Abstract
Localized protein synthesis is increasingly recognized as a means for polarized cells to modulate protein levels in subcellular regions and the distal reaches of their cytoplasm. The axonal and dendritic processes of neurons represent functional domains of cytoplasm that can be separated from their cell body by vast distances. This separation provides a biological setting where the cell uses locally synthesized proteins to both autonomously respond to stimuli and to retrogradely signal the cell body of events occurring is this distal environment. Other cell types undoubtedly take advantage of this localized mechanism, but these have not proven as amenable for isolation of functional subcellular domains. Consequently, neurons have provided an appealing experimental platform for study of mRNA transport and localized protein synthesis. Molecular biology approaches have shown both the population of mRNAs that can localize into axons and dendrites and an unexpectedly complex regulation of their transport into these processes. Several lines of evidence point to similar complexities and specificity for regulation of mRNA translation at subcellular sites. Proteomics studies are beginning to provide a comprehensive view of the protein constituents of subcellular domains in neurons and other cell types. However, these have currently fallen short of dissecting temporal regulation of new protein synthesis in subcellular sites and mechanisms used to ferry mRNAs to these sites.
Highlights
Localized protein synthesis is increasingly recognized as a means for polarized cells to modulate protein levels in subcellular regions and the distal reaches of their cytoplasm
Considering that many RNA motifs for localization are determined by secondary structure that have proven difficult to analyze through bioinformatics approaches, large scale analyses of RNA-protein interaction sites through cross-linking and immunoprecipitation will likely uncover functional RNA motifs that have been unrecognized to date. It is not clear whether these RNA co-immunoprecipitation approaches are of sufficient sensitivity to distinguish where the mRNA-protein interactions occur within the cell; i.e. will they be of sufficient sensitivity for the low amounts of protein and RNA isolated from subcellular compartments like axons and dendrites? proteins indirectly binding to mRNAs through protein-protein interactions likely contribute to specificity for when individual mRNAs are transported
Molecular biology approaches have been used to dissect this spatial regulation by providing profiles of localized mRNAs, and cell biology approaches have been used to both detect localized synthetic machinery and show its functionality
Summary
Tremendous distances separate subcellular domains from the cell body where most protein synthesis was thought to occur (Fig. 1A). The highly branched efferent processes that receive synaptic input in the nervous system, extend for hundreds of micrometers from the neuronal perikaryon. Subsequent studies have shown that protein synthesis in dendrites contributes to the synaptic plasticity that is thought to underlie learning and memory. There were a few early examples of neuronal mRNAs in axons [5,6,7], the presynaptic processes that can extend for thousands to tens of thousands.
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