- Email: [email protected]
RNA localization: New roles for an evolutionarily ancient mechanism
Seminars in Cell & Developmental Biology 18 (2007) 161–162
Editorial
RNA localization: New roles for an evolutionarily ancient mechanism
Eukaryotic cells utilize a number of mechanisms to control the expression of their genes, including regulation of gene expression at the transcriptional, post-transcriptional and translational levels. A mechanism that is receiving increasing attention is RNA localisation, which allows restricting the synthesis of cognate proteins to specific subcellular domains. The localisation of RNAs has been found to occur in a wide range of organisms, including fungi (e.g. budding yeast, Ustilago maydis), plants (e.g. cereal species, Arabidopsis), and various animal species (e.g. ascidians, echinoderms, Drosophila, zebrafish, Xenopus, and mammals). Moreover, a number of the proteins involved in this process are highly conserved between divergent species. This suggests that RNA localisation arose early during evolution and has been adapted for various contexts by different organisms. For instance in budding yeast, the localisation of specific mRNAs to the daughter cell specifies different mating types between mother and daughter cell [1]. In, for example, Drosophila and Xenopus oocytes and embryos it was found to be important for the establishment of the body axes [2]. Localised mRNAs have also been shown to act as cell fate determinants in the asymmetric division of neuroblasts in the Drosophila embryo. In mammals, the localisation of RNAs was shown to be involved in the regulation of the actin cytoskeleton in migrating cells, the formation of myelin sheaths formed by oligodendrocytes in the central nervous system, the guidance of developing axons [3] and dendrites, and possibly the establishment and modification of synapses [4]. To date, the majority of cellular processes involving RNA localisation studied occur during development or cellular differentiation. During development, the localisation of mRNAs that encode cytoplasmic determinants to certain regions of an embryo serves to pattern the embryo, for example to determine the fate of different regions of the embryo. Similarly, dividing cells use this mechanism to asymmetrically sort cell fate determinants into the daughter cells from a division, resulting in two cells with different fates. There are, however, indications that RNA localisation may also be important in a number of differentiated cell types [1,2,4]. In contrast to development and cellular differentiation, RNA localisation in differentiated cells is not aimed at giving rise to different cells. Instead, it serves to compartmentalise the cell itself into domains with specialised properties 1084-9521/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2007.03.001
or to facilitate the co-translational incorporation of locally synthesized proteins into target structures, such as organelles or macromolecular complexes. A series of surprising findings have been reported lately in the context of RNA localization. Until recently, RNA transport was generally assumed to occur in the form of ribonucleoprotein particles (RNPs) with the help of molecular motor proteins [5]. In yeast, Xenopus oocytes and mammalian neurons, key factors involved in RNA localization, such as She2p, Vg1 RNA-binding protein and Staufen1, have, however, recently been found to colocalize with the endoplasmic reticulum (ER) [6]. Future experiments will have to unravel how ER tubules or vesiculated ER might contribute to cytoplasmic RNA localization in these systems. Furthermore, a recent study suggested the endosomal sorting complex required for transport II (ESCRT-II) to be essential for the final step in the localization of bicoid mRNA to the anterior pole of the oocyte [7]. Even more surprisingly, ESCRT-II, which binds to bicoid mRNA directly, appears to recruit Staufen to the bicoid localization signal independently of its endosomal protein sorting function. Clearly, future studies will help in understanding this fascinating link between membranes and the ER on one side and a possible connection between the ESCRT-II complex and RNA localization on the other. A second surprise came in a recent study showing that the cytoplasmic localization of oskar mRNA depends on splicing of the mRNA in the nucleus [8]. Previously, it was shown that the 3 -UTR of oskar mRNA is sufficient for its localization to the posterior pole of the oocyte, although these experiments were done using reporters in oocytes that still expressed the endogenous oskar mRNA. The authors revisited the issue and demonstrated that an oskar mRNA produced from an oskar gene lacking introns fails to localize at the oocyte’s posterior pole, when the endogenous gene is removed. Specifically, it was shown that the first intron is required for localization to occur. It appears that the exon junctional complex (EJC) [9], consisting of Y14, Mago, eIF4AIII and Barentsz, may enable the oskar localization complex to assemble and achieve cytoplasmic localization. It will be particularly interesting to learn how these two processes are mechanistically linked. A third and fascinating issue is the recent notion that small RNAs, including microRNAs and non-coding RNAs, might play
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Editorial / Seminars in Cell & Developmental Biology 18 (2007) 161–162
an important role in locally regulating mRNA translation at neuronal synapses [10]. The brain cytoplasmic RNA BC1 is part of dendritic RNPs and has recently been shown by the Tiedge lab to regulate translational control by interacting with eIF4A and poly(A) binding protein [4]. Furthermore, a recent study by Ashraf et al. [11] establishes both Ca2+ -calmodulindependent kinase II (CaMKII) and Staufen as regulatory targets of RISC-mediated gene silencing in Drosophila. Finally, a study by Schratt et al. [12] identified a specific microRNA, miR-134, that regulates the local synthesis of Lim kinase 1 in dendrites [4]. BDNF treatment of hippocampal neurons relieved silencing of the LimK1 mRNA and induced dendritic spine growth. These data suggest that small RNAs might travel within RNPs to synapses to keep mRNAs translationally silent during transport [13]. It will be interesting to see whether these “neuronal granules” are RISC, transport RNPs or rather P-bodies and to understand the mechanistic link between RNA transport, translational control and small RNA-mediated gene silencing and RNA degradation. References [1] Du TG, Schmid M, Jansen RP. Why cells move messages: the biological functions of mRNA localization. Semin Cell Dev Biol 2007;18:171–7. [2] Palacios IM. How does an mRNA find its way? Intracellular localisation of transcripts. Semin Cell Dev Biol 2007;18:163–70. [3] Hengst U, Jaffrey SR. Function and translational regulation of mRNA in developing axons. Semin Cell Dev Biol 2007;18:209–15. [4] Dahm R, Kiebler M, Macchi P. RNA localisation in the nervous system. Semin Cell Dev Biol 2007;18:216–23. [5] Bullock SL. Translocation of mRNAs by molecular motors: think complex? Semin Cell Dev Biol 2007;18:194–201.
