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Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory
Neurobiology of Learning and Memory xxx (2015) xxx–xxx
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Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory Yong-Seok Lee a,⇑, Jin-A Lee b, Bong-Kiun Kaang c,⇑ a
Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul, South Korea Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, South Korea c Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea b
a r t i c l e
i n f o
Article history: Received 11 June 2015 Revised 1 August 2015 Accepted 3 August 2015 Available online xxxx Keywords: AUF1 ELAV Long-term facilitation Long-term potentiation RNA-binding protein
a b s t r a c t Formation of long-term memories requires coordinated gene expression, which can be regulated at transcriptional, post-transcriptional, and translational levels. Post-transcriptional stabilization and destabilization of mRNAs provides precise temporal and spatial regulation of gene expression, which is critical for consolidation of synaptic plasticity and memory. mRNA stability is regulated by interactions between the cis-acting elements of mRNAs, such as adenine–uridine-rich elements (AREs), and the transacting elements, ARE-binding proteins (AUBPs). There are several AUBPs in the nervous system. Among AUBPs, Hu/ELAV-like proteins and AUF1 are the most studied mRNA stabilizing and destabilizing factors, respectively. Here, we summarize compelling evidence for critical roles of these AUBPs in synaptic plasticity, as well as learning and memory, in both vertebrates and invertebrates. Furthermore, we also briefly review the deregulations of AUBPs in neurological disorders. Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction New experiences initiate molecular and cellular changes in synapses, and these changes often lead to memory formation. Some memories last only for seconds to minutes, but others are more enduring and may even exist for the remainder of the animal’s life. While short-term memory is supported by covalent modifications of pre-existing molecules, formation of long-term memories requires de novo mRNA and protein synthesis (Kandel, 2001; Lee, 2014; Lee & Silva, 2009). Following transcription, mRNAs are subjected to diverse post-transcriptional modifications, including 50 capping, polyadenylation, alternative splicing, nucleus–cytoplasmic shuttling, and degradation. Post-transcriptional regulation allows rapid gene expression and localized protein translation (Pascale & Govoni, 2012). In addition, regulation of mRNA stability efficiently regulates the timing of specific gene expressions. For example, it is critical for the immediate early genes to have very short half-lives in order to accurately regulate the cellular response to external stimuli (Sheng & Greenberg, 1990).
⇑ Corresponding authors at: Department of Life Science, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-756, South Korea (Y.-S. Lee). Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanangno 599, Gwanak-gu, Seoul 151-747, South Korea (B.-K. Kaang). E-mail addresses: [email protected] (Y.-S. Lee), [email protected] (B.-K. Kaang).
Many RNA-binding proteins play critical roles in the nervous system (Darnell & Richter, 2012). RNA-binding proteins in the nervous system include the Hu/ELAV-like proteins, AUF1, CPEB, KSRP, NOVAs, FMRP, and staufen. These proteins are involved in functions such as stabilization or destabilization of mRNA, polyadenylation, translational regulation, splicing regulation, and mRNA transport (Deschenes-Furry, Perrone-Bizzozero, & Jasmin, 2006). Furthermore, deregulation of these RNA-binding proteins contributes to a number of neurological disorders. For example, fragile X syndrome is caused by a CGG repeat expansion in the 50 untranslated region (UTR) of FMR1, which encodes the RNA-binding protein FMRP (Sidorov, Auerbach, & Bear, 2013). FMRP is a translational repressor and there is evidence that it regulates metabotropic glutamate receptor signaling in the brain (Dolen & Bear, 2008). The roles of FMRP and other RNA-binding proteins in the brain have been extensively reviewed previously (Darnell & Richter, 2012). The half-lives of mRNAs are regulated by interactions between cis-acting elements within mRNAs and trans-acting factors such as RNA-binding proteins (Pascale & Govoni, 2012; Wu & Brewer, 2012). Adenine–uridine-rich elements (AREs) are cis-elements frequently identified within the 30 UTRs of many unstable mRNAs encoding cytokines, lymphokines, proto-oncogenes, inflammatory mediators, and other signaling molecules (Brewer, 1991; Pascale & Govoni, 2012; Wu & Brewer, 2012). Typical AREs consist of AUUUA pentamers within a U-rich context, but other variations
http://dx.doi.org/10.1016/j.nlm.2015.08.004 1074-7427/Ó 2015 Elsevier Inc. All rights reserved.
Please cite this article in press as: Lee, Y.-S., et al. Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiology of Learning and Memory (2015), http://dx.doi.org/10.1016/j.nlm.2015.08.004
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also exist (Bronicki & Jasmin, 2013; Pascale & Govoni, 2012). Bioinformatical analyses predict that 5–8% of human transcripts contain ARE sequences that can modulate mRNA stability via interactions with ARE-binding proteins (AUBPs) (Halees, El-Badrawi, & Khabar, 2008), and more than 20 AUBPs have currently been identified in the mammalian genome (Wu & Brewer, 2012). Hu/ELAVlike proteins, T-cell intracellular antigen 1 (TIA-1), and TIA-1related protein (TIAR) function as mRNA stabilizing factors, whereas AUF1, tristetraproline (TTP), KH domain-splicing regulatory protein (KSRP), and butyrate-regulated factor-1 (BRF-1) negatively regulate mRNA stability (Barreau, Paillard, & Osborne, 2005). Interestingly, different AUBPs bind to the same mRNA targets either competitively or cooperatively (Wu & Brewer, 2012), suggesting that interactions between stabilizing and destabilizing factors contribute to mRNA homeostasis. Deficits in the regulation of mRNA stability are associated with diverse neurological disorders such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and schizophrenia (Bronicki & Jasmin, 2013; Pascale & Govoni, 2012). The present review focuses on the role of ARE-binding proteins Hu/ELAV-like proteins and AUF1 as regulators of mRNA stability during synaptic plasticity, learning, memory and neurological disorders.
