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. Author manuscript; available in PMC: 2020 May 1.
Published in final edited form as: Neurobiol Learn Mem. 2019 Apr 15;161:143–148. doi: 10.1016/j.nlm.2019.04.007

The ELAV family of RNA-binding proteins in synaptic plasticity and long-term memory

Anastasios A Mirisis 1, Thomas J Carew 1,*
PMCID: PMC6529270  NIHMSID: NIHMS1527332  PMID: 30998973

Abstract

The mechanisms of de novo gene expression and translation of specific gene transcripts have long been known to support long-lasting changes in synaptic plasticity and behavioral long-term memory. In recent years, it has become increasingly apparent that gene expression is heavily regulated not only on the level of transcription, but also through post-transcriptional gene regulation, which governs the subcellular localization, stability, and likelihood of translation of mRNAs. Specific families of RNA-binding proteins (RBPs) bind transcripts which contain AU-rich elements (AREs) within their 3′ UTR and thereby govern their downstream fate. These post-transcriptional gene regulatory mechanisms are coordinated through the same cell signaling pathways that play critical roles in long-term memory formation. In this review, we discuss recent results that demonstrate the roles that these ARE-binding proteins play in LTM formation.

Keywords: Post-transcriptional regulation, AU-rich elements, ELAV, Hu, long-term memory

Introduction

Long-term memory (LTM) formation in animals ranging from invertebrates to mammals has long been known to depend on de novo gene expression (Alberini, 2009; Davis and Squire, 1984; Kandel, 2001, 2012). Although covalent modification and protein synthesis alone allow for the formation of a memory and synaptic facilitation lasting for minutes to hours, a memory lasting from days to weeks requires active transcription. Pioneering work has revealed that the activity of the cAMP-response element binding (CREB) protein and the induction of specific transcripts such as c/ebp and Egr-1 are required for LTM formation (Alberini, 2009; Maddox et al., 2011; Yamagata et al., 1994).

The C/EBP family of transcription factors (consisting of 6 isoforms) are immediate early genes downstream of CREB (Alberini, 2009; Alberini et al., 1994; Kandel, 2012; Mirisis et al., 2016). The expression, translation, and downstream function of the IEG and transcription factor C/EBP is an evolutionarily conserved mechanism critical for the formation of LTM from mollusks to mammals (Alberini et al., 1994; Taubenfeld et al., 2001). In Aplysia, apc/ebp mRNA is induced rapidly (within 15 min) following serotonin treatment, and its activity as a transcription factor is required for LTM (Alberini et al., 1994). In rat hippocampus, c/ebpβ and c/ebpδ are induced at 9 h and 20 h following inhibitory avoidance (IA) training, and their activities as transcription factors are also required for LTM (Arguello et al., 2013; Taubenfeld et al., 2001). In Aplysia, the homolog of C/EBP has a short and long isoform and is most similar to mammalian C/EBPβ (Alberini et al., 1994). The constitutive activation of a C/EBP complex by PKA alone can support long-term synaptic facilitation in the absence of CREB-mediated transcription (Bartsch et al., 2000; Lee et al., 2006). C/EBP can regulate the transcription of a wide variety of genes based on dimerization with different partners and various post-translational modifications (Tsukada et al., 2011). C/EBPs, particularly the C/EBPβ and C/EBPδ isoforms, are regulated by learning-related stimuli across a wide range of species, as well as across diverse brain regions and learning tasks (Alberini et al., 1994; Arguello et al., 2013; Hatakeyama et al., 2006; Lee et al., 2001; Merhav et al., 2006; Milekic et al., 2007; Taubenfeld et al., 2001).

These findings invite three important inferences: (i) Strong and consequential induction of these specific gene transcripts must be precisely regulated to occur only following stimuli which are permissive for LTM formation, (ii) The gene transcripts must be transported to the appropriate subcellular location, and (iii) The gene transcripts must have a high probability of being translated following induction.

The fate of newly transcribed mRNAs is largely governed by the actions of trans-acting RNA binding elements. RNA-binding proteins (RBPs) directly bind to transcripts via specific binding elements and influence splicing, half-life, subcellular localization, and translation probability. In this review, we focus on post-transcriptional gene regulation by RNA-binding proteins as a critical molecular mechanism underlying learning and memory formation. Primarily, we focus on the non-splicing related functions of the ELAV family of RNA-binding proteins, specifically focusing on transcripts which are implicated in roles in LTM formation, although many more ELAV-target transcripts exists and may additionally be important in critical neuronal functions.

AU-rich elements mediate post-transcriptional gene regulation

AU-rich elements (AREs) are found in the 3′ UTR of many unstable mRNAs including c/ebp, and it is predicted that 5–8% of human mRNAs contain ARE sequences that can be bound and modulated by RBPs (Lee et al., 2015). AREs have traditionally been thought of as destabilizing RNA elements. Most of the RBPs that bind these elements, such as AUF1, ZFP36, KH domain-splicing regulatory protein, and butyrate-regulated factor 1, lead to rapid RNA decay (Figure 1). In Aplysia, overexpression of ApAUF1 significantly blocked the expression of apc/ebp following LTM training, but not through interference with transcription machinery, demonstrating a post-transcriptional event (Lee et al., 2012). Further, overexpression of ApAUF1 blocked the induction of long-term facilitation (LTF) at the sensory-motor neuron (SN-MN) synapse (Lee et al., 2012), underscoring the impact that these destabilizing RBPs exert on their target transcripts and their downstream fates.

Figure 1.

Figure 1

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Following transcription and RNA processing, ARE-containing mRNAs are susceptible to degradation mediated by RNA-binding proteins, such as AUF1. If ELAV is able to bind the mRNA, however, the transcript is stabilized, increasing translation probability and conferring the ability to be transported to distinct subcellular compartments.

