Subcellular RNA compartmentalization

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Abstract

The phenomenon of mRNA sorting to defined subcellular domains is observed in diverse organisms such as yeast and man. It is now becoming increasingly clear that specific 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 confined to the cell somata, some transcript species are specifically 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 different subcellular distribution patterns of different RNA species in a given neuronal cell type and RNA compartmentalization may differ depending on the electrical activity of nerve cells.

Furthermore, RNA transport is different in neurons of different 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 defined 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.

Introduction

The highly polarized nature of neuronal cells of the central and peripheral nervous system requires elaborate and accurate sorting mechanisms of their macromolecular constituents. Intracellular transport is detrimental for the generation and maintenance of the polarized morphology and ultimately for cell communication within the neuronal network. Continuous redistribution of macromolecules is probably required upon formation of new synapses as well as remodelling of pre-existing ones, for instance during the course of learning and memory consolidation. How a neuron achieves the equipment of distinct microdomains with a defined assortment of proteins that are needed at particular sites for a cell to function as it does such as membrane-associated receptors and other factors involved in synaptic plasticity is still being investigated. Initially, it has been assumed that proteins are generally synthesized in the cell body and are subsequently delivered to sites that may be located at considerable 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 processes indicating that a decentralized translation machinery might also be operative, at least in dendrites and in the initial axonal segment both of which possess protein synthesizing capacity (Steward and Levy, 1982; Steward and Ribak, 1986). Some RNAs are delivered to distal axonal segments [for review see Mohr and Richter (1995)] which are believed to lack components necessary for translation, at least in mammals (Lasek and Brady, 1981). Consequently, the physiological meaning of these transcripts has remained obscure. mRNA transport to distinct locations within the cell is not restricted to nerve cells but has been observed in various non-neuronal systems. Developing systems such as Xenopus and Drosophila oocytes and early embryos are particularly interesting models because mRNA transport is strictly controlled in a spatial and temporal manner and it is absolutely required to allow for correct body pattern formation [for review see St. Johnston (1995); Bassell and Singer (1997); Gavis (1997)]. While the molecular determinants of mRNA targeting in nerve cells are still largely unknown, studies performed in non-neuronal systems indicate the involvement of cis-acting signals inherent to the mRNA molecules to be transported and trans-acting protein factors which bind to these signals either directly or indirectly via protein/protein interactions to guide the RNAs to their ultimate intracellular destinations [for review see St. Johnston (1995); Bassell and Singer (1997); Gavis (1997)]. There is circumstantial evidence for similar mechanisms to exist in neurons. The present review will summarize our current knowledge of individual components of the subcellular mRNA transport machinery in nerve cells and the question concerning the functional significance of this process will be addressed.

Section snippets

Different classes of mRNAs are targeted to dendrites

Apart from BC1 RNA, a non-coding RNA polymerase III transcript (Tiedge et al., 1991) all of the few RNA species residing in dendrites of various nerve cells are mRNAs (Table 1). BC1 RNA forms part of a ribonucleoprotein particle and its function has not yet been determined (Kobayashi et al., 1992). This RNA is detectable in dendrites of various nerve cell types both in the rat central nervous system as well as in primary cultured neurons (Tiedge et al., 1991). Transcripts encoding the

mRNAs located in axons

While a clear physiological relevance, namely local protein biosynthesis, can be ascribed to mRNAs located in the dendrites of nerve cells, the role of transcripts residing in the axonal compartment is less clear. Notwithstanding, as summarized in Table 2, a variety of RNAs, often in substantial amounts, are clearly detectable in axons of various nerve cell types from vertebrates including mammals and invertebrates. Invertebrate neurons, however, differ considerably from those of vertebrates,

Conclusion and perspectives

The last few years have shown that specific mRNA sorting is observed in various eukaryotic cell types throughout the animal kingdom. It appears to be one of the fundamental mechanisms operative in cells in order to create and maintain polarity. Studying these phenomena in nerve cells is particularly interesting because neurons certainly represent one of the most complex cell types. They communicate via thousands of synapses with other nerve cells and their protein repertoire is extremely

Acknowledgements

The author thanks Dr Dietmar Richter (University of Hamburg) for helpful discussion and critical reading of the manuscript, Drs Dietmar Kuhl and Stefan Kindler (University of Hamburg) for their contribution of Fig. 1, Fig. 2, and the Deutsche Forschungsgemeinschaft for financial support.

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