2. Hu/ELAV-like proteins and synaptic plasticity The Hu/ELAV-like genes are mammalian homologs of the Drosophila embryonic lethal abnormal vision (elav) gene, which is critically involved in neuronal development and maintenance in flies (Robinow, Campos, Yao, & White, 1988). The name Hu originated from the name of the index patient, who had small cell lung carcinoma expressing antigenic ELAV-like proteins (Szabo et al., 1991). There are four proteins in the mammalian ELAV-like protein family: HuB, HuC, HuD, and HuR. Among the Hu proteins, HuR is ubiquitously expressed in most cell types, whereas expression of the other three Hu proteins (neuronal ELAVs or nELAVs) is specific to neurons (Pascale & Govoni, 2012). Subcellular localizations also differ among the Hu proteins; HuR is primarily localized to the nucleus, but neuronal Hu proteins are preferentially expressed in the cytoplasm. However, all four Hu proteins are transported between the nucleus and the cytoplasm (Dreyfuss, Kim, & Kataoka, 2002; Keene, 1999). Hu proteins bind to target mRNAs containing ARE sequences and increases mRNA stability by antagonizing the action of destabilizing AUBPs such as AUF1 (Bronicki & Jasmin, 2013). Recent studies found that Hu proteins-target mRNAs contain other consensus motifs than the classical AREs. For example, all four Hu proteins can bind U-rich sequences interspersed with Gs or As (Lebedeva et al., 2011). In addition to their role as mRNA stabilizers, Hu proteins regulate alternative splicing and polyadenylation (Ratti et al., 2008; Zhu, Zhou, Hasman, & Lou, 2007). Although several studies have shown that signaling pathways involving protein kinase C (PKC), coactivator-associated arginine methyltransferase 1 (CARM1), and phosphatidylinositol 3kinase (PI3K) regulate the expression and function of HuD, further investigations are needed to better understand the molecular mechanism regulating Hu proteins (Bronicki & Jasmin, 2013). Expression of ELAV-like proteins are increased in the rodent hippocampus after learning a task like the radial arm maze and Morris water maze, or after experiencing contextual fear conditioning (Bolognani, Merhege, Twiss, & Perrone-Bizzozero, 2004; Quattrone et al., 2001). Quattrone and colleagues initially used an antibody for all three neuronal ELAV-like proteins, with results indicating increases after learning (Quattrone et al., 2001). Injections of antisense RNA for HuC into the hippocampus impaired learning on a radial arm maze, thereby demonstrating a critical role of ELAV-like proteins in mammalian learning
(Quattrone et al., 2001). Subsequent studies demonstrated that HuD expression is increased after learning and that the expression of growth associated protein 43 (GAP-43), a target of HuD, is posttranscriptionally increased (Bolognani et al., 2004; Pascale et al., 2004). GAP-43 is a nervous system specific protein and is thought to regulate LTP and learning. LTP stimulation increased the expression of GAP-43 in the hippocampus (Namgung, Matsuyama, & Routtenberg, 1997) and mice overexpressing GAP-43 showed enhanced LTP and learning (Routtenberg, Cantallops, Zaffuto, Serrano, & Namgung, 2000). These results suggest that the ELAVlike protein HuD is a positive regulator of synaptic plasticity, learning, and memory. The effects of HuD deletion on nervous system development and behavior have been investigated in HuD null mutant mice, with findings that HuD knockout mice have deficits in neurodevelopment and behavior (Akamatsu et al., 2005; DeBoer et al., 2014). Because the targets of HuD, including GAP43, are involved in cell proliferation and neurite growth, HuD was predicted to be involved in neural differentiation and/or neurite development. As predicted, HuD-deficient mice had decreased numbers of differentiating quiescent cells in the embryonic cerebral wall and increased numbers of slowly dividing stem cells in the subventricular zone (Akamatsu et al., 2005). Additionally, these null mutant mice demonstrated abnormal hind limb clasping, which is often associated with cortical deficits, as well as deficits in motor coordination on a rotarod task (Akamatsu et al., 2005). Defects in neuronal specification in the lower neocortical layers and impaired dendritogenesis in the CA3 region of the hippocampus have also been reported in HuD knockout mice (DeBoer et al., 2014). Importantly, spatial learning is impaired in the knockout mice, demonstrating the critical role of ELAV-like proteins in learning (DeBoer et al., 2014). However, transgenic mice overexpressing HuD concurrently with significant increases in GAP-43 expression also had deficits in hippocampus dependent learning and memory (Bolognani et al., 2007). Deficits in mossy fiber paired pulse facilitation and decreases in GAP-43 phosphorylation were suggested as underlying mechanisms for the behavioral deficits observed in HuD transgenic mice (Tanner et al., 2008). Consistent with other behavioral findings, excessive overexpression of GAP43 is also associated with impairments in learning and memory (Holahan, Honegger, Tabatadze, & Routtenberg, 2007), suggesting that HuD overexpression results in excessive GAP-43 expression, which subsequently impairs learning and synaptic plasticity in HuD transgenic mice. Together, these results demonstrate that deregulation of expression and/or activity of ELAV-like proteins and their target genes results in deficits in synaptic plasticity and associated behavior. ELAV-like proteins are also involved in synaptic plasticity in Aplysia, a marine snail with a simple nervous system (Yim et al., 2006). Synaptic facilitation in sensory neuron to motor neuron synapses is a cellular mechanism for behavioral sensitization in Aplysia. 5-Hydroxytryptamine (5-HT) is critical to both synaptic facilitation and behavioral sensitization. In sensory to motor synapses, brief 5-HT treatment induces short-term synaptic facilitation that lasts for several minutes, while repeated treatments of 5-HT (4–5 administrations) induce long-term facilitation that lasts for several hours to days (Kandel, 2001). Long-term facilitation and long-term behavioral sensitization in Aplysia requires de novo mRNA synthesis (Lee, Bailey, Kandel, & Kaang, 2008). Aplysia CCAAT enhancer-binding protein (ApC/EBP) is one of the immediate early genes expressed in response to repeated 5-HT treatments, and has an initiating function in consolidation of synaptic facilitation (Alberini, Ghirardi, Metz, & Kandel, 1994). ApC/EBP mRNA is induced within 15 min following the onset of 5-HT treatment, but also disappears within 4 h. Typical AREs were identified in the 30 UTR of ApC/EBP, suggesting that the stability of ApC/EBP can be regulated by AUBPs (Yim et al., 2006). Yim and colleagues
Please cite this article in press as: Lee, Y.-S., et al. Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiology of Learning and Memory (2015), http://dx.doi.org/10.1016/j.nlm.2015.08.004
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cloned an Aplysia homolog of Hu/ELAV, ApELAV1, and found that it binds to ApC/EBP mRNA and stabilizes it. Moreover, overexpression of ApC/EBP 30 UTR inhibited ApC/EBP mRNA expression and subsequently blocked long-term facilitation in response to 5-HT treatments, suggesting that overexpression of ApC/EBP 30 UTR interferes with the stabilizing activity of ApELAV1 (Yim et al., 2006). Although how ApELAV1 activity is regulated during synaptic facilitation remains to be elucidated, these data suggest that ApELAV1 is critically involved in the consolidation of long-term facilitation in Aplysia (Fig. 1). 3. AUF1 and synaptic plasticity AUF1, also known as heterogeneous nuclear ribonucleoprotein D (hnRNP D) has an AUBP function and is a mRNA destabilizing factor (Wu & Brewer, 2012). AUF1 was initially identified as a destabilizing factor for c-myc mRNA in vitro (Brewer, 1991). In mammals, four isoforms of AUF1 (p37, p40, p42, and p45) are generated by alternative splicing of a single transcript and each isoform differs in subcellular localization and RNA binding affinities (Wagner, DeMaria, Sun, Wilson, & Brewer, 1998; White, Brewer, & Wilson, 2013). AUF1 proteins show relatively relaxed target sequence specificity, as AUF1 can bind U-rich mRNA targets lacking typical AREs (Wilson, Sun, Lu, & Brewer, 1999). Once AUF1 proteins bind to ARE-harboring mRNA, it recruits additional trans-acting proteins such as eukaryotic translation initiation factor 4G (eIF4G) and poly A-binding protein (PABP) to form the AUF1- and Signal Transduction-Regulated Complex (ASTRC) (White et al., 2013). Although the molecular mechanism of AUF1-mediated mRNA decay remains incomplete, the ASTRC is thought to activate the deadenylation-dependent mRNA decay pathway whose function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons (Wu & Brewer, 2012). Despite increasing evidence on the regulation of AUF1 by
