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Subcellular Rna Compartmentalization Progress in Neurobiology Vol. 57, pp. 507 to 525, 1999 # 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0301-0082/98/$ - see front matter PII: S0301-0082(98)00066-5 SUBCELLULAR RNA COMPARTMENTALIZATION EVITA MOHR* University of Hamburg, Institut fuÈr Zellbiochemie und klinische Neurobiologie, Martinistraûe 52, 20246 Hamburg, Germany (Received 15 May 1998) AbstractÐThe phenomenon of mRNA sorting to de®ned subcellular domains is observed in diverse organisms such as yeast and man. It is now becoming increasingly clear that speci®c transport of mRNAs to extrasomal locations in nerve cells of the central and peripheral nervous system may play an important role in nerve cell development and synaptic plasticity. Although the majority of mRNAs that are expressed in a given neuron are con®ned to the cell somata, some transcript species are speci®cally delivered to dendrites and/or, albeit less frequently, to the axonal domain. The physiological role and the molecular mechanisms of mRNA compartmentalization is now being investigated extensively. Even though most of the fundamental aspects await to be fully characterized, a few interesting data are emerging. In particular, there are a number of dierent subcellular distribution patterns of dierent RNA species in a given neuronal cell type and RNA compartmentalization may dif- fer depending on the electrical activity of nerve cells. Furthermore, RNA transport is dierent in neurons of dierent developmental stages. Considerable evidence is now accumulating that mRNA sorting, at least to dendrites and the initial axonal segment, enables local synthesis of key proteins that are detrimental for synaptic function, nerve cell development and the establishment and maintenance of nerve cell polarity. The molecular determinants specifying mRNA compartmentalization to de®ned microdomains of nerve cells are just beginning to be unravelled. Targeting appears to be determined by sequence elements residing in the mRNA molecule to which proteins bind in a manner to direct these transcripts along cytoskeletal components to their site of function where they may be anchored to await transcriptional activation upon demand. # 1998 Elsevier Science Ltd. All rights reserved CONTENTS 1. Introduction 508 2. RNA targeting to dendrites 508 2.1. Dierent classes of mRNAs are targeted to dendrites 508 2.2. RNA transport takes place along the cytoskeletal network 511 2.3. Velocity of dendritic RNA transport 511 2.4. mRNA transport in immature and mature neurons 512 2.5. Components of the translational machinery in dendrites 513 2.6. Targeting signals necessary for dendritic mRNA transport 514 2.7. Local translation of dendritic mRNAs 517 2.8. Translation is not required for mRNA sorting to dendrites 518 3. mRNAs located in axons 519 3.1. Axonal transcripts in vertebrates 519 3.2. Axonal mRNAs in invertebrates 522 4. Conclusion and perspectives 522 Acknowledgements 523 References 523 * Corresponding author. Tel.: 49-40-4717 4553; Fax: 49-40-4717 4541; e-mail: [email protected]. 507 508 E. Mohr ABBREVIATIONS AMP Adenosine monophosphate mRNA Messenger RNA Arc Activity-regulated cytoskeleton-associated NMDA N-Methyl-D-aspartate protein NT-3 Neurotrophin-3 Arg3.1 Activity-regulated gene 3.1 oligo(dT) Oligo-deoxythymidine BB Brattleboro OML Outer molecular layer BDNF Brain-derived neurotrophic factor OMP Olfactory marker protein CaMKIIaa-Subunit of the Ca2+/calmodulin-dependent OT Oxytocin protein kinase II pcp-2 Purkinje cell protein-2 CDCH Caudodorsal cell hormone poly(A) Polyadenylated CREB Cyclic AMP response element binding protein RER Rough endoplasmic reticulum DNA Deoxyribonucleic acid RNA Ribonucleic acid eEF Eukaryotic elongation factor RNP Ribonucleoprotein eIF Eukaryotic initiation factor rRNA ribosomal RNA ELH Egg-laying hormone SCG Superior cervical ganglion GA Golgi-apparatus SRP Signal recognition particle GAP Growth-associated protein SSR Signal sequence receptor GlyR Glycine receptor SSTR1 Somatostatin receptor subtype 1 Golf a-Subunit of the olfactory system-speci®c TGN Trans-Golgi network heterotrimeric G-protein tRNA Transfer RNA Insp3r 1 Inositol-1,4,5-Trisphosphate receptor type 1 UTR Untranslated region kDa kiloDalton Vg 1 Vegetal 1 LTP Long term potentiation VP Vasopressin MAP Microtubule-associated protein MBP Myelin basic protein 1. INTRODUCTION are particularly interesting models because mRNA transport is strictly controlled in a spatial and tem- The highly polarized nature of neuronal cells of the poral manner and it is absolutely required to allow central and peripheral nervous system requires elab- for correct body pattern formation [for review see orate and accurate sorting mechanisms of their St. Johnston (1995); Bassell and Singer (1997); macromolecular constituents. Intracellular transport Gavis (1997)]. While the molecular determinants of is detrimental for the generation and maintenance of mRNA targeting in nerve cells are still largely the polarized morphology and ultimately for cell unknown, studies performed in non-neuronal sys- communication within the neuronal network. tems indicate the involvement of cis-acting signals Continuous redistribution of macromolecules is inherent to the mRNA molecules to be transported probably required upon formation of new synapses and trans-acting protein factors which bind to these as well as remodelling of pre-existing ones, for signals either directly or indirectly via protein/pro- instance during the course of learning and memory tein interactions to guide the RNAs to their ultimate consolidation. How a neuron achieves the equip- intracellular destinations [for review see St. ment of distinct microdomains with a de®ned assort- Johnston (1995); Bassell and Singer (1997); Gavis ment of proteins that are needed at particular sites (1997)]. There is circumstantial evidence for similar for a cell to function as it does such as membrane- mechanisms to exist in neurons. The present review associated receptors and other factors involved in will summarize our current knowledge of individual synaptic plasticity is still being investigated. Initially, components of the subcellular mRNA transport ma- it has been assumed that proteins are generally syn- chinery in nerve cells and the question concerning thesized in the cell body and are subsequently deliv- the functional signi®cance of this process will be ered to sites that may be located at considerable addressed. distances from the cell somata, for instance in axons and dendrites. In recent years, however, a variety of mRNA species have been detected in neuronal pro- cesses indicating that a decentralized translation ma- 2. RNA TARGETING TO DENDRITES chinery might also be operative, at least in dendrites 2.1. Dierent Classes of mRNAs are Targeted to and in the initial axonal segment both of which pos- Dendrites sess protein synthesizing capacity (Steward and Levy, 1982; Steward and Ribak, 1986). Some RNAs Apart from BC1 RNA, a non-coding RNA poly- are delivered to distal axonal segments [for review merase III transcript (Tiedge et al., 1991) all of the see Mohr and Richter (1995)] which are believed to few RNA species residing in dendrites of various lack components necessary for translation, at least nerve cells are mRNAs (Table 1). BC1 RNA forms in mammals (Lasek and Brady, 1981). part of a ribonucleoprotein particle and its function Consequently, the physiological meaning of these has not yet been determined (Kobayashi et al., transcripts has remained obscure. mRNA transport 1992). This RNA is detectable in dendrites of var- to distinct locations within the cell is not restricted ious nerve cell types both in the rat central nervous to nerve cells but has been observed in various non- system as well as in primary cultured neurons neuronal systems. Developing systems such as (Tiedge et al., 1991). Transcripts encoding the Xenopus and Drosophila oocytes and early embryos microtubule-associated protein (MAP) 2, a marker Subcellular RNA Compartmentalization 509 Table 1. RNAs located in dendrites of various nerve cell tissues Dendritic RNAs Species/tissue Reference Arc/Arg3.1 Rat/hippocampus Lyford et al. (1995); Link et al. (1995) BC1 Rat/hippocampus Tiedge et al. (1991) BDNF Rat/hippocampus Dugich-Djordjevic et al. (1992) CaMKIIa Rat/hippocampus Burgin et al. (1990) Dendrin Rat/forebrain Herb et al. (1997) GAP 43 Rat/brain Landry et al. (1994) Glycine receptor a-subunit Rat/spinal cord Racca et al. (1997) Glutamate receptors Rat/hippocampus Miyashiro et al. (1994) InsP3 receptor Mouse/cerebellum Furuichi et al. (1993) MAP2 Rat/hippocampus Garner et al. (1988) Neurogranin/RC3 Rat/brain Landry et al. (1994) Oxytocin Rat/hypothalamus Mohr et al. (1995) Pcp-2/L7 Mouse/cerebellum Bian et al. (1996) SSTR 1 Rat/cortex Mohr, unpublished results Vasopressin Rat/hypothalamus Mohr et al. (1995) Arc, activity-regulated cytoskeleton-associated protein; arg, activity-regulated gene; BC, brain cytosolic; BDNF, brain-derived neuro- trophic factor; CaMKIIa, a-subunit of the Ca2+/calmodulin-dependent protein kinase II; GAP, growth-associated protein; InsP3, inositol trisphosphate; MAP, microtubule-associated protein; pcp, Purkinje cell protein; SSTR, somatostatin receptor. of the dendritic cytoskeleton, was the ®rst mRNA mal part. In contrast, the mRNA for the a-subunit shown to be located in dendrites of neurons of the of Ca2+/calmodulin dependent protein kinase II rat central nervous system (Garner et al., 1988). The (CaMKIIa), a protein involved signal transduction dendritic compartmentalization
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