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regulation of protein synthesis both at perykaryal somatic and at distant extrasomatic sites.

Localized RNAs

The analysis of RNA transport and localization has in recent years matured into a novel discipline in cell biology and neuroscience. In traditional cell biology, proteins are manufactured in the perikaryal soma and subsequently delivered to their respective sites of function. Although this may often be so, it is now accepted that this scenario does not necessarily represent the whole story. In diverse cell types, RNAs have been identified that are targeted to specific subcellular locations for on-site translation (6). In 1982, the first such localized mRNA, encoding myelin basic protein, was identified in oligodendrocytes (7). Subsequently, RNA localization was documented also in Xenopus oocytes, Drosophila embryos, and a variety of somatic eukaryotic cell types ranging from fibroblasts to neurons (812).

In neurons, localized RNAs were discovered rather late, and only after the presence of polyribosomes in postsynaptic dendritic microdomains (13, 14) had already been documented for a while. The first three RNAs identified in dendrites were the mRNAs encoding MAP2 (15) and CaMKIIa (16) as well as BC1 RNA, a noncoding RNA polymerase III transcript (17). These were joined by neuropeptide-encoding transcripts in the axonal domain (18). Today, research is focused on the mechanism of RNA transport in neuronal processes and on the elucidation of the signals involved—both at the level of RNA (cis-acting elements) and proteins (trans-acting factors). This work eventually will shed light on how a neuron administers translation of a distinct mRNA at or near a synapse in an input-specific and activity-dependent manner (11, 19).

Neuronal Plasticity

In terms of subcellular location, the ultimate and critical determinant of cellular function is of course a correct spatio-temporal expression pattern of the protein repertoire, regardless of whether any given protein is delivered from the perikaryon or synthesized locally on site. Consequently, given the paramount importance of subcellular “location” in particular in neurons, protein targeting and anchoring mechanisms will directly impact long-term neuronal plasticity and are likely to figure prominently in the development of neurological disorders. In this respect, the discovery of novel scaffolding multidomain proteins that are involved in the functional organization of the postsynaptic density has significantly furthered our understanding of how signal transduction pathways might be regulated at the synapse. Activity-dependent modification of protein structure, location, and/or interaction may be essential for the molecular reorganization of postsynaptic functional architecture (20, 21). In addition, local translation of mRNA(s) encoding one or several of the scaffolding proteins also may contribute to the dynamic plasticity at a postsynaptic specialization after stimulation (21).

It then appears that neurons, being among the spatially most extended and functionally most complex of all eukaryotic cells, have to cope with organizational tasks that are indeed reminiscent of those associated with the maintenance and development of large metropolitan areas. And it thus holds true for cities and cells alike that the larger and more complex they are, the more relevant becomes an old New Yorker real estate adage that of all determinants of functional value, none are more important than the following three: location, location, location.

We thank the National Academy of Sciences for encouragement in planning this colloquium and for generous financial and administrative support. We also thank Mr. E.Patte of the National Academy of Sciences Executive Office and Ms. M.Gray-Kadar of the Beckman Center for their help in organizing the meeting and the National Academy for providing the excellent resources and facilities of the Arnold and Mabel Beckman Center in Irvine.

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