Interestingly, deletion of auf1 in mice led to a dramatic increase in the expression of mmp9, an ARE-containing transcript encoding a matrix metalloprotease, which is known to activate latent TGFβ−1 (Bai et al., 2017; Chenette et al., 2016). Since TGFβ−1 is a growth factor known to be critical for LTM formation in species ranging from rodents to Aplysia, (Caraci et al., 2015; Kopec et al., 2015), it is possible that the upregulation of MMP9 would interfere with endogenous molecular mechanisms promoting LTM formation.

The RNA-binding protein ELAV

In addition to RBPs which destabilize ARE-containing mRNAs, other RBPs actually stabilize these transcripts and prevent their degradation. One such member of this group is the family of ELAV (embryonic lethal abnormal vision) proteins. First discovered in Drosophila (Campos et al., 1985; Homyk et al., 1985), ELAV proteins bind ARE-containing transcripts. In mammals, ELAV proteins prevent their association of these transcripts with other ARE-binding RBPs which would otherwise promote exonuclease- or endonuclease-mediated degradation (Chen et al., 1995; Colombrita et al., 2013; Fan and Steitz, 1998; Ross, 1995). Therefore, the presence of AREs does not necessarily result in destabilization of a message, but rather can allow for post-transcriptional modulation of the levels of these transcripts by their association with other RBPs, which in turn promote their stabilization (Figure 1).

There are four ELAV family members in mammals: HuA/R, HuB, HuC, and HuD (Brennan and Steitz, 2001; Fan and Steitz, 1998). Whereas HuA/R is expressed ubiquitously throughout the organism, the other three family members (HuB, HuC, and HuD) are exclusively neuronal due to translational repression in other cell types (Brennan and Steitz, 2001; Choudhury et al., 2017; Colombrita et al., 2013). All four homologs contain three remarkably conserved RNA recognition motifs (RRMs). Although all three RRMs contribute to transcript stability, only the first two (RRM1 and RRM2) have been consistently shown to directly associate with ARE-containing transcripts (Fan and Steitz, 1998). RRM3 is thought to promote transcript stability (i) by steric hinderance for poly-A degrading exonucleases, and/or (ii) by promoting the association of ELAV with other RNA-stabilizing factors (Colombrita et al., 2013; Scheiba et al., 2014; Toba and White, 2008). RRM3 is also thought to be important for the interaction of ELAVs with ribosomal machinery, which would increase the translation probability of associated transcripts (Bolognani et al., 2004; Doller et al., 2008a; Doller et al., 2013).

Since ARE-containing mRNAs are rapidly destabilized at basal state, what governs the ability of ELAVs to selectively stabilize, shuttle, and promote the translation of these transcripts? Studies focusing on understanding how ELAV is recruited to perform these functions have revealed several post-translational modifications that alter its activity. The mammalian ELAV protein HuR is phosphorylated by PKC and p38 MAPK (Doller et al., 2007; Doller et al., 2008b; Doller et al., 2010; Doller et al., 2011; Eberhardt et al., 2012; Lafarga et al., 2009). Phosphorylation of ELAV in many systems has been shown to increase its binding affinity for AREs (Doller et al., 2008a; Doller et al., 2011; Eberhardt et al., 2012; Pascale et al., 2005), as well as modulate the binding affinity of ELAV to specific types of AREs (Doller et al., 2010; Eberhardt et al., 2012). In a synergistic process, p38 MAPK activation has also been shown to inhibit the activity of destabilizing ARE-binding proteins, which would act to significantly shift the balance towards mRNA stabilization (Briata et al., 2005). Noting the critical involvement of PKC and p38 MAPK in ELAV activation, it is important to understand the role that these kinases play in learning and memory formation. Several comprehensive reviews exploring the role of these and other kinases in the induction of LTM and its underlying synaptic plasticity have been previously published (Kandel, 2001, 2012; Mirisis et al., 2016; Sossin, 2007).

ELAV proteins play critical roles in stabilizing mRNAs during learning and memory formation. Two ELAV family members, ApELAV1 and ApELAV2, have been discovered and cloned in Aplysia, and ApELAV1 has been shown to bind to apc/ebp mRNA both in vitro and in vivo (Yim et al., 2006). Interestingly, microinjection of the 3′ UTR of c/ebp mRNA, which contains the putative binding sites (AREs) for ApELAV, into sensory neurons (SNs), blocks the induction of LTF in SN-MN co-culture (Yim et al., 2006).

In rats, HuD protein and mRNA levels are increased in hippocampus 24 h following spatial learning (Pascale et al., 2004). Concurrently, there is an increase in the interaction between HuD and GAP-43 mRNA (a known HuD target transcript) in hippocampus, as well as an increase in the mRNA and protein expression of GAP-43 (Pascale et al., 2004). Following contextual fear conditioning in rats, HuD protein levels are increased in the hilus and CA3 regions of the hippocampus (Bolognani et al., 2004). HuD was also observed to colocalize with polysomes in the somatic and dentritic compartments of CA3, CA1, and hilus pyramidal neurons (Bolognani et al., 2004).

Transgenic overexpression of HuD in mouse forebrain, however, leads to deficits in spatial learning as well as contextual and cued fear conditioning (Bolognani et al., 2007). This may be due to an endogenous specificity of HuD-mediated transcript stabilization which is not conserved when the protein is overexpressed throughout the forebrain. Additionally, there may be one or more phosphorylation events which are able to activate endogenous HuD, but unable to transduce signals when HuD is overexpressed.

In the context of addiction, HuD has been implicated in upregulation of Bdnf and Camk2a in nucleus accumbens (Oliver et al., 2018). Following cocaine conditioned place preference, a model of addiction-related behaviors, HuD mRNA and protein levels were significantly increased in mouse nucleus accumbens, concurrent with increases in Bdnf and Camk2a mRNA and protein. Mice which overexpressed HuD throughout the forebrain demonstrated increased cocaine conditioned place preference compared to control mice, implicating HuD in a role for enhancing addition behaviors by amplifying the underlying molecular effects of addiction (Oliver et al., 2018).

