Trends in Cell Biology
ReviewTo localize or not to localize: mRNA fate is in 3′UTR ends
Introduction
Asymmetric localization of mRNAs is an evolutionarily conserved mechanism exploited by most organisms to restrict protein synthesis to specific subcellular compartments [1]. Many of the best-characterized targeted mRNAs were initially identified in oocytes and early embryos, where they encode local cues that control axis formation and germline differentiation [2]. High-resolution hybridization techniques have recently shown that more than 70% of the transcripts present in Drosophila embryos are found in spatially distinct patterns, suggesting that mRNA localization is a widespread phenomenon that involves most transcripts [3].
mRNA localization is particularly relevant in somatic, highly polarized cells, including differentiated neurons, because the site of transcription can be far removed from the final location of the protein (the dendrites or growth cone, for example). In such cells, local protein synthesis circumvents the problem of transporting proteins over long distances, a process that in some cases can take a time longer than the protein half-life [4]. Moreover, translation of localized mRNA following extracellular stimulation allows greater spatial and temporal resolution of the adaptive response, ensuring a fast and efficient way to adjust to novel environmental conditions.
During the early stages of embryonic development a small number of neuronal progenitors give rise to thousands of distinct neuronal cells, each programmed to extend dendrites, and one axon that can respond to guidance cues and form synapses with appropriate partner cells. Each of these events requires the expression of large numbers of specific genes, which encode proteins that promote differentiation, cell survival, guided cell and growth cone migration, synapse formation and, later, synaptic plasticity 5, 6, 7 (Figure 1). Efforts to unravel the molecular basis of gene expression in neurons have been historically focused on transcriptional control. However, post-transcriptional processing of mRNAs, such as mRNA splicing, mRNA stability and translation, are increasingly recognized as essential steps in the propagation of genetic information from the nucleus to the peripheral subcellular compartments. Importantly, all aspects of mRNA processing are tightly regulated and influence key cellular programs and developmental aspects in a variety of organisms from yeast to mammals [8]. Here we discuss a series of recent and exciting studies that highlight how nuclear and cytoplasmic mRNA processing affects mRNA localization and, ultimately, protein expression in mammalian cells, with a particular emphasis on neurons.
Section snippets
Importance of the 3′UTR
Eukaryotic mRNAs share common features that include exons and introns, 5′ and 3′-untranslated regions (UTRs), a special modified base at the 5′ end (called cap), a stretch of adenines at the 3′ end (called poly(A) tail) and a number of signals present within both the mRNA coding and non-coding regions, which identify the translational start and end sites. Most mRNA regulatory elements are situated within the 5′ and 3′UTRs, where they act as platforms for the assembly of protein complexes to the
Mechanisms that generate 3′UTR variability
In eukaryotic cells, genes are initially transcribed as large mRNA precursors (pre-mRNAs) that undergo a series of nuclear modifications, including 5′ cap addition, polyadenylation and splicing, before being exported into the cytoplasm. In most cases these processes are highly interconnected and occur co-transcriptionally 8, 17, 18. Nuclear mRNA processing is also linked to downstream cytoplasmic events through the recruitment of nuclear proteins to mRNPs that remain associated with the mRNA
Concluding remarks
mRNA localization is a fundamental mechanism for the propagation of genetic information from the nucleus to distinct subcellular compartments. Although it is known that cis-localization elements located within 3′UTRs have the ability to influence the targeting of certain transcripts, it is becoming clear that nuclear and cytoplasmic 3′UTR remodeling of entire sets of mRNAs represents a very efficient way to orchestrate the cellular adaptive response (Figure 2). The finding that activation of
Acknowledgments
We thank Luca Crepaldi, Robert De Bruin, Ilaria Napoli and Adolfo Saiardi for many helpful suggestions. We apologize to authors whose work could not be cited because of space limitations. C.A. and A.R. are supported by the Medical Research Council.
Glossary
- Cis-element
- part of the sequence of an mRNA that influences its own expression.
- Trans-acting proteins
- proteins that bind mRNA cis-elements.
- miRNA
- microRNA; non-coding single-strand RNA of 21–23 nt in length that regulates gene expression by base pairing with the target mRNA.
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