with motor proteins that move them along the dendritic cytoskeleton (Doyle & Kiebler, 2011; Kanai, Dohmae, & Hirokawa, 2004).

Transport RBPs are mediators of subcellular RNA delivery. Such RBPs include zipcode binding protein (ZBP), Staufen, and heterogeneous nuclear ribonucleoprotein (hnRNP) A2 (Figure 3; Gao et al., 2008; Muslimov, Patel, Rose, & Tiedge, 2011; Shan, Munro, Barbarese, Carson, & Smith, 2003; Tang, Meulemans, Vazquez, Colaco, & Schuman, 2001; Zhang et al., 2001). Several neuronal mRNAs, including those encoding CaMKIIα, Arc, MAP2, and neurogranin, are delivered to dendrites via the hnRNP A2 pathway (which also mediates targeting of myelin basic protein mRNA in oligodendrocytes; Gao et al., 2008; Hoek, Kidd, Carson, & Smith, 1998; Shan et al., 2003; Tübing et al., 2010).

Dendritic Targeting and Regulatory RNA Control of Local Neuronal TranslationClick to view larger

Figure 3. RNA transport in dendrites.

The hnRNPA2 and ZBP pathways are two major RNA targeting mechanisms in neurons. RNA DTEs are recognized by transport RBPs to form RNPs. RNP interactions with molecular motors may require participation of additional adapter proteins. ZBP interacts with the β-actin mRNA zipcode while hnRNP A2 interacts with various RNA DTEs, including those in BC RNAs and MAP 2 mRNA.

Inset: hnRNP A2 interacts with the GA-motif DTE in the 5′ stem-loop domain of BC1 RNA. A second transport factor, which remains currently unidentified (Protein X, represented in a hypothetical rendering), is likely participating in dendritic BC RNA transport via DTE interactions (Muslimov et al., 2011).

Dendritic Localization of Regulatory BC RNAs

The double-stranded 5′ stem-loop domains of BC1 and BC200 RNAs contain similarly structured DTEs (Iacoangeli & Tiedge, 2013; Muslimov et al., 2006, 2011). BC RNA DTEs feature architectural motif components that underlie their dendritic targeting competence. In rodent BC1 RNA, the 5′ stem-loop domain harbors an apical GA motif (Muslimov et al., 2006). GA motifs are constructed around noncanonical (non-Watson-Crick) purine•purine nucleotide pairings, including in particular two G•A/A•G pairs arranged in tandem (Iacoangeli & Tiedge, 2013; Tiedge, 2006). These tandem pairs engage in the trans-Hoogsteen/sugar edge format of hydrogen bonding (Iacoangeli & Tiedge, 2013; Lescoute, Leontis, Massire, & Westhof, 2005). They, together with an additional non-Watson-Crick A•A pair, constitute the noncanonical core of the BC1 GA motif. This core is flanked on both sides by several G = C standard Watson-Crick base pairs, affording the motif with high structural stability (Muslimov et al., 2006).

The BC1 GA motif interacts with transport factor hnRNP A2 which is required for the delivery of BC1 RNA to synapto-dendritic domains (Muslimov et al., 2011). The motif is indispensable for dendritic targeting as conversion of its noncanonical purine•purine core to standard WC pairings abolishes hnRNP A2 binding and distal dendritic delivery (Muslimov et al., 2006, 2011). In addition, a GA motif-adjacent unpaired U residue at position 22 (U22) is requisite for dendritic targeting although it is not interacting with hnRNP A2 (Muslimov et al., 2006, 2011). Thus, other transport factors, in addition to hnRNP A2, may participate in BC RNA dendritic delivery.

Primate BC200 RNA, interacting with hnRNP A2 and being delivered to dendrites (Muslimov et al., 2011), copies the BC1 RNA DTE structural arrangements. A double-stranded 5′ stem-loop domain harbors a bipartite GA motif with noncanonical cores featuring A•A and tandem G•A/A•G pairings (Skryabin et al., 1998). As in BC1 RNA, these cores are flanked by standard Watson-Crick G = C pairs and a motif-adjacent unpaired U residue. The architectural attributes of BC1 and BC200 5′ motif structures are thus remarkably similar, and future work will provide further insight into the question of how interactions with RNA transport factors and dendritic delivery competence are encoded by BC RNA architectural motifs.

Recent work with transgenic mouse lines expressing mutant BC1 RNAs has confirmed a 5′ DTE requirement for dendritic localization (Robeck, Skryabin, Rozhdestvensky, Skryabin, & Brosius, 2016). However, apparent methodological insufficiencies are cause for concern (see accompanying technical comment, Sci. Rep. 6, 28300, 2016, published online). For example, the use of 35S-labeled probes with thick (30 μm) tissue sections is problematic as 50% of the emitted beta particles decompose within 25 μm (Bicknese, Shahrokh, Shohet, & Verkman, 1992), causing arbitrary variations in the spatial distribution of labeling intensities as a result of differential-absorption quenching artifacts (Smolen & Beaston-Wimmer, 1990).

Similar to BC RNA GA motifs, CGG-repeat RNA forms stable stem-loops that interact with hnRNP A2 (Sofola et al., 2007; Swanson & Orr, 2007). GA-motif BC RNA DTEs and CGG-repeat stem-loops both feature noncanonical purine•purine base pairing (G•G in the latter case) (Muslimov et al., 2006; Napierala, Michalowski, de Mezer, & Krzyzosiak, 2005; Sobczak et al., 2010; Tiedge, 2006; Zumwalt, Ludwig, Hagerman, & Dieckmann, 2007). GA targeting motifs and CGG-repeat stem-loops compete with each other for binding to hnRNP A2, causing reduced dendritic delivery of BC1 RNA in the presence of expanded CGG-repeat RNA (Muslimov et al., 2011). These observations are relevant with respect to the fragile X premutation disorder which is caused by CGG repeat expansion in the 5′ UTR of the FMR1 gene (Hagerman, 2013).