Importantly, several ELAV-target transcripts are particularly important in regulating memory-relevant neurotransmission pathways. The Rho-GTPase Cdc42 transcript has been shown to be heavily influenced by HuR binding (Liu et al., 2017), and Cdc42 is important for dendritic spine formation and clustering (Harvey et al., 2008; Murakoshi et al., 2011; Rogerson et al., 2014; Tolias et al., 2011). In fact, Cdc42 plays a role in supporting TGFβ signaling by promoting epithelial to mesenchymal transition (Zhang, 2009), underscoring the intertwined nature of the ELAV-mediated effects on transcript stabilization.

ELAV-mediated transcript shuttling

The ELAV proteins contain a long amino acid stretch known as the “hinge” region between RRM2 and RRM3, which is the least conserved domain between these family members and between species. The composition of the hinge region governs the subcellular localization of these proteins. HuA/R is predominantly nuclear but contains within its hinge region a specialized shuttling sequence, known as the HuR nucleocytoplasmic shuttling sequence (HNS), which allows it to shuttle between the nucleus and the cytoplasm (Brennan and Steitz, 2001; Doller et al., 2008b; Fan and Steitz, 1998). The other ELAV proteins are mostly cytoplasmic but are also thought to shuttle into and out of the nucleus (Colombrita et al., 2013).

HuR shuttling is governed by post-translational modifications of key residues, but the precise mechanism of shuttling activation remains to be understood. In vitro studies revealed that phosphorylation by PKCα and PKCδ regulate its nucleocytoplasmic shuttling ability (Doller et al., 2007; Doller et al., 2008b; Doller et al., 2010). In different systems, however, p38 MAPK activation is responsible for the cytoplasmic translocation of HuR (Lafarga et al., 2009). In cardiac ventricular myocytes, for example, treatment with phenylephrine and angiotensin II led to a cytoplasmic translocation of HuR which was blocked with SB203580 (an inhibitor of p38 MAPK), but was specifically not affected by chelerythrine (an inhibitor of PKC) (Slone et al., 2016).

Interestingly, in vitro treatment of cardiac fibroblasts with TGFβ has been shown to result in a strong nuclear to cytoplasmic translocation of HuR (Bai et al., 2012). This may be due to activation of p38 MAPK downstream of TGFβ signaling as part of the non-canonical TGFβ signaling pathway (Massague, 1998; Zhang, 2009).

HuD has also been implicated in shuttling mRNAs to distinct subcellular compartments within neurons. For example, HuD shuttles GAP-43 mRNA to growth cones following NGF stimulation of cultured PC12 neurons, where it colocalizes with polysomes and promotes the translation of its associated transcript, facilitating neuronal growth (Smith et al., 2004).

Shuttling of mRNAs to distinct subcellular compartments by ELAV proteins may have significant implications in memory formation. Groundbreaking studies in the composition of the synaptic compartment have revealed the importance of local translation for the establishment of a unique synaptic proteome (Kim and Martin, 2015; Poo et al., 2016). In 1997, two critical papers highlighted the importance of local synaptic interactions with nuclear events (Frey and Morris, 1997; Martin et al., 1997). In Aplysia, Martin et al. (1997) proposed the idea of “synaptic capture.” When serotonin-mediated LTF was induced in one SN-MN synapse in a bifuracated Aplysia sensory neuron preparation, a single exposure to serotonin, which is subthreshold for LTF induction, was able to induce LTF at an unstimulated synapse on a separate neuronal branch. Emetine had no effect when co-applied with a single pulse of serotonin on the unstimulated synapse, but did block LTF at both stimulated and unstimulated synapses when applied concurrently with the initial 5 pulses of serotonin on the stimulated branch (Martin et al., 1997). These findings highlight two critical principles: (i) there is a retrograde signal from the synapse to the soma to initiate transcription, and (ii) mRNAs can be stored locally at the synapse for rapid translation.

This observation of a local, protein synthesis-dependent tag at the synapse aligns with findings of ARE-containing mRNAs in dendrites. Arguello et al. (2013) found that c/ebpδ mRNA is localized to the dendritic compartment of isolated hippocampal neurons. Interestingly, despite their function as nuclear transcription factors, C/EBPs are localized to the cytoplasm and dendrites (Alberini, 2009; Metz and Ziff, 1991). This process is thought to functionally link the distal (synaptic) and nuclear compartments of the cell as a means of regulating transcription (Alberini, 2009; Metz and Ziff, 1991). Due to the induced nature of these transcription factors and their interaction with ELAV proteins, it is possible that ELAVs may control or even mediate the observed dendritic localization of these and other ARE-containing mRNAs. This complex process of ELAV-mediated transcript targeting and local dendritic translation would allow for the observed finely tuned downstream transcriptional consequences of molecular signaling.

ELAV proteins as promoters of translation

ELAV proteins promote the translation of their associated transcripts by directly interacting with cellular translation machinery. For example, Fukao et al. (2009) found that HuD promotes neuronal differentiation by interacting with eIF4A directly through RRM3. Whereas the interaction between HuD and actively transcribing mRNA was directly dependent on both the hinge region and RRM3, a single point mutation within the hinge region completely abolished the interaction between HuD and eIF4A. Suprisingly, HuD seemed to bind indiscriminately to the poly-A tail of mRNAs, implicating HuD in contributing to an increase in global translation, rather than an increase in specific translation of its target transcripts. Overexpression of wild-type HuD induced neurite outgrowth in PC12 cells which was blocked by overexpression of mutant HuD that was unable to interact with actively transcribing mRNA and/or with eIF4A (Fukao et al., 2009), demonstrating a clear functional importance of HuD-mediated translation in the morphology of rat cortical neurons.

Tebaldi et al. (2018) generated a nucleotide resolution map of the HuD-RNA interactome in motor neuron-like NSC-34 cells. They found that HuD binds 1,304 mRNAs, including transcripts encoding mTORC1-responsive ribosomal proteins and translation factors. Overexpression of HuD in motor neurons resulted in a global increase in translation, which was independent of mTOR. Surprisingly, small non-coding RNA Y3 amounted for 70% of the HuD interaction signal, implicating Y3 in a function as a molecular sink which dampers the effects of HuD on promoting translation (Tebaldi et al., 2018).