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phosphorylation, methylation, and ubiquitination (White et al., 2013), further detailed mechanism of AUF1 regulations need to be investigated. The physiological functions of AUF1 have been studied in mutant mice. Gouble and colleagues generated transgenic mice overexpressing p37AUF1, which has the strongest affinity for AREs in vitro (Gouble et al., 2002). Interestingly, only specific classes of ARE-containing mRNAs such as tumor necrosis factor a (TNFa) and granulocyte macrophage colony-stimulating factor (GMC-SF) decreased, whereas other ARE-harboring mRNAs for c-fos, c-myc, and c-jun significantly increased in several tissues of the transgenic mice (Gouble et al., 2002), suggesting that the p37AUF1 isoform of AUF1 may function as a stabilizing factor for some target mRNAs in vivo. In addition, the transgenic mice developed sarcomas in various tissues including esophagus, gastrointestinal tract, pancreas, bladder, testis, and lung (Gouble et al., 2002), demonstrating the importance of correct regulation of AUF1 to animal health. Consistent with these findings, knockout mice lacking all isoforms of AUF1 exhibited symptoms of endotoxic shock during the endotoxin challenge, which is accompanied by sustained expression of the ARE-containing mRNAs TNFa and interleukin-1b (IL-1b) in macrophages (Lu, Sadri, & Schneider, 2006). Accumulation of TNFa and interleukins is also associated with development of dermatitis during aging in AUF1 null mutant mice (Sadri & Schneider, 2009). Interestingly, deregulation of mRNA for cytokines results in accelerated cellular senescence and premature aging, which may also accelerate neurodegeneration (Pont, Sadri, Hsiao, Smith, & Schneider, 2012). Pont and colleagues demonstrated that AUF1, in addition to its role in destabilizing inflammatory cytokine mRNAs, activates the expression of the telomerase catalytic subunit Tert and thus controls normal aging (Pont et al., 2012). The role of AUF1 at synapses has been investigated in invertebrate nervous systems. As discussed above, the immediate early gene encoding ApC/EBP is a target of ApELAV1 (Yim et al., 2006),
Fig. 1. Roles of AU-rich element (ARE) binding proteins in regulating ApCEBP mRNA stability during long-term facilitation (LTF) in the sensory neuron of Aplysia. (1) In response to the repeated serotonin (5-HT) treatments, a transcription factor cAMP-responsive element binding protein (CREB) turns on the cAMP-responsive element (CRE)dependent gene expression of an immediate early gene ApC/EBP in the sensory neuron. (2) ApELAV1 binds to ARE sequences in the 30 UTR of the labile ApC/EBP mRNA and subsequently protects the ApC/EBP mRNA from rapid degradation. Otherwise, AUF1 would bind to ApC/EBP mRNA and triggers its decay. (3) Meanwhile, ApC/EBP mRNA is translated into the transcription factor ApC/EBP protein. (4) ApC/EBP translocates into the nucleus and subsequently activates the other downstream plasticity-related genes. (5) After 4 h after the ApC/EBP mRNA induction when the activity of ApAUF1 overrides the activity of ApELAV1, the ApC/EBP mRNA is degraded, which ends the LTF consolidation phase.
Please cite this article in press as: Lee, Y.-S., et al. Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiology of Learning and Memory (2015), http://dx.doi.org/10.1016/j.nlm.2015.08.004
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suggesting that the stability of ApC/EBP mRNA may also be regulated by other AUBPs, including destabilizing factors such as AUF1. Lee and colleagues identified an Aplysia homolog of AUF1 (ApAUF1) that has binding affinity to the ARE sequences in c-fos and ApC/EBP mRNA (Lee et al., 2012). In contrast to a stabilizing factor ApELAV1, ApAUF1 destabilizes the reporter mRNA containing the ApC/EBP 30 UTR, suggesting that ApAUF1 may be involved in the rapid degradation of ApC/EBP mRNA during consolidation (Fig. 1). Overexpression of ApAUF1 blocked the induction of ApC/ EBP mRNA in sensory neurons in response to repeated 5-HT treatments. ApAUF1 overexpression subsequently blocked long-term facilitation in sensory neuron to motor neuron synapses without affecting the basal synaptic transmission (Lee et al., 2012). These results suggest that ApAUF1 may function as a checkpoint for consolidation and long-term synaptic plasticity, although the mechanisms underlying ApAUF1 regulation have not yet been investigated. Furthermore, it is highly likely that mammalian homologs of ApAUF1 regulate synaptic plasticity, learning, and memory.
4. ELAV proteins and Alzheimer’s disease Coordinated regulation of gene expression is critical for formation of long-term memory, and its deregulation is often associated with cognitive disorders. As predicted, deregulations of mRNA stability disrupt coordinated gene expression and result in pathophysiological conditions in human brains. For example, altered HuD expression is associated with AD (Amadio et al., 2009; Kang et al., 2014; Lim & Alkon, 2014; Subhadra, Schaller, & Seeds, 2013). Amadio and colleagues found that expression of nELAV proteins was significantly decreased in the hippocampus of postmortem brains from patients with AD (Amadio et al., 2009). Moreover, nELAV protein expression was inversely correlated with the amount of amyloid b (Ab), which is a neurotoxic peptide abundantly found in AD brains (Amadio et al., 2009). Ab treatment reduced nELAV protein levels in SH-SY5Y cell and disrupted the interaction between nELAV and the mRNA of ADAM10 that is an a-secretase involved in generation of neuroprotective soluble amyloid precursor protein a (APPa) (Amadio et al., 2009). Consistently, ADAM10 protein level was found to be significantly reduced in AD brains (Amadio et al., 2009). Interestingly, the mRNA of an Abdegrading enzyme neprilysin which has been shown to be decreased in AD brains was found to be a binding partner of ELAV protein HuD (Lim & Alkon, 2014). These data show that ELAV proteins may regulate the stability of mRNAs that are involved in AD pathology. In contrast, other studies showed that the expression of ELAV protein HuD is increased in the frontal cortex and superior temporal gyrus of AD brains (Kang et al., 2014; Subhadra et al., 2013). Recently, Kang and colleagues showed that HuD binds to the 30 UTRs of APP and BACE1 (b-site APP-cleaving enzyme 1) mRNA and increased their protein levels (Kang et al., 2014). In addition, HuD binds to and increases levels of long noncoding (lnc) RNA BACE1AS which enhances BACE1 expression (Kang et al., 2014). Consistently, the levels of HuD, APP, BACE1, BACE1AS, and Ab are all elevated in the cortex of brains from patients with AD, suggesting that HuD promotes neurotoxic Ab (Kang et al., 2014). However, potential pathogenic and protective roles of HuD and other ELAV proteins involved in AD have not yet been elucidated. The discrepancy between these studies on Hu proteins in AD brains may arise from differences in the involved brain regions (hippocampus vs. cortex) or from the heterogeneity of pathophysiology in different patients with AD. Future studies on HuD in synaptic plasticity and pathogenesis may shed light on the understanding the role of AUBPs in healthy and diseased brains.
5. Other mRNA degradation mechanisms and neuronal functions Other mRNA decay mechanisms such as nonsense-mediated mRNA decay (NMD) and microRNA (miRNA)-mediated mRNA degradation also play critical roles in regulating neural functions including synaptic plasticity. NMD is an mRNA-surveillance mechanism that decays mRNAs harboring premature stop codon generated by mutations or aberrant splicing (Huang & Wilkinson, 2012; Schoenberg & Maquat, 2012). However, NMD also regulates the decay of normal mRNAs. Several plasticity-related genes such as arc and psd-95 have been shown as natural targets of NMD (Giorgi et al., 2007; Zheng et al., 2012). NMD machinery is composed of multiple proteins including up-frameshift proteins (UPF) (Huang & Wilkinson, 2012). Interestingly, mutations in UPF3B gene have been associated with intellectual disabilities, schizophrenia, and autism spectrum disorder, strongly suggesting that NMD is critically involved in learning and cognition (Addington et al., 2011; Laumonnier et al., 2010; Tarpey et al., 2007). miRNAs are short noncoding RNAs which regulate gene expression by controlling mRNA degradation and protein translation (Bartel, 2009). The miRNAs are also critically involved in regulating neuronal development, synaptic plasticity, learning, and memory. The roles of miRNAs in neuronal functions have been excellently reviewed elsewhere (Sim, Bakes, & Kaang, 2014; Wang, Kwon, & Tsai, 2012).
6. Perspectives There is compelling evidence that mRNA stability regulation by AUBPs is critical for normal synaptic functioning and associated behavior, particularly for learning and memory in both invertebrates and vertebrates. Although more systematic investigations are needed, we suggest the following simplified model for the roles of AUBPs in memory consolidation based on the cellular studies in invertebrate (Fig. 1). (1) Learning triggers the transcription of immediate early genes such as C/EBP required for memory consolidation. (2) Activity of stabilizing AUBPs such as ELAV proteins is increased to override the action of destabilizing AUBPs such as AUF1. (3) Subsequently, ELAV proteins facilitate the translation of the immediate early genes. (4) Products of the immediate early genes often function as transcription factors which stimulate the expression of other downstream plasticity genes. (5) As the downstream genes are transcribed, the destabilizing factors are activated while stabilizing factors are inactivated. Finally, the destabilizing factors accelerate the decay of mRNAs for immediate early genes and the consolidation phase is closed. It would be of great interest to investigate the molecular mechanisms underlying the spatio-temporal activations of different AUBPs during memory consolidation. Most research to date has focused primarily on the roles of AUBPs on the stability of mRNAs for immediate early genes such as c-fos, c-myc, and C/EBP (Brewer, 1991; Lee et al., 2012; Yim et al., 2006). However, AUBP-binding targets are more extensive than the previously known immediate early genes (Halees et al., 2008). For example, APP and BACE1 mRNAs which are associated with AD have recently been identified as binding partners of HuD as discussed above (Kang et al., 2014). Therefore, future research should investigate the pathophysiological roles of interactions between these newly identified AUBPs and ARE-containing mRNAs. More than 5% of human transcripts are potential binding partners of AUBPs (Halees et al., 2008), which may be functionally significant to observed phenotypes in normal or diseased brain. Previous studies either overexpressing or knocking-out AUBPs have examined the expression levels of several known targets such as C/EBP, GAP-43, TNFa, and IL-1b, in relation to expressed
Please cite this article in press as: Lee, Y.-S., et al. Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiology of Learning and Memory (2015), http://dx.doi.org/10.1016/j.nlm.2015.08.004
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phenotypes (Bolognani et al., 2007; Lee et al., 2012; Pont et al., 2012; Yim et al., 2006). Effects of manipulating specific AUBPs such as AUF1 and ELAV-like proteins on global gene expression profiles in the nervous system have not been investigated as potential contributors to the observed phenotypes. Another important issue is that many AUBPs can bind to and regulate the same ARE-containing mRNAs. For example, both ApELAVs and ApAUF1 bind to ApC/EBP mRNA and regulate its stability, with opposite effects in Aplysia neurons (Lee et al., 2012; Yim et al., 2006). PKCa and PKCe pathways regulate HuD-mediated mRNA stabilization in mammalian neurons (Lim & Alkon, 2014; Pascale et al., 2005), but the mechanisms for coordinating the effects of different AUBPs with opposing activities have not been elucidated in synaptic plasticity and learning. More comprehensive expression profiles of putative AUBP targets during memory consolidation will contribute to further understanding of these mechanisms. RNA-binding proteins other than the well-known AUBPs are also implicated in regulation of mRNA stability in the nervous system. FUS (fused in sarcoma) is a DNA/RNA-binding protein that was originally identified as a fusion oncogene in human liposarcoma. FUS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology, suggesting a role in synaptic plasticity (Fujii et al., 2005, 2009). Udagawa and colleagues recently demonstrated that FUS promotes stability of GluA1 by binding to the 30 terminus of GluA1 mRNA to control poly-A tail maintenance, supporting its role in regulating synaptic mRNA stability (Udagawa et al., 2015). Interestingly, the ELAV-like protein HuR is a positive regulator for FUS and TDP-43, whose mutations or dysregulation are associated with FTD/amyotrophic lateral sclerosis (ALS) (Lu et al., 2014; Ryu et al., 2014). This finding demonstrates that there is a cascade of RNA-binding proteins involved in coordinating gene expression, and that deregulation of this cascade may contribute to diseased states. Understanding the regulatory mechanisms of AUBPs and other RNA stability regulating factors in the brain will contribute to development of novel treatment strategies for cognitive disorders such as AD, FTD and ALS. Acknowledgments This work was supported by the National Honour Scientist Program through a grant to B.-K.K. and NRF-2014R1A3A1063542 to Y.-S.L. References Addington, A. M., Gauthier, J., Piton, A., Hamdan, F. F., Raymond, A., Gogtay, N., ... Rouleau, G. A. (2011). A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Molecular Psychiatry, 16, 238–239. Akamatsu, W., Fujihara, H., Mitsuhashi, T., Yano, M., Shibata, S., Hayakawa, Y., ... Okano, H. (2005). The RNA-binding protein HuD regulates neuronal cell identity and maturation. Proceedings of the National Academy of Sciences of the United States of America, 102, 4625–4630. Alberini, C. M., Ghirardi, M., Metz, R., & Kandel, E. R. (1994). C/EBP is an immediateearly gene required for the consolidation of long-term facilitation in Aplysia. Cell, 76, 1099–1114. Amadio, M., Pascale, A., Wang, J., Ho, L., Quattrone, A., Gandy, S., ... Pasinetti, G. M. (2009). NELAV proteins alteration in Alzheimer’s disease brain: A novel putative target for amyloid-beta reverberating on AbetaPP processing. Journal of Alzheimer’s Disease, 16, 409–419. Barreau, C., Paillard, L., & Osborne, H. B. (2005). AU-rich elements and associated factors: Are there unifying principles? Nucleic Acids Research, 33, 7138–7150. Bartel, D. P. (2009). MicroRNAs: Target recognition and regulatory functions. Cell, 136, 215–233. Bolognani, F., Merhege, M. A., Twiss, J., & Perrone-Bizzozero, N. I. (2004). Dendritic localization of the RNA-binding protein HuD in hippocampal neurons: Association with polysomes and upregulation during contextual learning. Neuroscience Letters, 371, 152–157. Bolognani, F., Qiu, S., Tanner, D. C., Paik, J., Perrone-Bizzozero, N. I., & Weeber, E. J. (2007). Associative and spatial learning and memory deficits in transgenic mice
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Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory Yong-Seok Lee a,⇑, Jin-A Lee b, Bong-Kiun Kaang c,⇑ a
Department of Life Science, College of Natural Sciences, Chung-Ang University, Seoul, South Korea Department of Biotechnology and Biological Sciences, Hannam University, Daejeon, South Korea c Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea b
a r t i c l e
i n f o
Article history: Received 11 June 2015 Revised 1 August 2015 Accepted 3 August 2015 Available online xxxx Keywords: AUF1 ELAV Long-term facilitation Long-term potentiation RNA-binding protein
a b s t r a c t Formation of long-term memories requires coordinated gene expression, which can be regulated at transcriptional, post-transcriptional, and translational levels. Post-transcriptional stabilization and destabilization of mRNAs provides precise temporal and spatial regulation of gene expression, which is critical for consolidation of synaptic plasticity and memory. mRNA stability is regulated by interactions between the cis-acting elements of mRNAs, such as adenine–uridine-rich elements (AREs), and the transacting elements, ARE-binding proteins (AUBPs). There are several AUBPs in the nervous system. Among AUBPs, Hu/ELAV-like proteins and AUF1 are the most studied mRNA stabilizing and destabilizing factors, respectively. Here, we summarize compelling evidence for critical roles of these AUBPs in synaptic plasticity, as well as learning and memory, in both vertebrates and invertebrates. Furthermore, we also briefly review the deregulations of AUBPs in neurological disorders. Ó 2015 Elsevier Inc. All rights reserved.
1. Introduction New experiences initiate molecular and cellular changes in synapses, and these changes often lead to memory formation. Some memories last only for seconds to minutes, but others are more enduring and may even exist for the remainder of the animal’s life. While short-term memory is supported by covalent modifications of pre-existing molecules, formation of long-term memories requires de novo mRNA and protein synthesis (Kandel, 2001; Lee, 2014; Lee & Silva, 2009). Following transcription, mRNAs are subjected to diverse post-transcriptional modifications, including 50 capping, polyadenylation, alternative splicing, nucleus–cytoplasmic shuttling, and degradation. Post-transcriptional regulation allows rapid gene expression and localized protein translation (Pascale & Govoni, 2012). In addition, regulation of mRNA stability efficiently regulates the timing of specific gene expressions. For example, it is critical for the immediate early genes to have very short half-lives in order to accurately regulate the cellular response to external stimuli (Sheng & Greenberg, 1990).
⇑ Corresponding authors at: Department of Life Science, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul 156-756, South Korea (Y.-S. Lee). Department of Biological Sciences, College of Natural Sciences, Seoul National University, Gwanangno 599, Gwanak-gu, Seoul 151-747, South Korea (B.-K. Kaang). E-mail addresses: [email protected] (Y.-S. Lee), [email protected] (B.-K. Kaang).
Many RNA-binding proteins play critical roles in the nervous system (Darnell & Richter, 2012). RNA-binding proteins in the nervous system include the Hu/ELAV-like proteins, AUF1, CPEB, KSRP, NOVAs, FMRP, and staufen. These proteins are involved in functions such as stabilization or destabilization of mRNA, polyadenylation, translational regulation, splicing regulation, and mRNA transport (Deschenes-Furry, Perrone-Bizzozero, & Jasmin, 2006). Furthermore, deregulation of these RNA-binding proteins contributes to a number of neurological disorders. For example, fragile X syndrome is caused by a CGG repeat expansion in the 50 untranslated region (UTR) of FMR1, which encodes the RNA-binding protein FMRP (Sidorov, Auerbach, & Bear, 2013). FMRP is a translational repressor and there is evidence that it regulates metabotropic glutamate receptor signaling in the brain (Dolen & Bear, 2008). The roles of FMRP and other RNA-binding proteins in the brain have been extensively reviewed previously (Darnell & Richter, 2012). The half-lives of mRNAs are regulated by interactions between cis-acting elements within mRNAs and trans-acting factors such as RNA-binding proteins (Pascale & Govoni, 2012; Wu & Brewer, 2012). Adenine–uridine-rich elements (AREs) are cis-elements frequently identified within the 30 UTRs of many unstable mRNAs encoding cytokines, lymphokines, proto-oncogenes, inflammatory mediators, and other signaling molecules (Brewer, 1991; Pascale & Govoni, 2012; Wu & Brewer, 2012). Typical AREs consist of AUUUA pentamers within a U-rich context, but other variations
http://dx.doi.org/10.1016/j.nlm.2015.08.004 1074-7427/Ó 2015 Elsevier Inc. All rights reserved.
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also exist (Bronicki & Jasmin, 2013; Pascale & Govoni, 2012). Bioinformatical analyses predict that 5–8% of human transcripts contain ARE sequences that can modulate mRNA stability via interactions with ARE-binding proteins (AUBPs) (Halees, El-Badrawi, & Khabar, 2008), and more than 20 AUBPs have currently been identified in the mammalian genome (Wu & Brewer, 2012). Hu/ELAVlike proteins, T-cell intracellular antigen 1 (TIA-1), and TIA-1related protein (TIAR) function as mRNA stabilizing factors, whereas AUF1, tristetraproline (TTP), KH domain-splicing regulatory protein (KSRP), and butyrate-regulated factor-1 (BRF-1) negatively regulate mRNA stability (Barreau, Paillard, & Osborne, 2005). Interestingly, different AUBPs bind to the same mRNA targets either competitively or cooperatively (Wu & Brewer, 2012), suggesting that interactions between stabilizing and destabilizing factors contribute to mRNA homeostasis. Deficits in the regulation of mRNA stability are associated with diverse neurological disorders such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD), and schizophrenia (Bronicki & Jasmin, 2013; Pascale & Govoni, 2012). The present review focuses on the role of ARE-binding proteins Hu/ELAV-like proteins and AUF1 as regulators of mRNA stability during synaptic plasticity, learning, memory and neurological disorders.
2. Hu/ELAV-like proteins and synaptic plasticity The Hu/ELAV-like genes are mammalian homologs of the Drosophila embryonic lethal abnormal vision (elav) gene, which is critically involved in neuronal development and maintenance in flies (Robinow, Campos, Yao, & White, 1988). The name Hu originated from the name of the index patient, who had small cell lung carcinoma expressing antigenic ELAV-like proteins (Szabo et al., 1991). There are four proteins in the mammalian ELAV-like protein family: HuB, HuC, HuD, and HuR. Among the Hu proteins, HuR is ubiquitously expressed in most cell types, whereas expression of the other three Hu proteins (neuronal ELAVs or nELAVs) is specific to neurons (Pascale & Govoni, 2012). Subcellular localizations also differ among the Hu proteins; HuR is primarily localized to the nucleus, but neuronal Hu proteins are preferentially expressed in the cytoplasm. However, all four Hu proteins are transported between the nucleus and the cytoplasm (Dreyfuss, Kim, & Kataoka, 2002; Keene, 1999). Hu proteins bind to target mRNAs containing ARE sequences and increases mRNA stability by antagonizing the action of destabilizing AUBPs such as AUF1 (Bronicki & Jasmin, 2013). Recent studies found that Hu proteins-target mRNAs contain other consensus motifs than the classical AREs. For example, all four Hu proteins can bind U-rich sequences interspersed with Gs or As (Lebedeva et al., 2011). In addition to their role as mRNA stabilizers, Hu proteins regulate alternative splicing and polyadenylation (Ratti et al., 2008; Zhu, Zhou, Hasman, & Lou, 2007). Although several studies have shown that signaling pathways involving protein kinase C (PKC), coactivator-associated arginine methyltransferase 1 (CARM1), and phosphatidylinositol 3kinase (PI3K) regulate the expression and function of HuD, further investigations are needed to better understand the molecular mechanism regulating Hu proteins (Bronicki & Jasmin, 2013). Expression of ELAV-like proteins are increased in the rodent hippocampus after learning a task like the radial arm maze and Morris water maze, or after experiencing contextual fear conditioning (Bolognani, Merhege, Twiss, & Perrone-Bizzozero, 2004; Quattrone et al., 2001). Quattrone and colleagues initially used an antibody for all three neuronal ELAV-like proteins, with results indicating increases after learning (Quattrone et al., 2001). Injections of antisense RNA for HuC into the hippocampus impaired learning on a radial arm maze, thereby demonstrating a critical role of ELAV-like proteins in mammalian learning
(Quattrone et al., 2001). Subsequent studies demonstrated that HuD expression is increased after learning and that the expression of growth associated protein 43 (GAP-43), a target of HuD, is posttranscriptionally increased (Bolognani et al., 2004; Pascale et al., 2004). GAP-43 is a nervous system specific protein and is thought to regulate LTP and learning. LTP stimulation increased the expression of GAP-43 in the hippocampus (Namgung, Matsuyama, & Routtenberg, 1997) and mice overexpressing GAP-43 showed enhanced LTP and learning (Routtenberg, Cantallops, Zaffuto, Serrano, & Namgung, 2000). These results suggest that the ELAVlike protein HuD is a positive regulator of synaptic plasticity, learning, and memory. The effects of HuD deletion on nervous system development and behavior have been investigated in HuD null mutant mice, with findings that HuD knockout mice have deficits in neurodevelopment and behavior (Akamatsu et al., 2005; DeBoer et al., 2014). Because the targets of HuD, including GAP43, are involved in cell proliferation and neurite growth, HuD was predicted to be involved in neural differentiation and/or neurite development. As predicted, HuD-deficient mice had decreased numbers of differentiating quiescent cells in the embryonic cerebral wall and increased numbers of slowly dividing stem cells in the subventricular zone (Akamatsu et al., 2005). Additionally, these null mutant mice demonstrated abnormal hind limb clasping, which is often associated with cortical deficits, as well as deficits in motor coordination on a rotarod task (Akamatsu et al., 2005). Defects in neuronal specification in the lower neocortical layers and impaired dendritogenesis in the CA3 region of the hippocampus have also been reported in HuD knockout mice (DeBoer et al., 2014). Importantly, spatial learning is impaired in the knockout mice, demonstrating the critical role of ELAV-like proteins in learning (DeBoer et al., 2014). However, transgenic mice overexpressing HuD concurrently with significant increases in GAP-43 expression also had deficits in hippocampus dependent learning and memory (Bolognani et al., 2007). Deficits in mossy fiber paired pulse facilitation and decreases in GAP-43 phosphorylation were suggested as underlying mechanisms for the behavioral deficits observed in HuD transgenic mice (Tanner et al., 2008). Consistent with other behavioral findings, excessive overexpression of GAP43 is also associated with impairments in learning and memory (Holahan, Honegger, Tabatadze, & Routtenberg, 2007), suggesting that HuD overexpression results in excessive GAP-43 expression, which subsequently impairs learning and synaptic plasticity in HuD transgenic mice. Together, these results demonstrate that deregulation of expression and/or activity of ELAV-like proteins and their target genes results in deficits in synaptic plasticity and associated behavior. ELAV-like proteins are also involved in synaptic plasticity in Aplysia, a marine snail with a simple nervous system (Yim et al., 2006). Synaptic facilitation in sensory neuron to motor neuron synapses is a cellular mechanism for behavioral sensitization in Aplysia. 5-Hydroxytryptamine (5-HT) is critical to both synaptic facilitation and behavioral sensitization. In sensory to motor synapses, brief 5-HT treatment induces short-term synaptic facilitation that lasts for several minutes, while repeated treatments of 5-HT (4–5 administrations) induce long-term facilitation that lasts for several hours to days (Kandel, 2001). Long-term facilitation and long-term behavioral sensitization in Aplysia requires de novo mRNA synthesis (Lee, Bailey, Kandel, & Kaang, 2008). Aplysia CCAAT enhancer-binding protein (ApC/EBP) is one of the immediate early genes expressed in response to repeated 5-HT treatments, and has an initiating function in consolidation of synaptic facilitation (Alberini, Ghirardi, Metz, & Kandel, 1994). ApC/EBP mRNA is induced within 15 min following the onset of 5-HT treatment, but also disappears within 4 h. Typical AREs were identified in the 30 UTR of ApC/EBP, suggesting that the stability of ApC/EBP can be regulated by AUBPs (Yim et al., 2006). Yim and colleagues
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cloned an Aplysia homolog of Hu/ELAV, ApELAV1, and found that it binds to ApC/EBP mRNA and stabilizes it. Moreover, overexpression of ApC/EBP 30 UTR inhibited ApC/EBP mRNA expression and subsequently blocked long-term facilitation in response to 5-HT treatments, suggesting that overexpression of ApC/EBP 30 UTR interferes with the stabilizing activity of ApELAV1 (Yim et al., 2006). Although how ApELAV1 activity is regulated during synaptic facilitation remains to be elucidated, these data suggest that ApELAV1 is critically involved in the consolidation of long-term facilitation in Aplysia (Fig. 1). 3. AUF1 and synaptic plasticity AUF1, also known as heterogeneous nuclear ribonucleoprotein D (hnRNP D) has an AUBP function and is a mRNA destabilizing factor (Wu & Brewer, 2012). AUF1 was initially identified as a destabilizing factor for c-myc mRNA in vitro (Brewer, 1991). In mammals, four isoforms of AUF1 (p37, p40, p42, and p45) are generated by alternative splicing of a single transcript and each isoform differs in subcellular localization and RNA binding affinities (Wagner, DeMaria, Sun, Wilson, & Brewer, 1998; White, Brewer, & Wilson, 2013). AUF1 proteins show relatively relaxed target sequence specificity, as AUF1 can bind U-rich mRNA targets lacking typical AREs (Wilson, Sun, Lu, & Brewer, 1999). Once AUF1 proteins bind to ARE-harboring mRNA, it recruits additional trans-acting proteins such as eukaryotic translation initiation factor 4G (eIF4G) and poly A-binding protein (PABP) to form the AUF1- and Signal Transduction-Regulated Complex (ASTRC) (White et al., 2013). Although the molecular mechanism of AUF1-mediated mRNA decay remains incomplete, the ASTRC is thought to activate the deadenylation-dependent mRNA decay pathway whose function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons (Wu & Brewer, 2012). Despite increasing evidence on the regulation of AUF1 by
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phosphorylation, methylation, and ubiquitination (White et al., 2013), further detailed mechanism of AUF1 regulations need to be investigated. The physiological functions of AUF1 have been studied in mutant mice. Gouble and colleagues generated transgenic mice overexpressing p37AUF1, which has the strongest affinity for AREs in vitro (Gouble et al., 2002). Interestingly, only specific classes of ARE-containing mRNAs such as tumor necrosis factor a (TNFa) and granulocyte macrophage colony-stimulating factor (GMC-SF) decreased, whereas other ARE-harboring mRNAs for c-fos, c-myc, and c-jun significantly increased in several tissues of the transgenic mice (Gouble et al., 2002), suggesting that the p37AUF1 isoform of AUF1 may function as a stabilizing factor for some target mRNAs in vivo. In addition, the transgenic mice developed sarcomas in various tissues including esophagus, gastrointestinal tract, pancreas, bladder, testis, and lung (Gouble et al., 2002), demonstrating the importance of correct regulation of AUF1 to animal health. Consistent with these findings, knockout mice lacking all isoforms of AUF1 exhibited symptoms of endotoxic shock during the endotoxin challenge, which is accompanied by sustained expression of the ARE-containing mRNAs TNFa and interleukin-1b (IL-1b) in macrophages (Lu, Sadri, & Schneider, 2006). Accumulation of TNFa and interleukins is also associated with development of dermatitis during aging in AUF1 null mutant mice (Sadri & Schneider, 2009). Interestingly, deregulation of mRNA for cytokines results in accelerated cellular senescence and premature aging, which may also accelerate neurodegeneration (Pont, Sadri, Hsiao, Smith, & Schneider, 2012). Pont and colleagues demonstrated that AUF1, in addition to its role in destabilizing inflammatory cytokine mRNAs, activates the expression of the telomerase catalytic subunit Tert and thus controls normal aging (Pont et al., 2012). The role of AUF1 at synapses has been investigated in invertebrate nervous systems. As discussed above, the immediate early gene encoding ApC/EBP is a target of ApELAV1 (Yim et al., 2006),
Fig. 1. Roles of AU-rich element (ARE) binding proteins in regulating ApCEBP mRNA stability during long-term facilitation (LTF) in the sensory neuron of Aplysia. (1) In response to the repeated serotonin (5-HT) treatments, a transcription factor cAMP-responsive element binding protein (CREB) turns on the cAMP-responsive element (CRE)dependent gene expression of an immediate early gene ApC/EBP in the sensory neuron. (2) ApELAV1 binds to ARE sequences in the 30 UTR of the labile ApC/EBP mRNA and subsequently protects the ApC/EBP mRNA from rapid degradation. Otherwise, AUF1 would bind to ApC/EBP mRNA and triggers its decay. (3) Meanwhile, ApC/EBP mRNA is translated into the transcription factor ApC/EBP protein. (4) ApC/EBP translocates into the nucleus and subsequently activates the other downstream plasticity-related genes. (5) After 4 h after the ApC/EBP mRNA induction when the activity of ApAUF1 overrides the activity of ApELAV1, the ApC/EBP mRNA is degraded, which ends the LTF consolidation phase.
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suggesting that the stability of ApC/EBP mRNA may also be regulated by other AUBPs, including destabilizing factors such as AUF1. Lee and colleagues identified an Aplysia homolog of AUF1 (ApAUF1) that has binding affinity to the ARE sequences in c-fos and ApC/EBP mRNA (Lee et al., 2012). In contrast to a stabilizing factor ApELAV1, ApAUF1 destabilizes the reporter mRNA containing the ApC/EBP 30 UTR, suggesting that ApAUF1 may be involved in the rapid degradation of ApC/EBP mRNA during consolidation (Fig. 1). Overexpression of ApAUF1 blocked the induction of ApC/ EBP mRNA in sensory neurons in response to repeated 5-HT treatments. ApAUF1 overexpression subsequently blocked long-term facilitation in sensory neuron to motor neuron synapses without affecting the basal synaptic transmission (Lee et al., 2012). These results suggest that ApAUF1 may function as a checkpoint for consolidation and long-term synaptic plasticity, although the mechanisms underlying ApAUF1 regulation have not yet been investigated. Furthermore, it is highly likely that mammalian homologs of ApAUF1 regulate synaptic plasticity, learning, and memory.
4. ELAV proteins and Alzheimer’s disease Coordinated regulation of gene expression is critical for formation of long-term memory, and its deregulation is often associated with cognitive disorders. As predicted, deregulations of mRNA stability disrupt coordinated gene expression and result in pathophysiological conditions in human brains. For example, altered HuD expression is associated with AD (Amadio et al., 2009; Kang et al., 2014; Lim & Alkon, 2014; Subhadra, Schaller, & Seeds, 2013). Amadio and colleagues found that expression of nELAV proteins was significantly decreased in the hippocampus of postmortem brains from patients with AD (Amadio et al., 2009). Moreover, nELAV protein expression was inversely correlated with the amount of amyloid b (Ab), which is a neurotoxic peptide abundantly found in AD brains (Amadio et al., 2009). Ab treatment reduced nELAV protein levels in SH-SY5Y cell and disrupted the interaction between nELAV and the mRNA of ADAM10 that is an a-secretase involved in generation of neuroprotective soluble amyloid precursor protein a (APPa) (Amadio et al., 2009). Consistently, ADAM10 protein level was found to be significantly reduced in AD brains (Amadio et al., 2009). Interestingly, the mRNA of an Abdegrading enzyme neprilysin which has been shown to be decreased in AD brains was found to be a binding partner of ELAV protein HuD (Lim & Alkon, 2014). These data show that ELAV proteins may regulate the stability of mRNAs that are involved in AD pathology. In contrast, other studies showed that the expression of ELAV protein HuD is increased in the frontal cortex and superior temporal gyrus of AD brains (Kang et al., 2014; Subhadra et al., 2013). Recently, Kang and colleagues showed that HuD binds to the 30 UTRs of APP and BACE1 (b-site APP-cleaving enzyme 1) mRNA and increased their protein levels (Kang et al., 2014). In addition, HuD binds to and increases levels of long noncoding (lnc) RNA BACE1AS which enhances BACE1 expression (Kang et al., 2014). Consistently, the levels of HuD, APP, BACE1, BACE1AS, and Ab are all elevated in the cortex of brains from patients with AD, suggesting that HuD promotes neurotoxic Ab (Kang et al., 2014). However, potential pathogenic and protective roles of HuD and other ELAV proteins involved in AD have not yet been elucidated. The discrepancy between these studies on Hu proteins in AD brains may arise from differences in the involved brain regions (hippocampus vs. cortex) or from the heterogeneity of pathophysiology in different patients with AD. Future studies on HuD in synaptic plasticity and pathogenesis may shed light on the understanding the role of AUBPs in healthy and diseased brains.
5. Other mRNA degradation mechanisms and neuronal functions Other mRNA decay mechanisms such as nonsense-mediated mRNA decay (NMD) and microRNA (miRNA)-mediated mRNA degradation also play critical roles in regulating neural functions including synaptic plasticity. NMD is an mRNA-surveillance mechanism that decays mRNAs harboring premature stop codon generated by mutations or aberrant splicing (Huang & Wilkinson, 2012; Schoenberg & Maquat, 2012). However, NMD also regulates the decay of normal mRNAs. Several plasticity-related genes such as arc and psd-95 have been shown as natural targets of NMD (Giorgi et al., 2007; Zheng et al., 2012). NMD machinery is composed of multiple proteins including up-frameshift proteins (UPF) (Huang & Wilkinson, 2012). Interestingly, mutations in UPF3B gene have been associated with intellectual disabilities, schizophrenia, and autism spectrum disorder, strongly suggesting that NMD is critically involved in learning and cognition (Addington et al., 2011; Laumonnier et al., 2010; Tarpey et al., 2007). miRNAs are short noncoding RNAs which regulate gene expression by controlling mRNA degradation and protein translation (Bartel, 2009). The miRNAs are also critically involved in regulating neuronal development, synaptic plasticity, learning, and memory. The roles of miRNAs in neuronal functions have been excellently reviewed elsewhere (Sim, Bakes, & Kaang, 2014; Wang, Kwon, & Tsai, 2012).
6. Perspectives There is compelling evidence that mRNA stability regulation by AUBPs is critical for normal synaptic functioning and associated behavior, particularly for learning and memory in both invertebrates and vertebrates. Although more systematic investigations are needed, we suggest the following simplified model for the roles of AUBPs in memory consolidation based on the cellular studies in invertebrate (Fig. 1). (1) Learning triggers the transcription of immediate early genes such as C/EBP required for memory consolidation. (2) Activity of stabilizing AUBPs such as ELAV proteins is increased to override the action of destabilizing AUBPs such as AUF1. (3) Subsequently, ELAV proteins facilitate the translation of the immediate early genes. (4) Products of the immediate early genes often function as transcription factors which stimulate the expression of other downstream plasticity genes. (5) As the downstream genes are transcribed, the destabilizing factors are activated while stabilizing factors are inactivated. Finally, the destabilizing factors accelerate the decay of mRNAs for immediate early genes and the consolidation phase is closed. It would be of great interest to investigate the molecular mechanisms underlying the spatio-temporal activations of different AUBPs during memory consolidation. Most research to date has focused primarily on the roles of AUBPs on the stability of mRNAs for immediate early genes such as c-fos, c-myc, and C/EBP (Brewer, 1991; Lee et al., 2012; Yim et al., 2006). However, AUBP-binding targets are more extensive than the previously known immediate early genes (Halees et al., 2008). For example, APP and BACE1 mRNAs which are associated with AD have recently been identified as binding partners of HuD as discussed above (Kang et al., 2014). Therefore, future research should investigate the pathophysiological roles of interactions between these newly identified AUBPs and ARE-containing mRNAs. More than 5% of human transcripts are potential binding partners of AUBPs (Halees et al., 2008), which may be functionally significant to observed phenotypes in normal or diseased brain. Previous studies either overexpressing or knocking-out AUBPs have examined the expression levels of several known targets such as C/EBP, GAP-43, TNFa, and IL-1b, in relation to expressed
Please cite this article in press as: Lee, Y.-S., et al. Regulation of mRNA stability by ARE-binding proteins in synaptic plasticity and memory. Neurobiology of Learning and Memory (2015), http://dx.doi.org/10.1016/j.nlm.2015.08.004
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phenotypes (Bolognani et al., 2007; Lee et al., 2012; Pont et al., 2012; Yim et al., 2006). Effects of manipulating specific AUBPs such as AUF1 and ELAV-like proteins on global gene expression profiles in the nervous system have not been investigated as potential contributors to the observed phenotypes. Another important issue is that many AUBPs can bind to and regulate the same ARE-containing mRNAs. For example, both ApELAVs and ApAUF1 bind to ApC/EBP mRNA and regulate its stability, with opposite effects in Aplysia neurons (Lee et al., 2012; Yim et al., 2006). PKCa and PKCe pathways regulate HuD-mediated mRNA stabilization in mammalian neurons (Lim & Alkon, 2014; Pascale et al., 2005), but the mechanisms for coordinating the effects of different AUBPs with opposing activities have not been elucidated in synaptic plasticity and learning. More comprehensive expression profiles of putative AUBP targets during memory consolidation will contribute to further understanding of these mechanisms. RNA-binding proteins other than the well-known AUBPs are also implicated in regulation of mRNA stability in the nervous system. FUS (fused in sarcoma) is a DNA/RNA-binding protein that was originally identified as a fusion oncogene in human liposarcoma. FUS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology, suggesting a role in synaptic plasticity (Fujii et al., 2005, 2009). Udagawa and colleagues recently demonstrated that FUS promotes stability of GluA1 by binding to the 30 terminus of GluA1 mRNA to control poly-A tail maintenance, supporting its role in regulating synaptic mRNA stability (Udagawa et al., 2015). Interestingly, the ELAV-like protein HuR is a positive regulator for FUS and TDP-43, whose mutations or dysregulation are associated with FTD/amyotrophic lateral sclerosis (ALS) (Lu et al., 2014; Ryu et al., 2014). This finding demonstrates that there is a cascade of RNA-binding proteins involved in coordinating gene expression, and that deregulation of this cascade may contribute to diseased states. Understanding the regulatory mechanisms of AUBPs and other RNA stability regulating factors in the brain will contribute to development of novel treatment strategies for cognitive disorders such as AD, FTD and ALS. Acknowledgments This work was supported by the National Honour Scientist Program through a grant to B.-K.K. and NRF-2014R1A3A1063542 to Y.-S.L. References Addington, A. M., Gauthier, J., Piton, A., Hamdan, F. F., Raymond, A., Gogtay, N., ... Rouleau, G. A. (2011). A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Molecular Psychiatry, 16, 238–239. Akamatsu, W., Fujihara, H., Mitsuhashi, T., Yano, M., Shibata, S., Hayakawa, Y., ... Okano, H. (2005). The RNA-binding protein HuD regulates neuronal cell identity and maturation. Proceedings of the National Academy of Sciences of the United States of America, 102, 4625–4630. Alberini, C. M., Ghirardi, M., Metz, R., & Kandel, E. R. (1994). C/EBP is an immediateearly gene required for the consolidation of long-term facilitation in Aplysia. Cell, 76, 1099–1114. Amadio, M., Pascale, A., Wang, J., Ho, L., Quattrone, A., Gandy, S., ... Pasinetti, G. M. (2009). NELAV proteins alteration in Alzheimer’s disease brain: A novel putative target for amyloid-beta reverberating on AbetaPP processing. Journal of Alzheimer’s Disease, 16, 409–419. Barreau, C., Paillard, L., & Osborne, H. B. (2005). AU-rich elements and associated factors: Are there unifying principles? Nucleic Acids Research, 33, 7138–7150. Bartel, D. P. (2009). MicroRNAs: Target recognition and regulatory functions. Cell, 136, 215–233. Bolognani, F., Merhege, M. A., Twiss, J., & Perrone-Bizzozero, N. I. (2004). Dendritic localization of the RNA-binding protein HuD in hippocampal neurons: Association with polysomes and upregulation during contextual learning. Neuroscience Letters, 371, 152–157. Bolognani, F., Qiu, S., Tanner, D. C., Paik, J., Perrone-Bizzozero, N. I., & Weeber, E. J. (2007). Associative and spatial learning and memory deficits in transgenic mice
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