Activity-Dependent Transport

BC RNA genes originated through retroposition (Kim, Martignetti, Shen, Brosius, & Deininger, 1994; Martignetti & Brosius, 1993a). Gene duplication and retroposition are two major but distinct mechanisms of genomic diversification in eukaryotes. Whereas genes encoding mRNAs (and thus proteins) are frequently dispersed in the genome by gene duplication, genes encoding non-protein-coding (including regulatory) RNAs are often dispersed by retroposition (Brosius, 1991, 2005; Cordaux & Batzer, 2009; Herbert, 2004; Kazazian, 2004). In the retroposition mechanism, cellular transcripts are reverse transcribed and inserted into the genome as retroposons, often in high copy numbers (Cordaux & Batzer, 2009; Iacoangeli & Tiedge, 2013; Kazazian, 2004;. Non-protein-coding RNA genes are frequently transcribed by RNA polymerase III (Pol III). Because such genes—in contrast to Pol II transcribed protein-coding genes—carry promoters within their RNA-coding regions, a retroposon derived form a Pol III transcript may acquire the status of a transcriptionally competent new gene (Iacoangeli & Tiedge, 2013).

The retroposition mechanism has been an innovative force in the shaping and remodeling of eukaryotic genomes. About 45% of the human genome has been retroposition-generated (Herbert, 2004), and over two thirds of the genomic content has been generated by this and other RNA-to-DNA conversion mechanisms (Brosius, 1999; De Koning, Gu, Castoe, Batzer, & Pollock, 2011). In stark contrast, protein-coding genes make up little more than 1% of the human genome (Taft, Pheasant, & Mattick, 2007).

About three quarters of the human genome are transcribed into RNAs (Djebali et al., 2012), most of them likely with regulatory functions. The need for RNA regulators has apparently increased significantly during mammalian phylogenetic development as a result of growing organismal complexities (Mattick, 2003; Taft et al., 2007). The evolution of such RNAs is rapid and ongoing, and evolutionary constraints are often such that it is more likely higher-order than primary structure that is under selective pressure in phylogenetic RNA development (Noller, 2005; Leontis, Lescoute, & Westhof, 2006; Pang, Frith, & Mattick, 2006) Such constraints may include motif recognition by RBPs which is often mediated by RNA 3D structure rather than sequence (Grandin, 2010; Lescoute et al., 2005; Noller, 2005).

Also by retroposition, BC1 RNA has served as a master gene for ID element amplification and dissemination in rodent genomes (Kim et al., 1994). ID elements are identical or similar to the 5′ BC1 domain, including the cis-acting DTE (Kim et al., 1994; Muslimov et al., 1997). Thus, an ID element, retroposed into a host mRNA gene and transcribed in neurons, may confer dendritic targeting competence to that mRNA (Buckley et al., 2011). The retroposition mechanism has thus helped disseminate elements with DTE potential in rodent genomes during phylogenetic development (Iacoangeli & Tiedge, 2013; Muslimov et al., 2014).

ID elements have been identified in introns of cytoplasmic transcripts to which they confer dendritic targeting competence (Buckley et al., 2011). They are also contained in a number of neuronal mRNAs that are targeted to dendrites in an activity-dependent manner (Muslimov et al., 2014). This mechanism relies on high-affinity interactions of noncanonical RNA motif structures with hnRNP A2. The ID element 4 subtype (ID4) interacts with hnRNP A2 in a Ca2+ concentration range of 50 nM to 5 μM, and the binding affinity peaks with a KD = 200 pM at 500 nM Ca2+. mRNAs that carry ID-type noncanonical motif DTEs are delivered to dendrites upon β-adrenergic receptor activation which, in turn, causes influx of Ca2+ through voltage-dependent calcium channels (Muslimov et al., 2014). Intracellular Ca2+ waves can be triggered by transient rises in postsynaptic [Ca2+]i, reaching dendritic [Ca2+]i amplitudes of 1 μM or more (Berridge, Lipp, & Bootman, 2000; Grienberger & Konnerth, 2012; Ross, 2012). Once such a Ca2+ transient has reached a local threshold of 500 nM, it can cause a switch to the high-affinity conformation of the ID targeting element, enabling binding of hnRNP A2 and dendritic delivery (Muslimov et al., 2014). The activity-dependent ID dendritic delivery mechanism allows neurons to supply synapto-dendritic domains with select RNAs on demand.

In conclusion, dendritic RNA targeting is an essential prerequisite for the locally controlled, activity-dependent synthesis of proteins at the synapse. Impaired neuronal RNA transport mechanisms, increasing evidence indicates, may be contributing to physiological and cognitive dysfunction in neurological disorders.

Outlook

In-depth understanding of molecular-cellular mechanisms that regulate dendritic RNA transport and local protein synthesis is critically important in dissecting how dysregulation of such mechanisms can cause disease. We anticipate that future work will elucidate mechanisms of (i) synapse-to-soma or synapse-to-nucleus signaling, (ii) proximal vs. distal dendritic RNA delivery, (iii) local transition from microtubule-based dendritic delivery to actin-based distribution and docking in postsynaptic microdomains, (iv) local regulation of protein synthesis in response to stimulation or injury, during development or in disease, and (v) local translational control in synaptic plasticity, learning, memory, and cognition.

