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A Special Series of Reviews: RNA Localization |
a Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
b Program in Developmental Biology, Research Institute, Hospital for Sick Children, Toronto, Canada M5G 1X8; and
c Department of Molecular and Medical Genetics, University of Toronto, Canada
THE INITIAL STEPS in cell fate specification, embryonic patterning, and cellular differentiation involve the establishment of intracellular asymmetry. These asymmetries are established by the selective localization of vesicles, organelles, or macromolecules. Over the past decade it has become evident that localization of RNA molecules is a key method for producing cellular asymmetry in organisms as diverse as yeast and humans. This issue of the journal contains four reviews that address the mechanisms and functions of RNA localization in different animal species and in distinct cell types.
It has been clearly demonstrated in Drosophila oocytes that mRNA localization usually functions to spatially restrict the production of the encoded protein 1, 2) . Several examples have also been described in somatic cells (reviewed in Bassell et al.). RNA localization thus serves two complementary functions: first, it results in a high local concentration of the protein; second, it prevents high levels of the protein from being present elsewhere.
A further function of RNA localization has been uncovered in oocytes and embryos. Here, diffusion of the protein from its RNA source leads to the establishment of a protein gradient, which provides spatial information to the cells that come to reside in different parts of the gradient (best exemplified by bicoid and nanos RNA localization in Drosophila; ref 1 ). In principle, such a gradient could also be used in any large cell to provide polarized intracellular information.
RNA localization also has been implicated in the binary decisions involved in the specification of cell fates and the establishment of embryonic germ layers. This is accomplished through asymmetric segregation of localized transcripts into only one of the two cells produced by mitosis, causing the encoded protein to be restricted to only that cell. Examples include the role of prospero in differentiating neuroblasts in Drosophila (1) , ASH1 in the determination of mating type in budding yeast 3, 4) , and VegT in the establishment of the embryonic germ layers in Xenopus (2) .
The importance of mRNA localization in restricting the spatial distribution of the encoded protein is further highlighted by the discovery of a link between RNA localization and translation. In Drosophila, oskar and nanos transcripts are localized to and translated at the posterior pole of the oocyte (1) . These transcripts are translationally repressed either during their transport to the posterior (oskar) or if they fail to be localized (nanos). Translational control of localized RNAs may be intimately linked, on one hand, to translation factors that are integral components of localization particles, and on the other hand to association with the cytoskeleton 3, 4) .
Apart from mRNAs, there are now several examples of localized non-protein-coding RNAs in Xenopus (e.g., Xlsirts; ref 2 ), Drosophila (e.g., Pgc; ref 1 ), and mammalian somatic cells (e.g., BC1; refs 3, 4 ). These may serve as structural components of particular organelles such as the germinal granules, function in RNA transport, or be involved in transcript anchoring to the cytoskeleton.
Identification of the components of the RNA sorting, transport, and localization apparatus is proceeding at a rapid pace and is leading to insights not only into localization mechanisms, but also into how these mechanisms may have evolved. For example, several individual cis-acting localization elements have been found to contribute to compound cis-acting domains, usually located within the 3' UTR of the cognate mRNAs 1-4) . Each element encodes a subset of the information necessary for RNA localization. Trans-acting factors that interact with these elements are now being identified. Evolutionary conservation of localization mechanisms is highlighted by the fact that the mammalian zip code binding protein involved in the localization of ß-actin transcripts in fibroblasts is homologous with the Vera protein involved in the localization of Vg1 transcripts in Xenopus oocytes 2, 4) . In Drosophila it has been shown that cis-acting elements involved in translational control are often closely linked to those that control RNA localization (1) . It is likely that this theme will be repeated in other systems.
Several classes of localized RNAs are transported directionally on cytoskeletal elements. Early studies from Xenopus and Drosophila demonstrated the involvement of microtubules in long-distance RNA translocation (e.g., Vg1 and bicoid transcripts) and actin microfilaments in transcript anchoring (e.g., Vg1) 1, 2) . Recent results from yeast and somatic cells indicate that microfilaments may also function in RNA transport over short distances (e.g., ASH1 transcripts; see refs 3, 4 ). Apart from the cytoskeleton, there is now evidence for the involvement of the endoplasmic reticulum in the localization of mRNAs (e.g., Vg1 transcripts in Xenopus oocytes; ref 2 ). A distinct mechanism for transcript localization combines generalized RNA degradation with local protection from degradation in a particular cytoplasmic region (e.g., Hsp83 RNA in Drosophila embryos; ref 1 ). Whether the protected transcripts in this case are anchored to the cytoskeleton or to other organelles such as the germinal granules remains to be determined.
Progress has also been made in understanding external influences that regulate transcript localization. Signal transduction pathways may mobilize the localization machinery and also be involved in providing positional cues for orienting the transport apparatus. Examples come from oocytes, neuronal growth cones, and fibroblast lamellae 1, 2, 4) .
The reviews in this issue of The FASEB Journal present our current understanding of the mechanisms and functions of RNA localization in cellular and developmental processes. They highlight how genetic and molecular approaches, together with high-resolution imaging, have led to key mechanistic insights. It is hoped that these reviews will serve to introduce this research area to a broad audience of molecular, cellular, and developmental biologists and provide perspectives on future directions in this exciting research area.
FOOTNOTES
1 Correspondence: L.D.E., Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030, USA. E-mail: lde{at}mdacc.tme.edu; or H.D.L., Program in Developmental Biology, Research Institute, Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada M5G 1X8. E-mail: lipshitz{at}sickkids.on.ca 
REFERENCES
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