ELAV-mediated transcript splicing

In addition to stabilizing, shuttling, and promoting the translation of target transcripts, ELAV proteins are critical for the proper splicing of several mRNAs. For example, in brains of Alzheimer’s disease patients, there is differential splicing of 150 targets of neuronal ELAV proteins. This is thought to result from pathological binding of ELAV to non-coding Y RNAs, which sequester ELAV from its target transcripts and lead to aberrant splicing (Scheckel et al., 2016). In Drosophila, ELAV regulates splicing of the mRNAs erect wing, neuroglian, and armadillo by binding to AREs in their respective 3′ UTRs and modulating splice site choice, promoting alternative splicing of this transcript (Koushika et al., 2000; Lisbin et al., 2001; Soller and White, 2003).

In addition to direct implications on splicing, ELAV is thought to play a role in regulating alternative polyadenylation in the nervous system. HuR may promote lengthening of the 3′ UTR of target transcripts by its binding and stabilization of AREs in that region (Mansfield and Keene, 2012; Miura et al., 2014). In fact, alternative polyadenylation has been observed in Alzheimer’s disease neuropathology and is thought to result, at least in part, from a dysregulation of RBPs (Barbash et al., 2017).

miRNAs as mediators of transcript stability

In addition to the actions of the RBPs mentioned above, micro RNAs (miRNAs) play a critical role in regulating the probability that a transcript will be translated. miRNAs are short, non-coding RNA molecules which bind, primarily in the 3′ UTR of their target sequences, and act to repress translation (Bartel, 2009; Filipowicz et al., 2008; Shukla et al., 2011). In Aplysia SNs, the miRNA miR-124 is known to play a critical role in modulating the translation of CREB1. miR-124 binds within the 3′-UTR of CREB1 mRNA and prevents its translation in the absence of serotonin regulation (Rajasethupathy et al., 2009). In the presence of serotonin, miR-124 is rapidly downregulated, resulting in the de-repression of CREB1 translation, thus releasing the post-transcriptional inhibitory constraint on synaptic plasticity and long-term facilitation (Rajasethupathy et al., 2009). Upregulation of CREB1 translation allows for the direct upregulation of apc/ebp gene expression through an increase in CREB-mediated transcription, which allows for the induction of downstream cellular and synaptic processes critical in LTM formation.

TGFβ as a critical regulator of gene expression in LTM formation

The TGFβ superfamily includes a large number of polypeptide growth factors which, among other biological functions including cell proliferation, motility, adhesion, and death, also play a role in modulating neural circuitry (Lacmann et al., 2007; Massague, 1998; Specht et al., 2003). TGFβ signaling involves the binding of extracellular ligand to a transmembrane TGFβ receptor complex, which in turn results in downstream activation of either the canonical TGFβ signaling pathway through Smad proteins, and/or a non-canonical pathway involving, among other molecular events, activation of PKC, MAPK, and PI3K (Massague, 1998, 2000; Massague and Chen, 2000; Massague and Wotton, 2000; Zhang, 2009), which may lead to the downstream activation of ELAV.

Signaling through distinct GF families has been found to be specifically engaged, both spatially and temporally, during LTM formation in Aplysia (Kopec et al., 2015). In the first trial of a two-trial training paradigm, TrkB signaling at the sensory neuron synapse is required for apc/ebp gene expression at 45 min following the onset of the training trial, and TGFβ signaling is required at the sensory neuron soma during the second training trial (at 45 min) for prolonged increase in apc/ebp mRNA level (Kopec et al., 2015).

Caraci et al. (2015) found that treatment of mouse hippocampal slices with the specific TGFβ inhibitor SB431542 impairs long-term potentiation (LTP). Further, intrahippocampal injection of SB431542 impairs object recognition memory in mouse, but is rescued by concurrent treatment with recombinant TGFβ−1 (Caraci et al., 2015).

There is considerable evidence that TGFβ−1 initiates stabilization of mRNAs via an RNA binding complex (Amara et al., 1995). In cardiac fibroblasts, TGFβ−1 treatment induced HuR (a member of the mammalian ELAV family) translocation from the nucleus to the cytoplasm where it bound the ARE region of the 3′ UTR in TGFβ−1 mRNA thus stabilizing the mRNA and increasing protein level (Bai et al., 2012). These data suggest the intriguing possibility that, in addition to TGFβr-II signaling initiating a cascade to prolong the expression of critical learning-related genes like c/ebp or Egr-1, other GF ligands could be induced and stabilized in the same way (including a TGFβ−1-like ligand itself). Indeed, GF ligands (Lim and Alkon, 2012) as well as their receptors (Balmer et al., 2001) can be regulated by ARE RNA binding proteins.

Interestingly, TGFβ−1 is secreted from cells as part of a “latent complex” which requires either proteolytic cleavage or integrin-mediated structural rearrangement in order to release the active TGFβ−1 ligand dimer (Rifkin et al., 2018; Robertson et al., 2015; Robertson and Rifkin, 2016). As previously mentioned, mmp9 is a metalloprotease transcript which contains AREs in its 3′ UTR (Chenette et al., 2016). At steady state, AUF1 binds mmp9, which leads to its rapid decay. When AUF1 is knocked out, mmp9 expression is dramatically increased, leading to muscle wasting in a mouse model (Chenette et al., 2016). In addition to its role in regulating the extracellular matrix of muscles, MMP9 has additionally been shown to activate TGFβ in mammals (Bai et al., 2017; Kobayashi et al., 2014), pointing to a possible positive feedback loop whereby TGFβ signaling activates ELAV, which then stabilizes the mmp9 transcript, allowing for its prolonged expression and continued TGFβ activation. In fact, MMP9 has been implicated in roles in neural function and synaptic plasticity including supporting dendritic spine morphogenesis and the induction of LTP in hippocampal slices (Dziembowska and Wlodarczyk, 2012; Lepeta and Kaczmarek, 2015; Michaluk et al., 2011; Stefaniuk et al., 2017; Wiera et al., 2015).

Intriguingly, the metalloprotease ApTBL-1 is expressed in the Aplysia nervous system and is thought to mediate the activation of TGFβ in this system (Herdegen et al., 2014; Liu et al., 1997). Further, ApTBL-1 contains AREs in its 3′ UTR, and the expression of this metalloprotease is dramatically increased following LTM training (Conte et al., 2017; Herdegen et al., 2014; Liu et al., 1997), pointing to a possible conserved mechanism whereby transcript stabilizing RBPs such as ELAV are responsible for promoting a positive feedback loop to maintain TGFβ signaling in neural circuits.

Highlights.

  • AU-rich elements confer instability to mRNAs, but stabilizing RNA-binding proteins can bind these elements and promote stabilization.

  • The ELAV family of RNA-binding proteins promote stabilization, transcript shuttling, and translation.

  • The activity of ELAV proteins can be regulated by phosporylation.

  • TGFβ signaling regulates the activity of ELAV proteins.

Funding-

This work was supported by NIMH RO1 MH 041083 to TJC and a Hellenic Medical Society of New York Leonidas Lantzounis Research Grant to AAM.

Footnotes

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Declaration of Interest- None.

References

  1. Alberini CM (2009). Transcription factors in long-term memory and synaptic plasticity. Physiol Rev 89, 121–145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alberini CM, Ghirardi M, Metz R, and Kandel ER (1994). C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia. Cell 76, 1099–1114. [DOI] [PubMed] [Google Scholar]
  3. Amara FM, Chen FY, and Wright JA (1995). Defining a novel cis element in the 3′-untranslated region of mammalian ribonucleotide reductase component R2 mRNA: role in transforming growth factor-beta 1 induced mRNA stabilization. Nucleic Acids Res 23, 1461–1467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Arguello AA, Ye X, Bozdagi O, Pollonini G, Tronel S, Bambah-Mukku D, Huntley GW, Platano D, and Alberini CM (2013). CCAAT enhancer binding protein delta plays an essential role in memory consolidation and reconsolidation. J Neurosci 33, 3646–3658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bai D, Gao Q, Li C, Ge L, Gao Y, and Wang H (2012). A conserved TGFbeta1/HuR feedback circuit regulates the fibrogenic response in fibroblasts. Cell Signal 24, 1426–1432. [DOI] [PubMed] [Google Scholar]
  6. Bai X, Li YY, Zhang HY, Wang F, He HL, Yao JC, Liu L, and Li SS (2017). Role of matrix metalloproteinase-9 in transforming growth factor-beta1-induced epithelial-mesenchymal transition in esophageal squamous cell carcinoma. Onco Targets Ther 10, 2837–2847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Balmer LA, Beveridge DJ, Jazayeri JA, Thomson AM, Walker CE, and Leedman PJ (2001). Identification of a novel AU-Rich element in the 3′ untranslated region of epidermal growth factor receptor mRNA that is the target for regulated RNA-binding proteins. Mol Cell Biol 21, 2070–2084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Barbash S, Garfinkel BP, Maoz R, Simchovitz A, Nadorp B, Guffanti A, Bennett ER, Nadeau C, Turk A, Paul L, et al. (2017). Alzheimer′s brains show inter-related changes in RNA and lipid metabolism. Neurobiol Dis 106, 1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bartel DP (2009). MicroRNAs: target recognition and regulatory functions. Cell 136, 215–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Bartsch D, Ghirardi M, Casadio A, Giustetto M, Karl KA, Zhu H, and Kandel ER (2000). Enhancement of memory-related long-term facilitation by ApAF, a novel transcription factor that acts downstream from both CREB1 and CREB2. Cell 103, 595–608. [DOI] [PubMed] [Google Scholar]
  11. Bolognani F, Merhege MA, Twiss J, and Perrone-Bizzozero NI (2004). Dendritic localization of the RNA-binding protein HuD in hippocampal neurons: association with polysomes and upregulation during contextual learning. Neurosci Lett 371, 152–157. [DOI] [PubMed] [Google Scholar]
  12. Bolognani F, Qiu S, Tanner DC, Paik J, Perrone-Bizzozero NI, and Weeber EJ (2007). Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD. Neurobiol Learn Mem 87, 635–643. [DOI] [PubMed] [Google Scholar]
  13. Brennan CM, and Steitz JA (2001). HuR and mRNA stability. Cell Mol Life Sci 58, 266–277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Briata P, Forcales SV, Ponassi M, Corte G, Chen CY, Karin M, Puri PL, and Gherzi R (2005). p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Mol Cell 20, 891–903. [DOI] [PubMed] [Google Scholar]
  15. Campos AR, Grossman D, and White K (1985). Mutant alleles at the locus elav in Drosophila melanogaster lead to nervous system defects. A developmental-genetic analysis. J Neurogenet 2, 197–218. [DOI] [PubMed] [Google Scholar]
  16. Caraci F, Gulisano W, Guida CA, Impellizzeri AA, Drago F, Puzzo D, and Palmeri A (2015). A key role for TGF-beta1 in hippocampal synaptic plasticity and memory. Sci Rep 5, 11252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Chen CY, Xu N, and Shyu AB (1995). mRNA decay mediated by two distinct AU-rich elements from c-fos and granulocyte-macrophage colony-stimulating factor transcripts: different deadenylation kinetics and uncoupling from translation. Mol Cell Biol 15, 5777–5788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chenette DM, Cadwallader AB, Antwine TL, Larkin LC, Wang J, Olwin BB, and Schneider RJ (2016). Targeted mRNA Decay by RNA Binding Protein AUF1 Regulates Adult Muscle Stem Cell Fate, Promoting Skeletal Muscle Integrity. Cell Rep 16, 1379–1390. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Choudhury SD, Vs A, Mushtaq Z, and Kumar V (2017). Altered translational repression of an RNA-binding protein, Elav by AOA2-causative Senataxin mutation. Synapse 71. [DOI] [PubMed] [Google Scholar]
  20. Colombrita C, Silani V, and Ratti A (2013). ELAV proteins along evolution: back to the nucleus? Mol Cell Neurosci 56, 447–455. [DOI] [PubMed] [Google Scholar]
  21. Conte C, Herdegen S, Kamal S, Patel J, Patel U, Perez L, Rivota M, Calin-Jageman RJ, and Calin-Jageman IE (2017). Transcriptional correlates of memory maintenance following long-term sensitization of Aplysia californica. Learn Mem 24, 502–515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Davis HP, and Squire LR (1984). Protein synthesis and memory: a review. Psychol Bull 96, 518–559. [PubMed] [Google Scholar]
  23. Doller A, Akool el S, Huwiler A, Muller R, Radeke HH, Pfeilschifter J, and Eberhardt W (2008a). Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cdelta elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol Cell Biol 28, 2608–2625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Doller A, Huwiler A, Muller R, Radeke HH, Pfeilschifter J, and Eberhardt W (2007). Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2. Mol Biol Cell 18, 2137–2148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Doller A, Pfeilschifter J, and Eberhardt W (2008b). Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR. Cell Signal 20, 2165–2173. [DOI] [PubMed] [Google Scholar]
  26. Doller A, Schlepckow K, Schwalbe H, Pfeilschifter J, and Eberhardt W (2010). Tandem phosphorylation of serines 221 and 318 by protein kinase Cdelta coordinates mRNA binding and nucleocytoplasmic shuttling of HuR. Mol Cell Biol 30, 1397–1410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Doller A, Schulz S, Pfeilschifter J, and Eberhardt W (2013). RNA-dependent association with myosin IIA promotes F-actin-guided trafficking of the ELAV-like protein HuR to polysomes. Nucleic Acids Res 41, 9152–9167. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Doller A, Winkler C, Azrilian I, Schulz S, Hartmann S, Pfeilschifter J, and Eberhardt W (2011). High-constitutive HuR phosphorylation at Ser 318 by PKC{delta} propagates tumor relevant functions in colon carcinoma cells. Carcinogenesis 32, 676–685. [DOI] [PubMed] [Google Scholar]
  29. Dziembowska M, and Wlodarczyk J (2012). MMP9: a novel function in synaptic plasticity. Int J Biochem Cell Biol 44, 709–713. [DOI] [PubMed] [Google Scholar]
  30. Eberhardt W, Doller A, and Pfeilschifter J (2012). Regulation of the mRNA-binding protein HuR by posttranslational modification: spotlight on phosphorylation. Curr Protein Pept Sci 13, 380–390. [DOI] [PubMed] [Google Scholar]
  31. Fan XC, and Steitz JA (1998). Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs. EMBO J 17, 3448–3460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Filipowicz W, Bhattacharyya SN, and Sonenberg N (2008). Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9, 102–114. [DOI] [PubMed] [Google Scholar]
  33. Frey U, and Morris RG (1997). Synaptic tagging and long-term potentiation. Nature 385, 533–536. [DOI] [PubMed] [Google Scholar]
  34. Fukao A, Sasano Y, Imataka H, Inoue K, Sakamoto H, Sonenberg N, Thoma C, and Fujiwara T (2009). The ELAV protein HuD stimulates cap-dependent translation in a Poly(A)- and eIF4A-dependent manner. Mol Cell 36, 1007–1017. [DOI] [PubMed] [Google Scholar]
  35. Harvey CD, Yasuda R, Zhong H, and Svoboda K (2008). The spread of Ras activity triggered by activation of a single dendritic spine. Science 321, 136–140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Hatakeyama D, Sadamoto H, Watanabe T, Wagatsuma A, Kobayashi S, Fujito Y, Yamashita M, Sakakibara M, Kemenes G, and Ito E (2006). Requirement of new protein synthesis of a transcription factor for memory consolidation: paradoxical changes in mRNA and protein levels of C/EBP. J Mol Biol 356, 569–577. [DOI] [PubMed] [Google Scholar]
  37. Herdegen S, Conte C, Kamal S, Calin-Jageman RJ, and Calin-Jageman IE (2014). Immediate and persistent transcriptional correlates of long-term sensitization training at different CNS loci in Aplysia californica. PLoS One 9, e114481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Homyk T Jr., Isono K, and Pak WL (1985). Developmental and physiological analysis of a conditional mutation affecting photoreceptor and optic lobe development in Drosophila melanogaster. J Neurogenet 2, 309–324. [DOI] [PubMed] [Google Scholar]
  39. Kandel ER (2001). The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038. [DOI] [PubMed] [Google Scholar]
  40. Kandel ER (2012). The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 5, 14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Kim S, and Martin KC (2015). Neuron-wide RNA transport combines with netrin-mediated local translation to spatially regulate the synaptic proteome. Elife 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kobayashi T, Kim H, Liu X, Sugiura H, Kohyama T, Fang Q, Wen FQ, Abe S, Wang X, Atkinson JJ, et al. (2014). Matrix metalloproteinase-9 activates TGF-beta and stimulates fibroblast contraction of collagen gels. Am J Physiol Lung Cell Mol Physiol 306, L1006–1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kopec AM, Philips GT, and Carew TJ (2015). Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica. Neuron 86, 1228–1239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Koushika SP, Soller M, and White K (2000). The neuron-enriched splicing pattern of Drosophila erect wing is dependent on the presence of ELAV protein. Mol Cell Biol 20, 1836–1845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Lacmann A, Hess D, Gohla G, Roussa E, and Krieglstein K (2007). Activity-dependent release of transforming growth factor-beta in a neuronal network in vitro. Neuroscience 150, 647–657. [DOI] [PubMed] [Google Scholar]
  46. Lafarga V, Cuadrado A, Lopez de Silanes I, Bengoechea R, Fernandez-Capetillo O, and Nebreda AR (2009). p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S checkpoint. Mol Cell Biol 29, 4341–4351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Lee JA, Kim HK, Kim KH, Han JH, Lee YS, Lim CS, Chang DJ, Kubo T, and Kaang BK (2001). Overexpression of and RNA interference with the CCAAT enhancer-binding protein on long-term facilitation of Aplysia sensory to motor synapses. Learn Mem 8, 220–226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Lee JA, Lee SH, Lee C, Chang DJ, Lee Y, Kim H, Cheang YH, Ko HG, Lee YS, Jun H, et al. (2006). PKA-activated ApAF-ApC/EBP heterodimer is a key downstream effector of ApCREB and is necessary and sufficient for the consolidation of long-term facilitation. J Cell Biol 174, 827–838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Lee YS, Choi SL, Jun H, Yim SJ, Lee JA, Kim HF, Lee SH, Shim J, Lee K, Jang DJ, et al. (2012). AU-rich element-binding protein negatively regulates CCAAT enhancer-binding protein mRNA stability during long-term synaptic plasticity in Aplysia. Proc Natl Acad Sci U S A 109, 15520–15525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Lee YS, Lee JA, and Kaang BK (2015). Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiol Learn Mem 124, 28–33. [DOI] [PubMed] [Google Scholar]
  51. Lepeta K, and Kaczmarek L (2015). Matrix Metalloproteinase-9 as a Novel Player in Synaptic Plasticity and Schizophrenia. Schizophr Bull 41, 1003–1009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Lim CS, and Alkon DL (2012). Protein kinase C stimulates HuD-mediated mRNA stability and protein expression of neurotrophic factors and enhances dendritic maturation of hippocampal neurons in culture. Hippocampus 22, 2303–2319. [DOI] [PubMed] [Google Scholar]
  53. Lisbin MJ, Qiu J, and White K (2001). The neuron-specific RNA-binding protein ELAV regulates neuroglian alternative splicing in neurons and binds directly to its pre mRNA. Genes Dev 15, 2546–2561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Liu L, Zhuang R, Xiao L, Chung HK, Luo J, Turner DJ, Rao JN, Gorospe M, and Wang JY (2017). HuR Enhances Early Restitution of the Intestinal Epithelium by Increasing Cdc42 Translation. Mol Cell Biol 37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Liu QR, Hattar S, Endo S, MacPhee K, Zhang H, Cleary LJ, Byrne JH, and Eskin A (1997). A developmental gene (Tolloid/BMP-1) is regulated in Aplysia neurons by treatments that induce long-term sensitization. J Neurosci 17, 755–764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Maddox SA, Monsey MS, and Schafe GE (2011). Early growth response gene 1 (Egr-1) is required for new and reactivated fear memories in the lateral amygdala. Learn Mem 18, 24–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Mansfield KD, and Keene JD (2012). Neuron-specific ELAV/Hu proteins suppress HuR mRNA during neuronal differentiation by alternative polyadenylation. Nucleic Acids Res 40, 2734–2746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, and Kandel ER (1997). Synapse-specific, long-term facilitation of aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell 91, 927–938. [DOI] [PubMed] [Google Scholar]
  59. Massague J (1998). TGF-beta signal transduction. Annu Rev Biochem 67, 753–791. [DOI] [PubMed] [Google Scholar]
  60. Massague J (2000). How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1, 169–178. [DOI] [PubMed] [Google Scholar]
  61. Massague J, and Chen YG (2000). Controlling TGF-beta signaling. Genes Dev 14, 627–644. [PubMed] [Google Scholar]
  62. Massague J, and Wotton D (2000). Transcriptional control by the TGF-beta/Smad signaling system. EMBO J 19, 1745–1754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Merhav M, Kuulmann-Vander S, Elkobi A, Jacobson-Pick S, Karni A, and Rosenblum K (2006). Behavioral interference and C/EBPbeta expression in the insular-cortex reveal a prolonged time period for taste memory consolidation. Learn Mem 13, 571–574. [DOI] [PubMed] [Google Scholar]
  64. Metz R, and Ziff E (1991). cAMP stimulates the C/EBP-related transcription factor rNFIL-6 to trans-locate to the nucleus and induce c-fos transcription. Genes Dev 5, 1754–1766. [DOI] [PubMed] [Google Scholar]
  65. Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, Mercik K, Medvedev N, Wilczek E, De Roo M, Zuschratter W, et al. (2011). Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J Cell Sci 124, 3369–3380. [DOI] [PubMed] [Google Scholar]
  66. Milekic MH, Pollonini G, and Alberini CM (2007). Temporal requirement of C/EBPbeta in the amygdala following reactivation but not acquisition of inhibitory avoidance. Learn Mem 14, 504–511. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Mirisis AA, Alexandrescu A, Carew TJ, and Kopec AM (2016). The Contribution of Spatial and Temporal Molecular Networks in the Induction of Long-term Memory and Its Underlying Synaptic Plasticity. AIMS Neurosci 3, 356–384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Miura P, Sanfilippo P, Shenker S, and Lai EC (2014). Alternative polyadenylation in the nervous system: to what lengths will 3′ UTR extensions take us? Bioessays 36, 766–777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. Murakoshi H, Wang H, and Yasuda R (2011). Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature 472, 100–104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Oliver RJ, Brigman JL, Bolognani F, Allan AM, Neisewander JL, and Perrone-Bizzozero NI (2018). Neuronal RNA-binding protein HuD regulates addiction-related gene expression and behavior. Genes Brain Behav 17, e12454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Pascale A, Amadio M, Scapagnini G, Lanni C, Racchi M, Provenzani A, Govoni S, Alkon DL, and Quattrone A (2005). Neuronal ELAV proteins enhance mRNA stability by a PKCalpha-dependent pathway. Proc Natl Acad Sci U S A 102, 12065–12070. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Pascale A, Gusev PA, Amadio M, Dottorini T, Govoni S, Alkon DL, and Quattrone A (2004). Increase of the RNA-binding protein HuD and posttranscriptional up-regulation of the GAP-43 gene during spatial memory. Proc Natl Acad Sci U S A 101, 1217–1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Poo MM, Pignatelli M, Ryan TJ, Tonegawa S, Bonhoeffer T, Martin KC, Rudenko A, Tsai LH, Tsien RW, Fishell G, et al. (2016). What is memory? The present state of the engram. BMC Biol 14, 40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Rajasethupathy P, Fiumara F, Sheridan R, Betel D, Puthanveettil SV, Russo JJ, Sander C, Tuschl T, and Kandel E (2009). Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63, 803–817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Rifkin DB, Rifkin WJ, and Zilberberg L (2018). LTBPs in biology and medicine: LTBP diseases. Matrix Biol 71–72, 90–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
  76. Robertson IB, Horiguchi M, Zilberberg L, Dabovic B, Hadjiolova K, and Rifkin DB (2015). Latent TGF-beta-binding proteins. Matrix Biol 47, 44–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Robertson IB, and Rifkin DB (2016). Regulation of the Bioavailability of TGF-beta and TGF-beta-Related Proteins. Cold Spring Harb Perspect Biol 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  78. Rogerson T, Cai DJ, Frank A, Sano Y, Shobe J, Lopez-Aranda MF, and Silva AJ (2014). Synaptic tagging during memory allocation. Nat Rev Neurosci 15, 157–169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Ross J (1995). mRNA stability in mammalian cells. Microbiol Rev 59, 423–450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Scheckel C, Drapeau E, Frias MA, Park CY, Fak J, Zucker-Scharff I, Kou Y, Haroutunian V, Ma′ayan A, Buxbaum JD, et al. (2016). Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain. Elife 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Scheiba RM, de Opakua AI, Diaz-Quintana A, Cruz-Gallardo I, Martinez-Cruz LA, Martinez-Chantar ML, Blanco FJ, and Diaz-Moreno I (2014). The C-terminal RNA binding motif of HuR is a multi-functional domain leading to HuR oligomerization and binding to U-rich RNA targets. RNA Biol 11, 1250–1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Shukla GC, Singh J, and Barik S (2011). MicroRNAs: Processing, Maturation, Target Recognition and Regulatory Functions. Mol Cell Pharmacol 3, 83–92. [PMC free article] [PubMed] [Google Scholar]
  83. Slone S, Anthony SR, Wu X, Benoit JB, Aube J, Xu L, and Tranter M (2016). Activation of HuR downstream of p38 MAPK promotes cardiomyocyte hypertrophy. Cell Signal 28, 1735–1741. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Smith CL, Afroz R, Bassell GJ, Furneaux HM, Perrone-Bizzozero NI, and Burry RW (2004). GAP-43 mRNA in growth cones is associated with HuD and ribosomes. J Neurobiol 61, 222–235. [DOI] [PubMed] [Google Scholar]
  85. Soller M, and White K (2003). ELAV inhibits 3′-end processing to promote neural splicing of ewg pre-mRNA. Genes Dev 17, 2526–2538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sossin WS (2007). Isoform specificity of protein kinase Cs in synaptic plasticity. Learn Mem 14, 236–246. [DOI] [PubMed] [Google Scholar]
  87. Specht H, Peterziel H, Bajohrs M, Gerdes HH, Krieglstein K, and Unsicker K (2003). Transforming growth factor beta2 is released from PC12 cells via the regulated pathway of secretion. Mol Cell Neurosci 22, 75–86. [DOI] [PubMed] [Google Scholar]
  88. Stefaniuk M, Beroun A, Lebitko T, Markina O, Leski S, Meyza K, Grzywacz A, Samochowiec J, Samochowiec A, Radwanska K, et al. (2017). Matrix Metalloproteinase-9 and Synaptic Plasticity in the Central Amygdala in Control of Alcohol-Seeking Behavior. Biol Psychiatry 81, 907–917. [DOI] [PubMed] [Google Scholar]
  89. Taubenfeld SM, Wiig KA, Monti B, Dolan B, Pollonini G, and Alberini CM (2001). Fornix-dependent induction of hippocampal CCAAT enhancer-binding protein [beta] and [delta] Co-localizes with phosphorylated cAMP response element-binding protein and accompanies long-term memory consolidation. J Neurosci 21, 84–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Tebaldi T, Zuccotti P, Peroni D, Kohn M, Gasperini L, Potrich V, Bonazza V, Dudnakova T, Rossi A, Sanguinetti G, et al. (2018). HuD Is a Neural Translation Enhancer Acting on mTORC1-Responsive Genes and Counteracted by the Y3 Small Non-coding RNA. Mol Cell 71, 256–270 e210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Toba G, and White K (2008). The third RNA recognition motif of Drosophila ELAV protein has a role in multimerization. Nucleic Acids Res 36, 1390–1399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Tolias KF, Duman JG, and Um K (2011). Control of synapse development and plasticity by Rho GTPase regulatory proteins. Prog Neurobiol 94, 133–148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Tsukada J, Yoshida Y, Kominato Y, and Auron PE (2011). The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. Cytokine 54, 6–19. [DOI] [PubMed] [Google Scholar]
  94. Wiera G, Szczot M, Wojtowicz T, Lebida K, Koza P, and Mozrzymas JW (2015). Impact of matrix metalloproteinase-9 overexpression on synaptic excitatory transmission and its plasticity in rat CA3-CA1 hippocampal pathway. J Physiol Pharmacol 66, 309–315. [PubMed] [Google Scholar]
  95. Yamagata K, Kaufmann WE, Lanahan A, Papapavlou M, Barnes CA, Andreasson KI, and Worley PF (1994). Egr3/Pilot, a zinc finger transcription factor, is rapidly regulated by activity in brain neurons and colocalizes with Egr1/zif268. Learn Mem 1, 140–152. [PubMed] [Google Scholar]
  96. Yim SJ, Lee YS, Lee JA, Chang DJ, Han JH, Kim H, Park H, Jun H, Kim VN, and Kaang BK (2006). Regulation of ApC/EBP mRNA by the Aplysia AU-rich element-binding protein, ApELAV, and its effects on 5-hydroxytryptamine-induced long-term facilitation. J Neurochem 98, 420–429. [DOI] [PubMed] [Google Scholar]
  97. Zhang YE (2009). Non-Smad pathways in TGF-beta signaling. Cell Res 19, 128–139. [DOI] [PMC free article] [PubMed] [Google Scholar]

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