Recent work has shown that translational dysregulation may underlie human cognitive and behavioral dysfunction (Darnell, 2011). A properly maintained excitation-inhibition balance is a hallmark of neuronal function as any skewing of such balance beyond physiological ranges may cause hypo- or hyperexcitability. Dysregulation of translation initiation causes ASD-like phenotypes in mouse models (Aguilar-Valles et al., 2015; Gkogkas et al., 2013; Santini et al., 2013). Recent genome-wide analyses reveal aberrant expression of non-protein-coding RNAs in ASD patients (Parikshak et al., 2016; Ziats & Rennert, 2013). BC1 KO mice exhibit ASD-like behavioral manifestations (Iacoangeli et al., 2017). Undoubtedly, future advances in the area of translational regulation in neurons will improve our understanding of how translational dysregulation contributes to neurological and cognitive disorders.

Acknowledgments

We thank the members of the Robert F. Furchgott Center for advice and discussion. Work in the authors’ laboratory was in part supported by NIH grants NS046769 and DA026110 (to H.T.).

References

Aguilar-Valles, A., Matta-Camacho, E., Khoutorsky, A., Gkogkas, C., Nader, K., Lacaille, J. C., & Sonenberg, N. (2015). Inhibition of group i metabotropic glutamate receptors reverses autistic-like phenotypes caused by deficiency of the translation repressor eif4e binding protein 2. Journal of Neuroscience 35(31), 11125–11132.Find this resource:

Andreassi, C., & Riccio, A. (2009). To localize or not to localize: mRNA fate is in 3'UTR ends. Trends in Cell Biology 19(9), 465–474.Find this resource:

Bartley, A. F., Huang, Z. J., Huber, K. M., & Gibson, J. R. (2008). Differential activity-dependent, homeostatic plasticity of two neocortical inhibitory circuits. Journal of Neurophysiology 100(4), 1983–1994.Find this resource:

Bassell, G. J., & Kelic, S. (2004). Binding proteins for mRNA localization and local translation, and their dysfunction in genetic neurological disease. Current Opinion in Neurobiology 14(5), 574–581.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:

Berridge, M. J., Lipp, P., & Bootman, M. D. (2000). The versatility and universality of calcium signalling. Nature Reviews Molecular Cell Biology 1(1), 11–21.Find this resource:

Besse, F., & Ephrussi, A. (2008). Translational control of localized mRNAs: Restricting protein synthesis in space and time. Nature Reviews Molecular Cell Biology 9(12), 971–980.Find this resource:

Bhakar, A. L., Dolen, G., & Bear, M. F. (2012). The pathophysiology of fragile X (and what it teaches us about synapses). Annual Review of Neuroscience 35, 417–443.Find this resource:

Bicknese, S., Shahrokh, Z., Shohet, S. B., & Verkman, A. S. (1992). Single photon radioluminescence. I. Theory and spectroscopic properties. Biophysical Journal 63(5), 1256–1266.Find this resource:

Blichenberg, A., Schwanke, B., Rehbein, M., Garner, C.C., Richter, D., & Kindler, S. (1999). Identification of a cis-acting dendritic targeting element in MAP2 mRNAs. Journal of Neuroscience 19(20), 8818–8829.Find this resource:

Bourgeois, C. F., Mortreux, F., & Auboeuf, D. (2016). The multiple functions of RNA helicases as drivers and regulators of gene expression. Nature Reviews Molecular Cell Biology 17(7), 426–438.Find this resource:

Briz, V., Restivo, L., Pasciuto, E., Juczewski, K., Mercaldo, V., Lo, A. C., … Bagni, C. (2017). The non-coding RNA BC1 regulates experience-dependent structural plasticity and learning. Nature Communications 8(1), 293.Find this resource:

Brosius, J. (1991). Retroposons—seeds of evolution. Science 251(4995), 753.Find this resource:

Brosius, J. (1999). Genomes were forged by massive bombardments with retroelements and retrosequences. Genetica 107(1–3), 209–238.Find this resource:

Brosius, J. (2005). Echoes from the past—are we still in an RNP world? Cytogenetic and Genome Research 110(1–4), 8–24.Find this resource:

Buckley, P. T., Lee, M. T., Sul, J. Y., Miyashiro, K. Y., Bell, T. J., Fisher, S. A., … Eberwine, J. (2011). Cytoplasmic intron sequence-retaining transcripts can be dendritically targeted via ID element retrotransposons. Neuron 69(5), 877–884.Find this resource:

Bullock, S. L., Ringel, I., Ish-Horowicz, D., & Lukavsky, P. J. (2010). A'-form RNA helices are required for cytoplasmic mRNA transport in Drosophila. Nature Structural & Molecular Biology 17(6), 703–709.Find this resource:

Burgin, K. E., Waxham, M. N., Rickling, S., Westgate, S.A., Mobley, W. C., & Kelly, P. T. (1990). In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. Journal of Neuroscience 10(6), 1788–1798.Find this resource:

Ceman, S., O’Donnell, 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., & Joseph, S. (2015). Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins. Biochimie 114, 147–154.Find this resource:

Chen, W., Böcker, W., Brosius, J., & Tiedge, H. (1997). Expression of neural BC200 RNA in human tumours. Journal of Pathology 183(3), 345–351.Find this resource:

Cho, K. K., Hoch, R., Lee, A.T., Patel, T., Rubenstein, J.L., & Sohal, V. S. (2015). Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6(+/–) mice. Neuron 85(6), 1332–1343.Find this resource:

Cho, R. Y., Konecky, R. O., & Carter, C. S. (2006). Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 103(52), 19878–19883.Find this resource:

Choe, J., Ryu, I., Park, O. H., Park, J., Cho, H., Yoo, J. S., … Kim, Y. K. (2014). eIF4AIII enhances translation of nuclear cap-binding complex-bound mRNAs by promoting disruption of secondary structures in 5'UTR. Proceedings of the National Academy of Sciences of the United States of America 111(43), E4577–E4586.Find this resource:

Chuang, S. C., Zhao, W., Bauchwitz, R., Yan, Q., Bianchi, R., & Wong, R. K. (2005). Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. Journal of Neuroscience 25(35), 8048–8055.Find this resource:

Cordaux, R., & Batzer, M. A. (2009). The impact of retrotransposons on human genome evolution. Nature Reviews Genetics 10(10), 691–703.Find this resource:

Costa-Mattioli, M., Sossin, W.S., Klann, E., & Sonenberg, N. (2009). Translational control of long-lasting synaptic plasticity and memory. Neuron 61(1), 10–26.Find this resource:

Crino, P., Khodakhah, K., Becker, K., Ginsberg, S., Hemby, S., & Eberwine, J. (1998). Presence and phosphorylation of transcription factors in developing dendrites. Proceedings of the National Academy of Sciences of the United States of America 95(5), 2313–2318.Find this resource:

D’Cruz, A. M., Ragozzino, M. E., Mosconi, M. W., Shrestha, S., Cook, E. H., & Sweeney, J. A. (2013). Reduced behavioral flexibility in autism spectrum disorders. Neuropsychology 27(2), 152–160.Find this resource:

Dahm, R., Kiebler, M., & Macchi, P. (2007). RNA localisation in the nervous system. Seminars in Cell & Developmental Biology 18(2), 216–223.Find this resource:

Darnell, J. C. (2011). Defects in translational regulation contributing to human cognitive and behavioral disease. Current Opinion in Genetics & Development 21(4), 465–473.Find this resource:

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

Darnell, J. C., & Klann, E. (2013). The translation of translational control by FMRP: Therapeutic targets for FXS. Nature Neuroscience 16(11), 1530–1536.Find this resource:

Darnell, J. C. (2014). Molecular biology. Ribosome rescue and neurodegeneration. Science 345(6195), 378–379.Find this resource:

De Koning, A. P., Gu, W., Castoe, T. A., Batzer, M. A., & Pollock, D. D. (2011). Repetitive elements may comprise over two-thirds of the human genome. PLOS Genetics 7(12), e1002384.Find this resource:

De Roo, M., Klauser, P., Mendez, P., Poglia, L., & Muller, D. (2008). Activity-dependent PSD formation and stabilization of newly formed spines in hippocampal slice cultures. Cerebral Cortex 18(1), 151–161.Find this resource:

De Rubeis, S., Fernández, E., Buzzi, A., Di Marino, D., & Bagni, C. (2012) Molecular and cellular aspects of mental retardation in the Fragile X syndrome: From gene mutation/s to spine dysmorphogenesis. In M. Kreutz & C. Sala (Eds.), Synaptic plasticity. Advances in experimental medicine and biology (pp. 517–551). Vienna, Austria: Springer.Find this resource:

DeChiara, T. M., & Brosius, J. (1987). Neural BC1 RNA: cDNA clones reveal nonrepetitive sequence content. Proceedings of the National Academy of Sciences of the United States of America 84(9), 2624–2628.Find this resource:

Djebali, S., Davis, C. A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., … Gingeras, T. R. (2012). Landscape of transcription in human cells. Nature 489(7414), 101–108.Find this resource:

Doyle, M., & Kiebler, M. A. (2011). Mechanisms of dendritic mRNA transport and its role in synaptic tagging. EMBO Journal 30(17), 3540–3552.Find this resource:

El-Husseini, A. E., Schnell, E., Chetkovich, D. M., Nicoll, R. A., & Bredt, D. S. (2000). PSD-95 involvement in maturation of excitatory synapses. Science 290(5495), 1364–1368.Find this resource:

Eom, T., Antar, L. N., Singer, R. H., & Bassell, G. J. (2003). Localization of a β-actin messenger ribonucleoprotein complex with zipcode-binding protein modulates the density of dendritic filopodia and filopodial synapses. Journal of Neuroscience 23(32), 10433–10444.Find this resource:

Eom, T., Berardi, V., Zhong, J., Risuleo, G., & Tiedge, H. (2011). Dual nature of translational control by regulatory BC RNAs. Molecular and Cellular Biology 31(22), 4538–4549.Find this resource:

Eom, T., Muslimov, I. A., Tsokas, P., Berardi, V., Zhong, J., Sacktor, T. C., & Tiedge, H. (2014). Neuronal BC RNAs cooperate with eIF4B to mediate activity-dependent translational control. Journal of Cell Biology 207(2), 237–252.Find this resource:

Fabian, M. R., Sonenberg, N., & Filipowicz, W. (2010). Regulation of mRNA translation and stability by microRNAs. Annual Review of Biochemistry 79, 351–379.Find this resource:

Fries, P. (2009). Neuronal gamma-band synchronization as a fundamental process in cortical computation. Annual Review of Neuroscience 32, 209–224.Find this resource:

Furuichi, T., Simon-Chazottes, D., Fujino, I., Yamada, N., Hasegawa, M., Miyawaki, A., … Mikoshiba, K. (1993). Widespread expression of inositol 1,4,5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system. Receptors Channels 1(1), 11–24.Find this resource:

Gao, Y., Tatavarty, V., Korza, G., Levin, M.K., & Carson, J.H. (2008). Multiplexed dendritic targeting of alpha calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway. Molecular Biology of the Cell 19(5), 2311–2327.Find this resource:

Garner, C. C., Tucker, R. P., & Matus, A. (1988). Selective localization of messenger RNA for cytoskeletal protein MAP2 in dendrites. Nature 336(6200), 674–677.Find this resource:

Gkogkas, C. G., Khoutorsky, A., Ran, I., Rampakakis, E., Nevarko, T., Weatherill, D. B., … Sonenberg, N. (2013). Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493(7432), 371–377.Find this resource:

Goebel-Goody, S. M., Wilson-Wallis, E. D., Royston, S., Tagliatela, S. M., Naegele, J. R., & Lombroso, P. J. (2012). Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model. Genes, Brain and Behavior 11(5), 586–600.Find this resource:

Grandin, K. (Ed.) (2010). The Nobel Prizes 2009. Stockholm, Sweden: Nobel Foundation.Find this resource:

Grienberger, C., & Konnerth, A. (2012). Imaging calcium in neurons. Neuron 73(5), 862–885.Find this resource:

Grossman, A. W., Aldridge, G. M., Weiler, I. J., & Greenough, W. T. (2006). Local protein synthesis and spine morphogenesis: Fragile X syndrome and beyond. Journal of Neuroscience 26(27), 7151–7155.Find this resource:

Hagerman, R. J. (2013). Epilepsy drives autism in neurodevelopmental disorders. Developmental Medicine & Child Neurology 55(2), 101–102.Find this resource:

Herb, A., Wisden, W., Catania, M. V., Marechal, D., Dresse, A., & Seeburg, P. H. (1997). Prominent dendritic localization in forebrain neurons of a novel mRNA and its product, dendrin. Molecular and Cellular Neuroscience 8(5), 367–374.Find this resource:

Herbert, A. (2004). The four Rs of RNA-directed evolution. Nature Genetics 36(1), 19–25.Find this resource:

Hinnebusch, A. G. (2017). Structural insights into the mechanism of scanning and start codon recognition in eukaryotic translation initiation. Trends in Biochemical Sciences 42(8), 589–611.Find this resource:

Hoek, K. S., Kidd, G. J., Carson, J. H., & Smith, R. (1998). hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Biochemistry 37(19), 7021–7029.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:

Huang, Y. S., Jung, M. Y., Sarkissian, M., & Richter, J. D. (2002). N-methyl-D-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA polyadenylation at synapses. EMBO Journal 21(9), 2139–2148.Find this resource:

Huber, K. M., Kayser, M. S., & Bear, M. F. (2000). Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288(5469), 1254–1257.Find this resource:

Hughes, J. R. 1958. Post-tetanic potentiation. Physiological Reviews 38(1), 91–113.Find this resource:

Iacoangeli, A., Lin, Y., Morley, E. J., Muslimov, I. A., Bianchi, R., Reilly, J., … Tiedge, H.( 2004). BC200 RNA in invasive and preinvasive breast cancer. Carcinogenesis 25(11), 2125–2133.Find this resource:

Iacoangeli, A., & Tiedge, H. (2013). Translational control at the synapse: Role of RNA regulators. Trends in Biochemical Sciences 38(1), 47–55.Find this resource:

Iacoangeli, A., Dosunmu, A., Eom, T., Stefanov, D. G., & Tiedge, H. (2017). Regulatory BC1 RNA in cognitive control. Learning & Memory 24(7), 267–277.Find this resource:

Ishimura, R., Nagy, G., Dotu, I., Zhou, H., Yang, X.L., Schimmel, P., … Ackerman, S. L. (2014). RNA function. Ribosome stalling induced by mutation of a CNS-specific tRNA causes neurodegeneration. Science 345(6195), 455–459.Find this resource:

Jackson, R. J., Hellen, C. U., & Pestova, T. V. (2010). The mechanism of eukaryotic translation initiation and principles of its regulation. Nature Reviews Molecular Cell Biology 11(2), 113–127.Find this resource:

Job, C., & Eberwine, J. (2001). Localization and translation of mRNA in dendrites and axons. Nature Reviews Neuroscience 2(12), 889–898.Find this resource:

Kalueff, A. V., Stewart, A. M., Song, C., Berridge, K. C., Graybiel, A. M., & Fentress, J. C. (2016). Neurobiology of rodent self-grooming and its value for translational neuroscience. Nature Reviews Neuroscience 17(1), 45–59.Find this resource:

Kanai, Y., Dohmae, N., & Hirokawa, N. (2004). Kinesin transports RNA: Isolation and characterization of an RNA-transporting granule. Neuron 43(4), 513–525.Find this resource:

Kang, H., & Schuman, E. M. (1996). A requirement for local protein synthesis in neurotrophin-induced hippocampal synaptic plasticity. Science 273(5280), 1402–1406.Find this resource:

Kazazian, H. H., Jr. (2004). Mobile elements: Drivers of genome evolution. Science 303(5664), 1626–1632.Find this resource:

Kennedy, M. J., & Ehlers, M. D. (2006). Organelles and trafficking machinery for postsynaptic plasticity. Annual Review of Neuroscience 29, 325–362.Find this resource:

Kim, J., Martignetti, J. A., Shen, M. R., Brosius, J., & Deininger, P. (1994). Rodent BC1 RNA gene as a master gene for ID element amplification. Proceedings of the National Academy of Sciences of the United States of America 91(9), 3607–3611.Find this resource:

Kim, J., Kass, D. H., & Deininger, P. L. (1995). Transcription and processing of the rodent ID repeat family in germline and somatic cells. Nucleic Acids Research 23(12), 2245–2251.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:

Kleiman, R., Banker, G., & Steward, O. (1993). Subcellular distribution of rRNA and poly(A) RNA in hippocampal neurons in culture. Molecular Brain Research 20(4), 305–312.Find this resource:

Kwon, S., Abramson, T., Munro, T. P., John, C.M., Kohrmann, M., & Schnapp, B. J. (2002). UUCAC- and vera-dependent localization of VegT RNA in Xenopus oocytes. Current Biology 12(7), 558–564.Find this resource:

Landry, C. F., Watson, J. B., Kashima, T., & Campagnoni, A. T. (1994). Cellular influences on RNA sorting in neurons and glia: An in situ hybridization histochemical study. Molecular Brain Research 27(1), 1–11.Find this resource:

Lee, H. Y., Ge, W. P., Huang, W., He, Y., Wang, G. X., Rowson-Baldwin, A., … Jan, L. Y. (2011). Bidirectional regulation of dendritic voltage-gated potassium channels by the fragile X mental retardation protein. Neuron 72(4), 630–642.Find this resource:

Leontis, N. B., Lescoute, A., & Westhof, E. (2006). The building blocks and motifs of RNA architecture. Current Opinion in Structural Biology 16(3), 279–287.Find this resource:

Lescoute, A., Leontis, N. B., Massire, C., & Westhof, E. (2005). Recurrent structural RNA motifs, isostericity matrices and sequence alignments. Nucleic Acids Research 33(8), 2395–2409.Find this resource:

Lin, D., Pestova, T. V., Hellen, C. U., & Tiedge H. (2008). Translational control by a small RNA: dendritic BC1 RNA targets the eukaryotic initiation factor 4A helicase mechanism. Molecular and Cellular Biology 28(9), 3008–3019.Find this resource:

Link, W., Konietzko, U., Kauselmann, G., Krug, M., Schwanke, B., Frey, U., & Kuhl, D. (1995). Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proceedings of the National Academy of Sciences of the United States of America 92(12), 5734–5738.Find this resource:

Loew, L. M. & Hell, S. W. (2013). Superresolving dendritic spines. Biophysical Journal 104(4), 741–743.Find this resource:

Lu, R., Wang, H., Liang, Z., Ku, L., O'Donnell W. T., Li, W., … Feng, Y. (2004). The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development. Proceedings of the National Academy of Sciences of the United States of America 101(42), 15201–15206.Find this resource:

Lyford, G. L., Yamagata, K., Kaufmann, W. E., Barnes, C.A., Sanders, L. K., Copeland, N. G., … Worley, P. F. (1995). Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites. Neuron 14(2), 433–445.Find this resource:

Martignetti, J. A., & Brosius, J. (1993a). BC200 RNA: A neural RNA polymerase III product encoded by a monomeric Alu element. Proceedings of the National Academy of Sciences of the United States of America 90(24), 11563–11567.Find this resource:

Martignetti, J. A., & Brosius, J. (1993b). Neural BC1 RNA as an evolutionary marker: Guinea pig remains a rodent. Proceedings of the National Academy of Sciences of the United States of America 90(20), 9698–9702.Find this resource:

Martin, K. C. & Zukin, R. S. (2006). RNA trafficking and local protein synthesis in dendrites: An overview. Journal of Neuroscience 26(27), 7131–7134.Find this resource:

Mathews, M. B., Sonenberg, N., & Hershey, J. W. B. (Eds.) (2007). Translational control in biology and medicine. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.Find this resource:

Mattick, J. S. (2003). Challenging the dogma: The hidden layer of non-protein-coding RNAs in complex organisms. Bioessays 25(10), 930–939.Find this resource:

McFarlane, H. G., Kusek, G. K., Yang, M., Phoenix, J. L., Bolivar, V. J., & Crawley, J. N. (2008). Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes, Brain and Behavior 7(2), 152–163.Find this resource:

Méthot, N., Pause, A., Hershey, J. W., & Sonenberg, N. (1994). The translation initiation factor eIF-4B contains an RNA-binding region that is distinct and independent from its ribonucleoprotein consensus sequence. Molecular and Cellular Biology 14(4), 2307–2316.Find this resource:

Méthot, N., Pickett, G., Keene, J. D., & Sonenberg, N. (1996). In vitro RNA selection identifies RNA ligands that specifically bind to eukaryotic translation initiation factor 4B: The role of the RNA recognition motif. RNA 2(1), 38–50.Find this resource:

Moore, M. J. (2005). From birth to death: The complex lives of eukaryotic mRNAs. Science 309(5740), 1514–1518.Find this resource:

Mori, Y., Imaizumi, K., Katayama, T., Yoneda, T., & Tohyama, M. (2000). Two cis-acting elements in the 3' untranslated region of alpha-CaMKII regulate its dendritic targeting. Nature Neuroscience 3(11), 1079–1084.Find this resource:

Muddashetty, R. S., Nalavadi, V. C., Gross, C., Yao, X., Xing, L., Laur, O., … Bassell, G. J. (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:

Muslimov, I. A., Santi, E., Homel, P., Perini, S., Higgins, D., & Tiedge H. (1997). RNA transport in dendrites: A cis-acting targeting element is contained within neuronal BC1 RNA. Journal of Neuroscience 17(12), 4722–4733.Find this resource:

Muslimov, I. A., Lin, Y., Heller, M., Brosius, J., Zakeri, Z., & Tiedge H. (2002). A small RNA in testis and brain: Implications for male germ cell development. Journal of Cell Science 115(6), 1243–1250.Find this resource:

Muslimov, I. A., Nimmrich, V., Hernandez, A. I., Tcherepanov, A., Sacktor, T. C., & Tiedge H. (2004). Dendritic transport and localization of protein kinase Mzeta mRNA: Implications for molecular memory consolidation. Journal of Biological Chemistry 279(50), 52613–52622.Find this resource:

Muslimov, I. A., Iacoangeli, A., Brosius, J., & Tiedge H. (2006). Spatial codes in dendritic BC1 RNA. Journal of Cell Biology 175(3), 427–439.Find this resource:

Muslimov, I. A., Patel, M. V., Rose, A., & Tiedge, H. (2011). Spatial code recognition in neuronal RNA targeting: Role of RNA-hnRNP A2 interactions. Journal of Cell Biology 194(3), 441–457.Find this resource:

Muslimov, I. A., Tuzhilin, A., Tang, T. H., Wong, R. K., Bianchi, R., & Tiedge H. (2014). Interactions of noncanonical motifs with hnRNP A2 promote activity-dependent RNA transport in neurons. Journal of Cell Biology 205(4), 493–510.Find this resource:

Musumeci, S. A., Bosco, P., Calabrese, G., Bakker, C., De Sarro, G. B., Elia, M., … Oostra, B. A. (2000). Audiogenic seizures susceptibility in transgenic mice with fragile X syndrome. Epilepsia 41(1), 19–23.Find this resource:

Napierala, M., Michalowski, D., de Mezer, M., & Krzyzosiak, W. J. (2005). Facile FMR1 mRNA structure regulation by interruptions in CGG repeats. Nucleic Acids Research 33(2), 451–463.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:

Narayanan, U., Nalavadi, V., Nakamoto, M., Thomas, G., Ceman, S., Bassell, G. J., & Warren, S. T. (2008). S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. Journal of Biological Chemistry 283(27), 18478–18482.Find this resource:

Niere, F., Wilkerson, J. R., & Huber, K. M. (2012). Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. Journal of Neuroscience 32(17), 5924–5936.Find this resource:

Noller, H. F. (2005). RNA structure: Reading the ribosome. Science 309(5740), 1508–1514.Find this resource:

Pang, K. C., Frith, M. C., & Mattick, J. S. (2006). Rapid evolution of noncoding RNAs: Lack of conservation does not mean lack of function. Trends in Genetics 22(1), 1–5.Find this resource:

Parikshak, N. N., Swarup, V., Belgard, T. G., Irimia, M., Ramaswami, G., Gandal, M. J., … Geschwind, D. H. (2016). Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism. Nature 540(7633), 423–427.Find this resource:

Pasciuto, E., Borrie, S. C., Kanellopoulos, A. K., Santos, A. R., Cappuyns, E., D'Andrea, L., … Bagni, C. (2015). Autism spectrum disorders: Translating human deficits into mouse behavior. Neurobiology of Learning and Memory 124, 71–87.Find this resource:

Pestova, T., Lorsch, J. R., & Hellen, C. U. (2007). The mechanism of translation initiation in eukaryotes. In M. B. Mathews, N. Sonenberg, & J. W. B. Hershey (Eds.), Translational control in biology and medicine (pp. 87–128). Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.Find this resource:

Pfeiffer, B. E., & Huber, K. M. (2006). Current advances in local protein synthesis and synaptic plasticity. Journal of Neuroscience 26(27), 7147–7150.Find this resource:

Raught, B., Peiretti, F., Gingras, A. C., Livingstone, M., Shahbazian, D., Mayeur, G. L., … Hershey, J. W. (2004). Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO Journal 23(8), 1761–1769.Find this resource:

Restivo, L., Ferrari, F., Passino, E., Sgobio, C., Bock, J., Oostra, B. A., … Ammassari-Teule, M. (2005). Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proceedings of the National Academy of Sciences of the United States of America 102(32), 11557–11562.Find this resource:

Robeck, T., Skryabin, B. V., Rozhdestvensky, T. S., Skryabin, A. B., & Brosius, J. (2016). BC1 RNA motifs required for dendritic transport in vivo. Scientific Reports 6, 28300.Find this resource:

Ross, W. N. (2012). Understanding calcium waves and sparks in central neurons. Nature Reviews Neuroscience 13(3), 157–168.Find this resource:

Roux, P. P. & Topisirovic, I. (2012). Regulation of mRNA translation by signaling pathways. Cold Spring Harbor Perspectives in Biology 4(11), a012252.Find this resource:

Santini, E., Huynh, T. N., MacAskill, A. F., Carter, A. G., Pierre, P., Ruggero, D., … Klann, E. (2013). Exaggerated translation causes synaptic and behavioural aberrations associated with autism. Nature 493(7432), 411–415.Find this resource:

Santos, A. R., Kanellopoulos, A. K., & Bagni, C. (2014). Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: What a fly and mouse model can teach us. Learning & Memory 21(10), 543–555.Find this resource:

Schuman, E. M., Dynes, J. L., & Steward, O. (2006). Synaptic regulation of translation of dendritic mRNAs. Journal of Neuroscience 26(27), 7143–7146.Find this resource:

Shahbazian, D., Roux, P. P., Mieulet, V., Cohen, M. S., Raught, B., Taunton, J., … Sonenberg, N. (2006). The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity. EMBO Journal 25(12), 2781–2791.Find this resource:

Shan, J., Munro, T. P., Barbarese, E., Carson, J. H., & Smith, R. (2003). A molecular mechanism for mRNA trafficking in neuronal dendrites. Journal of Neuroscience 23(26), 8859–8866.Find this resource:

Shav-Tal, Y., & Singer, R. H. (2005). RNA localization. Journal of Cell Science 118(18), 4077–4081.Find this resource:

Silverman, J. L., Tolu, S. S., Barkan, C. L., & Crawley, J. N. (2010). Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35(4), 976–989.Find this resource:

Skryabin, B. V., Kremerskothen, J., Vassilacopoulou, D., Disotell, T. R., Kapitonov, V. V., Jurka, J., & Brosius, J. (1998). The BC200 RNA gene and its neural expression are conserved in Anthropoidea (Primates). Journal of Molecular Evolution 47(6), 677–685.Find this resource:

Smolen, A. J., & Beaston-Wimmer, P. (1990). Quantitative analysis of in situ hybridization using image analysis. In M.-F. Chesselt (Ed.), In situ hybridization histochemistry (pp. 175–188). Boca Raton: CRC Press.Find this resource:

Sobczak, K., Michlewski, G., de Mezer, M., Kierzek, E., Krol, J., Olejniczak, M., … Krzyzosiak, W. J. (2010). Structural diversity of triplet repeat RNAs. Journal of Biological Chemistry 285(17), 12755–12764.Find this resource:

Sofola, O. A., Jin, P., Qin, Y., Duan, R., Liu, H., de Haro, M., … Botas, J. (2007). RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTAS. Neuron 55(4), 565–571.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:

Stiles, J., & Jernigan, T. L. (2010). The basics of brain development. Neuropsychology Review 20(4), 327–348.Find this resource:

Strumbos, J. G., Brown, M. R., Kronengold, J., Polley, D. B., & Kaczmarek, L. K. (2010). Fragile X mental retardation protein is required for rapid experience-dependent regulation of the potassium channel Kv3.1b. Journal of Neuroscience 30(31), 10263–10271.Find this resource:

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

Sutton, M. A., & Schuman, E. M. (2006). Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127(1), 49–58.Find this resource:

Swanson, M. S. & Orr, H. T. (2007). Fragile X tremor/ataxia syndrome: Blame the messenger! Neuron 55(4), 535–537.Find this resource:

Taft, R. J., Pheasant, M., & Mattick, J. S. (2007). The relationship between non-protein-coding DNA and eukaryotic complexity. Bioessays 29(3), 288–299.Find this resource:

Tang, S. J., Meulemans, D., Vazquez, L., Colaco, N., & Schuman, E. (2001). A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites. Neuron 32(3), 463–475.Find this resource:

Tiedge, H., Fremeau, R. T. Jr., Weinstock, P. H., Arancio, O., & Brosius J. (1991). Dendritic location of neural BC1 RNA. Proceedings of the National Academy of Sciences of the United States of America 88(6), 2093–2097.Find this resource:

Tiedge, H., Chen, W., & Brosius J. (1993). Primary structure, neural-specific expression, and dendritic location of human BC200 RNA. Journal of Neuroscience 13(6), 2382–2390.Find this resource:

Tiedge, H., & Brosius J. (1996). Translational machinery in dendrites of hippocampal neurons in culture. Journal of Neuroscience 16(22), 7171–7181.Find this resource:

Tiedge, H. (2006). K-turn motifs in spatial RNA coding. RNA Biology 3(4), 133–139.Find this resource:

Tübing, F., Vendra, G., Mikl, M., Macchi, P., Thomas, S., & Kiebler, M. A. (2010). Dendritically localized transcripts are sorted into distinct ribonucleoprotein particles that display fast directional motility along dendrites of hippocampal neurons. Journal of Neuroscience 30(11), 4160–4170.Find this resource:

Uhlhaas, P. J. & Singer, W. (2012). Neuronal dynamics and neuropsychiatric disorders: Toward a translational paradigm for dysfunctional large-scale networks. Neuron 75(6), 963–980.Find this resource:

Van Der Kelen, K., Beyaert, R., Inze, D., & De Veylder, L. (2009). Translational control of eukaryotic gene expression. Critical Reviews in Biochemistry and Molecular Biology 44(4), 143–168.Find this resource:

van Gorp, A. G., van der Vos, K. E., Brenkman, A. B., Bremer, A., van den Broek, N., Zwartkruis, F., … Coffer, P. J. (2009). AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B. Oncogene 28(1), 95–106.Find this resource:

Wang, H., Iacoangeli, A., Popp, S., Muslimov, I. A., Imataka, H., Sonenberg, N., … Tiedge ,H. (2002). Dendritic BC1 RNA: Functional role in regulation of translation initiation. Journal of Neuroscience 22(23), 10232–10241.Find this resource:

Wang, H., Iacoangeli, A., Lin, D., Williams, K., Denman, R. B., Hellen, C. U., & Tiedge H. (2005). Dendritic BC1 RNA in translational control mechanisms. Journal of Cell Biology 171(5), 811–821.Find this resource:

Wang, Y., Begley, M., Li, Q., Huang, H. T., Lako, A., Eck, M. J., … Zhao, J. J. (2016). Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival. Proceedings of the National Academy of Sciences of the United States of America 113(35), 9810–9815.Find this resource:

Weiler, I. J., Irwin, S. A., Klintsova, A. Y., Spencer, C. M., Brazelton, A. D., Miyashiro, K., … Greenough, W. T. (1997). Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proceedings of the National Academy of Sciences of the United States of America 94(10), 5395–5400.Find this resource:

Wells, D. G. (2006). RNA-binding proteins: A lesson in repression. Journal of Neuroscience 26(27), 7135–7138.Find this resource:

Yoder-Hill, J., Pause, A., Sonenberg, N., & Merrick, W. C. (1993). The p46 subunit of eukaryotic initiation factor (eIF)-4F exchanges with eIF-4A. Journal of Biological Chemistry 268(8), 5566–5573.Find this resource:

Zhang, H. L., Eom, T., Oleynikov, Y., Shenoy, S. M., Liebelt, D. A., Dictenberg, J. B., … Bassell, G. J. (2001). Neurotrophin-induced transport of a β-actin mRNP complex increases β-actin levels and stimulates growth cone motility. Neuron 31(2), 261–275.Find this resource:

Zhong, J., Chuang, S.C., Bianchi, R., Zhao, W., Lee, H., Fenton, A.A., … Tiedge H. (2009). BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability. Journal of Neuroscience 29(32), 9977–9986.Find this resource:

Ziats, M. N. & Rennert, O. M. (2013). Aberrant expression of long noncoding RNAs in autistic brain. Journal of Molecular Neuroscience 49(3), 589–593.Find this resource:

Zumwalt, M., Ludwig, A., Hagerman, P. J., & Dieckmann, T. (2007). Secondary structure and dynamics of the r(CGG) repeat in the mRNA of the fragile X mental retardation 1 (FMR1) gene. RNA Biology 4(2), 93–100.Find this resource: