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Dynamic Spatio-Temporal Control of Neuronal Gene Expression 437 Author's personal copy ! Dendritic RNA Transport: Dynamic Spatio-Temporal Control of Neuronal Gene Expression 437 Dendritic, RNA Transport: Dynamic Spatio-Temporal Control of , Neuronal, Gene Expression , J B Dictenberg, , Hunter College, New York, NY, USA response to neuronal stimulation, an idea that currently R H Singer, , Albert Einstein College of Medicine, Bronx, has enormous support and has led to breakthroughs NY, USA, in visualizing specific transcript motility in living cells. , ã 2009 Elsevier, Ltd. All rights reserved. , Structure and Composition of Dendritic , Transport mRNPs , mRNAs are transported into dendrites in the form of Introduction, , large, electron-dense RNA- and protein-containing Dendrites, are master integrators of information flow granules. Since these transport granules are distinct , in the brai, n and the sites of postsynaptic structural from stress granules, they will be referred to as trans- modificati, ons that regulate the plasticity of synapse port messenger ribonucleoproteins (mRNPs). Neu- strength ,in response to neurotransmission. Recent ronal cytoplasmic transport mRNPs appear quite data sugg,est that dendrites are also an important site heterogeneous in size and have been estimated , for the dyn, amic regulation of localized gene expression by ultrastructural methods to be between 200 and in the nervo, us system, with subsets of synapses possess- 600 mm in diameter and greater in mass than polyri- ing the ab,ility to independently alter synapse strength bosome complexes (>500 S). They are formed initi- , through th, e local synthesis of proteins. An important ally when nucleocytoplasmic shuttling RNA-binding componen, t to this regulation is the active transport of a proteins (RBPs) associate with nascent transcripts in select grou, p of messenger RNAs (mRNAs) from the the nucleus to prevent premature ribosomal loading , cell body ,into dendrites and targeting of these mRNAs and translation and to aid in nuclear export of to specific, translation sites. Since several long-lasting mRNAs. While the composition of proteins in trans- forms of ,plasticity require protein synthesis, synaptic port mRNPs may change on exit to the cytoplasm, stimulatio,n appears to be an important mechanism for exchanging factors specific to export, for example, , the regula,tion of mRNA trafficking within dendrites. several RBPs appear to remain associated with tran- , scripts until they are delivered to distal dendritic sites , for translation. Numerous biochemical and proteo- Discovery, of Dendritic mRNA Transport , mic experiments suggests that these cytoplasmic neu- Early spec,ulations about the nature of synaptic connec- ronal transport mRNPs are not homogeneous in tions led ,to the idea that cytoskeletal proteins played composition, containing many different RBPs, such , an import,ant structural role in neuronal function, and as Staufen, zipcode-binding protein 1 (ZBP1), het- the identi,fication of translational machinery in den- eronuclear RNP-A2 (hnRNP-A2), Pur-alpha and drites but, not axons by ultrastructural methods and the fragile X mental retardation protein (FMRP), as actin pro,tein localized to dendritic spines spawned well as many mRNA species, such as calcium/ , an era of, investigation into the nature of localized calmodulin-dependent protein kinase II (CaMKII)- gene expr,ession that is still ongoing. As it was found alpha, activity-regulated cytoskeletal-associated (Arc), that micro, tubule-associated protein 2 (MAP2) was beta-actin, and the noncoding BC1. Included in the , expressed, selectively in the dendritic compartment, hundreds of diverse mRNAs that have been iso- markers f,or neuronal polarity became the subject of lated from dendrites biochemically are several subu- great curi,osity. Subsequent work tracked total mRNA nits of glutamate receptor subtypes and translational , movemen,ts in cultured neurons by pulse labeling with machinery components, such as ribosome subunits radioactive, nucleotides to visualize time-dependent and elongation factor 1a. In addition, transport migration, of mRNA into dendrites and showed the mRNPs contain multiple cytoskeletal motors such asymmetr,ic localization of cytoskeletal mRNAs to as conventional kinesin (Kif5) and dynein, which , dendrites,, such as MAP2. More recently, eloquent contribute to plus end- and minus end-directed trans- molecular, approaches have demonstrated the presence port along microtubules within dendrites. While of numero, us diverse mRNAs by directly aspirating the protein content may be diverse, the RBPs in , cytoplasm from transected dendrites and identification t,ransport mRNPs all appear to be important for by polymerase chain reaction. These studies served r,epression of translation of mRNAs until reaching as the foundation for the idea that many regulatory t,heir distal site, where they are derepressed by regu- and cytoskeletal mRNAs may be selectively trans- l,atory signals. Both biochemical work and ultra- ported into neuronal dendrites on microtubules and structural work have shown that they contain many subsequently activated for translation at synapses in densely packed ribosomes but are not translationally !"#$#%&'()*+,&-,.(/0&1#*("#(,!"##$%&'()*+',&'--+'.,/0...' ! Author's personal copy 438 Dendritic! RNA Transport: Dynamic Spatio-Temporal Control of Neuronal Gene Expression competent as they lack proteins essential for initiation mRNAs, such as MAP2, CaMKII-alpha, Arc, and , (e.g., eIF4), . It is interesting to note that these mRNPs g-aminobutyric acid-A-receptor subunit and there- are dramati, cally remodeled on neuronal depolariza- fore may play an important role in mRNA targeting tion, presum, ably releasing ribosomes and mRNAs using similar machinery in neurons. However, the fact , into local, active translational complexes. The compo- that a 640 nt element of MAP2 mRNA 30UTR was sition of,transport mRNPs suggests that they represent found to be necessary for dendritic targeting suggests motile pretr, anslation units that undergo dynamic that there may be additional required elements pres- , remodeling, in response to signals that induce their ent in the 30UTR that control localization or stability. dendritic, transport and subsequent translation. Another example of a bipartite element is the beta- , actin mRNA, which contains both a 54 nt and a 43 nt Sequence, and Structural Characteristics of zipcode, required for efficient localization to neuro- Localization, Signals in Neuronal Transport mRNPs , nal processes and growth cones. While some zipcodes A unifying, theme in the analysis of many localized in localized mRNAs such as beta-actin are necessary mRNAs, is the requirement for a cis-acting sequence for localization of the native mRNAs, most zipcodes , for targeti, ng the transcript to specific sites, or ‘zip- have been tested using reporter mRNAs, and there- codes.’ ,These zipcodes are mostly localized to the fore their requirement in the localization of native , 30 untranslated regions (UTRs) of transcripts, where mRNAs is not known. Future work using genetic , they are, bound by trans-acting RBPs involved in the deletions or antisense technology can more directly localization, process (see Table 1). The zipcodes may address these shortcomings. contain , several units that function in a multistep Some mRNAs, such as bicoid in Drosophila, may pathway, to mRNA localization. One example is the contain zipcode elements that are repeated several , localization, of myelin basic protein (MBP) mRNA to times in the 30UTR to effect a more efficient localization the myeli, n-rich oligodendrocyte compartment. This as the deletion of one or more redundant elements is not is a two-st, ep process involving an 11 nt element (the sufficient to completely abolish targeting but rather , RNA transp, ort signal, RTS) sufficient to direct a diminishes the amount of mRNA localized over time. reporter, mRNA into processes and a distinct 342 nt This is a feature shared by the beta-actin mRNA 30UTR element, (the RNA localization region) required for zipcode, which has a consensus sequence of ACACCC , MBP mR, NA targeting to or retention at the myelin- repeated twice within one zipcode element (the 54 nt specific , subcompartment in oligodendrocytes. The chicken zipcode). Although some zipcodes may be 11 nt RTS, has been shown to mediate granule forma- conserved between mRNAs, there is no clear indication tion and, dendritic trafficking with hnRNP-A2 in yet that the same proteins are involved in their locali- , primary, hippocampal cultures as well; however, a zation. Rather diverse collections of RBPs have been requirement, for this 11 nt sequence in the transport found to associate with transcripts that have conserved of the native, MBP mRNA has not been established. It zipcodes. This has inspired a thorough analysis of , is interes, ting to note that a conserved version of the secondary structural features in zipcodes that may be RTS has, also been found in several other dendritic more important than primary sequence conservation , , , Table 1 , RNA-binding proteins and their corresponding cis-acting sequences in brain , RNA-binding protein mRNA Sequence and location Required for localizationa , , ZBP1 beta-actin ACACCC, within 54 nt zipcode in 30UTR , þ hnRNPA2 MBP GCCAAGGAGCC, 3 UTR , 0 , MAP2 GCCAAGGAGUC, coding CPEB , CaMKII-alpha UUUUUUAUU X 2 (separated by 82 nt), 30UTR HuD tau 240 nt, 30UTR , þ MARTA1/2, MAP2 640 nt, 30UTR Unknown, CaMKII-alpha 3.0 kb, 30UTR / þ À , 94 nt, 30UTR , aPlus sign,( ) indicates cis-acting
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