[6] Schmid M, Jaedicke A, Du TG, Jansen RP. Coordination of endoplasmic reticulum and mRNA localization to the yeast bud. Curr Biol 2006;16:1538–43. [7] Irion U, St Johnston D. bicoid RNA localization requires specific binding of an endosomal sorting complex. Nature 2007;445:554–8. [8] Hachet O, Ephrussi A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 2004;428:959–63. [9] Giorgi C, Moore MJ. The nuclear nurture and cytoplasmic nature of localized mRNPs. Semin Cell Dev Biol 2007;18:186–93. [10] Ashraf SI, Kunes S. A trace of silence: memory and microRNA at the synapse. Curr Opin Neurobiol 2006;16:535–9. [11] Ashraf SI, McLoon AL, Sclarsic SM, Kunes S. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 2006;124:191–205. [12] Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, et al. A brain-specific microRNA regulates dendritic spine development. Nature 2006;439:283–9. [13] Kiebler MA, Bassell GJ. Neuronal RNA granules: movers and makers. Neuron 2006;51:685–90.
Ralf Dahm Michael A. Kiebler ∗ Medical University of Vienna, Center for Brain Research, Division of Neuronal Cell Biology, Spitalgasse 4, A-1090 Vienna, Austria ∗ Corresponding
author. Tel.: +43 01 4277 62920; fax: +43 01 4277 62928. E-mail addresses: [email protected] (R. Dahm), [email protected] (M.A. Kiebler) Available online 12 March 2007
Editorial
RNA localization: New roles for an evolutionarily ancient mechanism
Eukaryotic cells utilize a number of mechanisms to control the expression of their genes, including regulation of gene expression at the transcriptional, post-transcriptional and translational levels. A mechanism that is receiving increasing attention is RNA localisation, which allows restricting the synthesis of cognate proteins to specific subcellular domains. The localisation of RNAs has been found to occur in a wide range of organisms, including fungi (e.g. budding yeast, Ustilago maydis), plants (e.g. cereal species, Arabidopsis), and various animal species (e.g. ascidians, echinoderms, Drosophila, zebrafish, Xenopus, and mammals). Moreover, a number of the proteins involved in this process are highly conserved between divergent species. This suggests that RNA localisation arose early during evolution and has been adapted for various contexts by different organisms. For instance in budding yeast, the localisation of specific mRNAs to the daughter cell specifies different mating types between mother and daughter cell [1]. In, for example, Drosophila and Xenopus oocytes and embryos it was found to be important for the establishment of the body axes [2]. Localised mRNAs have also been shown to act as cell fate determinants in the asymmetric division of neuroblasts in the Drosophila embryo. In mammals, the localisation of RNAs was shown to be involved in the regulation of the actin cytoskeleton in migrating cells, the formation of myelin sheaths formed by oligodendrocytes in the central nervous system, the guidance of developing axons [3] and dendrites, and possibly the establishment and modification of synapses [4]. To date, the majority of cellular processes involving RNA localisation studied occur during development or cellular differentiation. During development, the localisation of mRNAs that encode cytoplasmic determinants to certain regions of an embryo serves to pattern the embryo, for example to determine the fate of different regions of the embryo. Similarly, dividing cells use this mechanism to asymmetrically sort cell fate determinants into the daughter cells from a division, resulting in two cells with different fates. There are, however, indications that RNA localisation may also be important in a number of differentiated cell types [1,2,4]. In contrast to development and cellular differentiation, RNA localisation in differentiated cells is not aimed at giving rise to different cells. Instead, it serves to compartmentalise the cell itself into domains with specialised properties 1084-9521/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.semcdb.2007.03.001
or to facilitate the co-translational incorporation of locally synthesized proteins into target structures, such as organelles or macromolecular complexes. A series of surprising findings have been reported lately in the context of RNA localization. Until recently, RNA transport was generally assumed to occur in the form of ribonucleoprotein particles (RNPs) with the help of molecular motor proteins [5]. In yeast, Xenopus oocytes and mammalian neurons, key factors involved in RNA localization, such as She2p, Vg1 RNA-binding protein and Staufen1, have, however, recently been found to colocalize with the endoplasmic reticulum (ER) [6]. Future experiments will have to unravel how ER tubules or vesiculated ER might contribute to cytoplasmic RNA localization in these systems. Furthermore, a recent study suggested the endosomal sorting complex required for transport II (ESCRT-II) to be essential for the final step in the localization of bicoid mRNA to the anterior pole of the oocyte [7]. Even more surprisingly, ESCRT-II, which binds to bicoid mRNA directly, appears to recruit Staufen to the bicoid localization signal independently of its endosomal protein sorting function. Clearly, future studies will help in understanding this fascinating link between membranes and the ER on one side and a possible connection between the ESCRT-II complex and RNA localization on the other. A second surprise came in a recent study showing that the cytoplasmic localization of oskar mRNA depends on splicing of the mRNA in the nucleus [8]. Previously, it was shown that the 3 -UTR of oskar mRNA is sufficient for its localization to the posterior pole of the oocyte, although these experiments were done using reporters in oocytes that still expressed the endogenous oskar mRNA. The authors revisited the issue and demonstrated that an oskar mRNA produced from an oskar gene lacking introns fails to localize at the oocyte’s posterior pole, when the endogenous gene is removed. Specifically, it was shown that the first intron is required for localization to occur. It appears that the exon junctional complex (EJC) [9], consisting of Y14, Mago, eIF4AIII and Barentsz, may enable the oskar localization complex to assemble and achieve cytoplasmic localization. It will be particularly interesting to learn how these two processes are mechanistically linked. A third and fascinating issue is the recent notion that small RNAs, including microRNAs and non-coding RNAs, might play
162
Editorial / Seminars in Cell & Developmental Biology 18 (2007) 161–162
an important role in locally regulating mRNA translation at neuronal synapses [10]. The brain cytoplasmic RNA BC1 is part of dendritic RNPs and has recently been shown by the Tiedge lab to regulate translational control by interacting with eIF4A and poly(A) binding protein [4]. Furthermore, a recent study by Ashraf et al. [11] establishes both Ca2+ -calmodulindependent kinase II (CaMKII) and Staufen as regulatory targets of RISC-mediated gene silencing in Drosophila. Finally, a study by Schratt et al. [12] identified a specific microRNA, miR-134, that regulates the local synthesis of Lim kinase 1 in dendrites [4]. BDNF treatment of hippocampal neurons relieved silencing of the LimK1 mRNA and induced dendritic spine growth. These data suggest that small RNAs might travel within RNPs to synapses to keep mRNAs translationally silent during transport [13]. It will be interesting to see whether these “neuronal granules” are RISC, transport RNPs or rather P-bodies and to understand the mechanistic link between RNA transport, translational control and small RNA-mediated gene silencing and RNA degradation. References [1] Du TG, Schmid M, Jansen RP. Why cells move messages: the biological functions of mRNA localization. Semin Cell Dev Biol 2007;18:171–7. [2] Palacios IM. How does an mRNA find its way? Intracellular localisation of transcripts. Semin Cell Dev Biol 2007;18:163–70. [3] Hengst U, Jaffrey SR. Function and translational regulation of mRNA in developing axons. Semin Cell Dev Biol 2007;18:209–15. [4] Dahm R, Kiebler M, Macchi P. RNA localisation in the nervous system. Semin Cell Dev Biol 2007;18:216–23. [5] Bullock SL. Translocation of mRNAs by molecular motors: think complex? Semin Cell Dev Biol 2007;18:194–201.
[6] Schmid M, Jaedicke A, Du TG, Jansen RP. Coordination of endoplasmic reticulum and mRNA localization to the yeast bud. Curr Biol 2006;16:1538–43. [7] Irion U, St Johnston D. bicoid RNA localization requires specific binding of an endosomal sorting complex. Nature 2007;445:554–8. [8] Hachet O, Ephrussi A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 2004;428:959–63. [9] Giorgi C, Moore MJ. The nuclear nurture and cytoplasmic nature of localized mRNPs. Semin Cell Dev Biol 2007;18:186–93. [10] Ashraf SI, Kunes S. A trace of silence: memory and microRNA at the synapse. Curr Opin Neurobiol 2006;16:535–9. [11] Ashraf SI, McLoon AL, Sclarsic SM, Kunes S. Synaptic protein synthesis associated with memory is regulated by the RISC pathway in Drosophila. Cell 2006;124:191–205. [12] Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M, et al. A brain-specific microRNA regulates dendritic spine development. Nature 2006;439:283–9. [13] Kiebler MA, Bassell GJ. Neuronal RNA granules: movers and makers. Neuron 2006;51:685–90.
Ralf Dahm Michael A. Kiebler ∗ Medical University of Vienna, Center for Brain Research, Division of Neuronal Cell Biology, Spitalgasse 4, A-1090 Vienna, Austria ∗ Corresponding
author. Tel.: +43 01 4277 62920; fax: +43 01 4277 62928. E-mail addresses: [email protected] (R. Dahm), [email protected] (M.A. Kiebler) Available online 12 March 2007