Key Points
-
mRNA localization is a widespread mechanism for targeting proteins to the regions of a cell where they are required, and has an important role in localizing cytoplasmic determinants, targeting protein secretion, and synaptic plasticity.
-
mRNAs can be localized by four different mechanisms: local synthesis, local protection from degradation, diffusion and anchoring, or active transport by molecular motors. The latter seems to be the most common mechanism, although it is also the most difficult one to show.
-
The only case in which it is known how an mRNA is linked to a motor is ASH1 mRNA in yeast. ASH1 mRNA is linked through She3 and She2 to the myosin, Myo4, which then transports the mRNA along actin cables into the bud tip. β-Actin mRNA might be localized by a similar mechanism in chicken fibroblasts, whereas prospero mRNA is localized to the basal cortex of Drosophila melanogaster neuroblasts by apical exclusion through myosin II and basal anchoring by a myosin VI.
-
Dynein transports pair-rule transcripts to the apical side of the D. melanogaster syncytial blastoderm embryo, in a process that requires the BicD and EGL proteins. This pathway also mediates nurse-cell-to-oocyte transport and apical mRNA localization in neuroblasts. bicoid and gurken mRNAs are also believed to be localized by dynein in the D. melanogaster oocyte, but must discriminate between different populations of microtubules to localize to the anterior and dorsal–anterior cortex, respectively.
-
Kinesin is required for the posterior localization of oskar mRNA in the D. melanogaster oocyte, but it remains to be shown whether it actively transports the mRNA there. Several other mRNAs might also be transported by kinesin, such as MBP mRNA in mammalian oligodendrocytes, Vg1 mRNA in the Xenopus laevis oocyte and CaMKIIα mRNA in mammalian dendrites, and the latter co-localizes with several RNA-binding proteins that form a complex with the kinesin tail.
-
Cis-acting localization elements usually reside in 3′ untranslated regions, but are occasionally found elsewhere in the mRNA. They are sometimes absent from the mature message, as is the case for oskar mRNA, where splicing of the first intron is necessary for transport to the posterior of the oocyte. The simplest localization element is the 10-nucleotide A2RE in MBP mRNA, which binds hnRNPA2 to direct the localization into oligodendrocyte processes. All other localization elements seem to be more complex and can contain multiple redundant signals, or form intricate secondary or higher-order structures.
-
It is now becoming apparent that the localization of many mRNAs requires the stepwise assembly of large RNA-protein complexes, in which some proteins associate with the mRNA in the nucleus, and others in the cytoplasm. Several RNA–binding proteins have been implicated in the localization of various mRNAs, such as Staufen, ZBP1/VERA and hnRNPA/B family members.
Abstract
mRNA localization is a common mechanism for targeting proteins to regions of the cell where they are required. It has an essential role in localizing cytoplasmic determinants, controlling the direction of protein secretion and allowing the local control of protein synthesis in neurons. New methods for in vivo labelling have revealed that several mRNAs are transported by motor proteins, but how most mRNAs are coupled to these proteins remains obscure.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aakalu, G., Smith, W. B., Nguyen, N., Jiang, C. & Schuman, E. M. Dynamic visualization of local protein synthesis in hippocampal neurons. Neuron 30, 489–502 (2001).
Dubowy, J. & Macdonald, P. M. Localization of mRNAs to the oocyte is common in Drosophila ovaries. Mech. Dev. 70, 193–195 (1998).
Eberwine, J., Miyashiro, K., Kacharmina, J. E. & Job, C. Local translation of classes of mRNAs that are targeted to neuronal dendrites. Proc. Natl Acad. Sci. USA 98, 7080–7085 (2001).
Shepard, K. A. et al. Widespread cytoplasmic mRNA transport in yeast: identification of 22 bud-localized transcripts using DNA microarray analysis. Proc. Natl Acad. Sci. USA 100, 11429–11434 (2003).
Li, P., Yang, X., Wasser, M., Cai, Y. & Chia, W. Inscuteable and Staufen mediate asymmetric localization and segregation of prospero RNA during Drosophila neuroblast cell divisions. Cell 90, 437–447 (1997).
Broadus, J., Furstenberg, S. & Doe, C. Q. Staufen-dependent localization of prospero mRNA contributes to neuroblast daughter cell fate. Nature 391, 792–795 (1998).
Knoblich, J. A., Jan, L. Y. & Jan, Y. N. Deletion analysis of the Drosophila Inscuteable protein reveals domains for cortical localization and asymmetric localization. Curr. Biol. 9, 155–158 (1999).
Hughes, J. R., Bullock, S. L. & Ish-Horowicz, D. inscuteable mRNA localization is dynein-dependent and regulates apicobasal polarity and spindle length in Drosophila neuroblasts. Curr. Biol. 14, 1950–1956 (2004).
Ephrussi, A., Dickinson, L. K. & Lehmann, R. oskar organizes the germ plasm and directs localization of the posterior determinant nanos. Cell 66, 37–50 (1991).
Gavis, E. R. & Lehmann, R. Localization of nanos RNA controls embryonic polarity. Cell 71, 310–313 (1992).
Aronov, S., Aranda, G., Behar, L. & Ginzberg, I. Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. J. Neurosci. 21, 6577–6587 (2001).
Steward, O. & Schuman, E. M. Compartmentalized synthesis and degradation of proteins in neurons. Neuron 40, 347–359 (2003).
Brenner, H. R., Witzemann, V. & Sakmann, B. Imprinting of acetylcholine receptor messenger RNA accumulation in mammalian neuromuscular synapses. Nature 344, 544–547 (1990).
Simon, A. M., Hoppe, P. & Burden, S. J. Spatial restriction of AChR gene expression to subsynaptic nuclei. Development 114, 545–553 (1992).
Saunders, C. & Cohen, R. S. The role of oocyte transcription, the 5′ UTR, and translation repression and derepression in Drosophila gurken mRNA and protein localisation. Mol. Cell 3, 43–54 (1999).
Thio, G. L., Ray, R. P., Barcelo, G. & Schupbach, T. Localization of gurken RNA in Drosophila oogenesis requires elements in the 5′ and 3′ regions of the transcript. Dev. Biol. 221, 435–446 (2000).
MacDougall, N., Clark, A., MacDougall, E. & Davis, I. Drosophila gurken (TGFα) mRNA localizes as particles that move within the oocyte in two dynein-dependent steps. Dev. Cell 4, 307–319 (2003). Shows that gurken mRNA is transported to the dorsal–anterior of the oocyte by dynein. This occurs in two distinct steps, which indicates that the mRNA moves along two different microtubule populations.
Ding, D., Parkhurst, S. M., Halsell, S. R. & Lipshitz, H. D. Dynamic hsp83 RNA localization during Drosophila oogenesis and embryogenesis. Mol. Cell. Biol. 13, 3773–3781 (1993).
Bashirullah, A. et al. Joint action of two RNA degradation pathways controls the timing of maternal transcript elimination at the midblastula transition in Drosophila melanogaster. EMBO J. 18, 2610–2620 (1999).
Bergsten, S. E. & Gavis, E. R. Role for mRNA localization in translational activation but not spatial restriction of nanos RNA. Development 126, 659–669 (1999).
Yoon, C., Kawakami, K. & Hopkins, N. Zebrafish vasa homologue RNA is localized to the cleavage planes of 2- and 4-cell-stage embryos and is expressed in the primordial germ cells. Development 124, 3157–3165 (1997).
Köprunner, M., Thisse, C., Thisse, B. & Raz, E. A zebrafish nanos-related gene is essential for the development of primordial germ cells. Genes Dev. 15, 2877–2885 (2001).
Wolke, U., Weidinger, G., Koprunner, M. & Raz, E. Multiple levels of posttranscriptional control lead to germ line-specific gene expression in the zebrafish. Curr. Biol. 12, 289–294 (2002).
Wang, C., Dickinson, L. K. & Lehmann, R. Genetics of nanos localisation in Drosophila. Dev. Dyn. 199, 103–115 (1994).
Jongens, T. A., Hay, B., Jan, L. Y. & Jan, Y. N. The germ cell-less gene product: a posteriorly localized component necessary for germ cell development in Drosophila. Cell 70, 569–584 (1992).
Nakamura, A., Amikura, R., Mukai, M., Kobayashi, S. & Lasko, P. F. Requirement for a noncoding RNA in Drosophila polar granules for germ cell establishment. Science 274, 2075–2079 (1996).
Raff, J. W., Whittlefield, W. G. F. & Glover, D. M. Two distinct mechanisms localise cyclin B transcripts in syncytial Drosophila embryos. Development 110, 1249–1261 (1990).
Ephrussi, A. & Lehmann, R. Induction of germ cell formation by oskar. Nature 358, 387–392 (1992).
Forrest, K. M. & Gavis, E. R. Live imaging of endogenous RNA reveals a diffusion and entrapment mechanism for nanos mRNA localization in Drosophila. Curr. Biol. 13, 1159–1168 (2003).
Jansen, R. P., Dowzer, C., Michaelis, C., Galova, M. & Nasmyth, K. Mother cell-specific HO expression in budding yeast depends on the unconventional myosin myo4p and other cytoplasmic proteins. Cell 84, 687–697 (1996).
Long, R. M. et al. Mating type switching in yeast controlled by asymmetric localization of ASH1 mRNA. Science 277, 383–387 (1997).
Takizawa, P. A., Sil, A., Swedlow, J. R., Herskowitz, I. & Vale, R. D. Actin-dependent localization of an RNA encoding a cell-fate determinant in yeast. Nature 389, 90–93 (1997).
Munchow, S., Sauter, C. & Jansen, R. P. Association of the class V myosin Myo4p with a localised messenger RNA in budding yeast depends on She proteins. J. Cell Sci. 112, 1511–1518 (1999).
Takizawa, P. A. & Vale, R. D. The myosin motor, Myo4p, binds Ash1 mRNA via the adapter protein, She3p. Proc. Natl Acad. Sci. USA 97, 5273–5278 (2000).
Bertrand, E. et al. Localization of ASH1 mRNA particles in living yeast. Mol. Cell 2, 437–445 (1998).
Beach, D. L., Salmon, E. D. & Bloom, K. Localization and anchoring of mRNA in budding yeast. Curr. Biol. 9, 569–578 (1999). Reference 35 and 36 report the first use of MS2–GFP tagging to visualize mRNA movement in vivo.
Chartrand, P., Meng, X. H., Singer, R. H. & Long, R. M. Structural elements required for the localization of ASH1 mRNA and of a green fluorescent protein reporter particle in vivo. Curr. Biol. 9, 333–336 (1999).
Gonzalez, I., Buonomo, S. B., Nasmyth, K. & von Ahsen, U. ASH1 mRNA localization in yeast involves multiple secondary structural elements and Ash1 protein translation. Curr. Biol. 9, 337–340 (1999).
Bohl, F., Kruse, C., Frank, A., Ferring, D. & Jansen, R. P. She2p, a novel RNA-binding protein tethers ASH1 mRNA to the Myo4p myosin motor via She3p. EMBO J. 19, 5514–5524 (2000). Describes how ASH1 mRNA is coupled to the myosin that transports it to the bud tip, providing the only proven example of a localized mRNA that is directly associated with a motor protein.
Long, R. M., Gu, W., Lorimer, E., Singer, R. H. & Chartrand, P. She2p is a novel RNA-binding protein that recruits the Myo4p–She3p complex to ASH1 mRNA. EMBO J. 19, 6592–6601 (2000).
Niessing, D., Huttelmaier, S., Zenklusen, D., Singer, R. H. & Burley, S. K. She2p is a novel RNA binding protein with a basic helical hairpin motif. Cell 119, 491–502 (2004). Reports the crystal structure of She2, and describes how it dimerizes to bind the ASH1 localization elements.
Gonsalvez, G. B. et al. RNA–protein interactions promote asymmetric sorting of the ASH1 mRNA ribonucleoprotein complex. RNA 9, 1383–1399 (2003).
Kruse, C. et al. Ribonucleoprotein-dependent localization of the yeast class V myosin Myo4p. J. Cell Biol. 159, 971–982 (2002).
Irie, K. et al. The Khd1 protein, which has three KH RNA-binding motifs, is required for proper localization of ASH1 mRNA in yeast. EMBO J. 21, 1158–1167 (2002).
Sundell, C. L. & Singer, R. H. Requirement of microfilaments in sorting of actin messenger RNA. Science 253, 1275–1277 (1991).
Latham, V. M., Yu, E. H., Tullio, A. N., Adelstein, R. S. & Singer, R. H. A Rho-dependent signaling pathway operating through myosin localizes β-actin mRNA in fibroblasts. Curr. Biol. 11, 1010–1016 (2001).
Latham, V. M. Jr, Kislauskis, E. H., Singer, R. H. & Ross, A. F. β-Actin mRNA localization is regulated by signal transduction mechanisms. J. Cell Biol. 126, 1211–1219 (1994).
Ross, A. F., Oleynikov, Y., Kislauskis, E. H., Taneja, K. L. & Singer, R. H. Characterization of a β-actin mRNA zipcode-binding protein. Mol. Cell. Biol. 17, 2158–2165 (1997).
Kislauskis, E. H., Zhu, X. & Singer, R. H. Sequences responsible for intracellular localization of β-actin messenger RNA also affect cell phenotype. J. Cell Biol. 127, 441–451 (1994).
Farina, K. L., Huttelmaier, S., Musunuru, K., Darnell, R. & Singer, R. H. Two ZBP1 KH domains facilitate β-actin mRNA localization, granule formation, and cytoskeletal attachment. J. Cell Biol. 160, 77–87 (2003).
Oleynikov, Y. & Singer, R. H. Real-time visualization of ZBP1 association with β-actin mRNA during transcription and localization. Curr. Biol. 13, 199–207 (2003).
Tyagi, S. & Alsmadi, O. Imaging native β-actin mRNA in motile fibroblasts. Biophys. J. 84, 4153–4162 (2004).
Hamada, S. et al. The transport of prolamine RNAs to prolamine protein bodies in living rice endosperm cells. Plant Cell 15, 2253–2264 (2003).
Schuldt, A. J. et al. Miranda mediates asymmetric protein and RNA localization in the developing nervous system. Genes Dev. 12, 1847–1857 (1998).
Shen, C. P. et al. Miranda as a multidomain adapter linking apically localized Inscuteable and basally localized Staufen and Prospero during asymmetric cell division in Drosophila. Genes Dev. 12, 1837–1846 (1998).
Matsuzaki, F., Ohshiro, T., Ikeshima-Kataoka, H. & Izumi, H. miranda localizes staufen and prospero asymmetrically in mitotic neuroblasts and epithelial cells in early Drosophila embryogenesis. Development 125, 4089–4098 (1998).
Petritsch, C., Tavosanis, G., Turck, C. W., Jan, L. Y. & Jan, Y. N. The Drosophila myosin VI Jaguar is required for basal protein targeting and correct spindle orientation in mitotic neuroblasts. Dev. Cell 4, 273–281 (2003).
Betschinger, J., Mechtler, K. & Knoblich, J. A. The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl. Nature 422, 326–330 (2003).
Barros, C. S., Phelps, C. B. & Brand, A. H. Drosophila nonmuscle myosin II promotes the asymmetric segregation of cell fate determinants by cortical exclusion rather than active transport. Dev. Cell 5, 829–840 (2003). Reports a novel role for Zipper in mRNA localization, in which it excludes prospero mRNA from the apical side of the neuroblast to restrict the mRNA to the basal cortex.
Davis, I. & Ish-Horowicz, D. Apical localization of pair-rule transcripts requires 3′ sequences and limits protein diffusion in the Drosophila blastoderm embryo. Cell 67, 927–940 (1991).
Lall, S. et al. Squid hnRNP protein promotes apical cytoplasmic transport and localization of Drosophila pair-rule transcripts. Cell 98, 171–180 (1999).
Wilkie, G. S. & Davis, I. Drosophila wingless and pair-rule transcripts localise apically by dynein-mediated transport of RNA particles. Cell 105, 209–219 (2001). The first demonstration of active transport of mRNA along microtubules by dynein.
Bullock, S. L., Zicha, D. & Ish-Horowicz, D. The Drosophila hairy RNA localization signal modulates the kinetics of cytoplasmic mRNA transport. EMBO J. 22, 2484–2494 (2003).
Bashirullah, A., Cooperstock, R. L. & Lipshitz, H. D. RNA localization in development. Annu. Rev. Biochem. 67, 335–394 (1998).
Bullock, S. L. & Ish-Horowicz, D. Conserved signals and machinery for RNA transport in Drosophila oogenesis and embryogenesis. Nature 414, 611–616 (2001). Shows that the same dynein–BicD–EGL pathway mediates apical mRNA localization in the D. melanogaster blastoderm embryo and nurse cell to oocyte transport in the ovary.
Mach, J. M. & Lehmann, R. An Egalitarian–BicaudalD complex is essential for oocyte specification and axis determination in Drosophila. Genes Dev. 11, 423–435 (1997).
Navarro, C., Puthalakath, H., Adams, J. M., Strasser, A. & Lehmann, R. Egalitarian binds dynein light chain to establish oocyte polarity and maintain oocyte fate. Nature Cell Biol. 6, 427–435 (2004).
Hoogenraad, C. C. et al. Mammalian Golgi-associated Bicaudal-D2 functions in the dynein–dynactin pathway by interacting with these complexes. EMBO J. 20, 4041–4054 (2001).
Matanis, T. et al. Bicaudal-D regulates COPI-independent Golgi-ER transport by recruiting the dynein–dynactin motor complex. Nature Cell Biol. 4, 986–992 (2002).
Hoogenraad, C. C. et al. Bicaudal D induces selective dynein-mediated microtubule minus end-directed transport. EMBO J. 22, 6004–6015 (2003).
Clark, I., Giniger, E., Ruohola-Baker, H., Jan, L. & Jan, Y. Transient posterior localisation of a kinesin fusion protein reflects anteroposterior polarity of the Drosophila oocyte. Curr. Biol. 4, 289–300 (1994).
Cha, B. J., Serbus, L. R., Koppetsch, B. S. & Theurkauf, W. E. Kinesin I-dependent cortical exclusion restricts pole plasm to the oocyte posterior. Nature Cell Biol. 4, 592–498 (2002).
Januschke, J. et al. Polar transport in the Drosophila oocyte requires Dynein and Kinesin I cooperation. Curr. Biol. 12, 1971–1981 (2002).
Duncan, J. E. & Warrior, R. The cytoplasmic dynein and kinesin motors have interdependent roles in patterning the Drosophila oocyte. Curr. Biol. 12, 1982–1991 (2002).
Neuman-Silberberg, F. & Schüpbach, T. The Drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGFα-like protein. Cell 75, 165–174 (1993).
St Johnston, D., Driever, W., Berleth, T., Richstein, S. & Nüsslein-Volhard, C. Multiple steps in the localization of bicoid RNA to the anterior pole of the Drosophila oocyte. Development (Suppl.) 107, 13–19 (1989).
Pokrywka, N. J. & Stephenson, E. C. Microtubules mediate the localization of bicoid RNA during Drosophila oogenesis. Development 113, 55–66 (1991).
Cha, B., Koppetsch, B. S. & Theurkauf, W. E. In vivo analysis of Drosophila bicoid mRNA localization reveals a novel microtubule-dependent axis specification pathway. Cell 106, 35–46 (2001). Presents evidence that bicoid mRNA is selectively transported along a specific anterior population of oocyte microtubules.
Wang, S. & Hazelrigg, T. Implications for bcd mRNA localization from spatial distribution of exu protein in Drosophila oogenesis. Nature 369, 400–403 (1994).
Wilhelm, J. E. et al. Isolation of a ribonucleoprotein complex involved in mRNA localization in Drosophila oocytes. J. Cell Biol. 148, 427–440 (2000).
Nakamura, A., Amikura, R., Hanyu, K. & Kobayashi, S. Me31B silences translation of oocyte-localizing RNAs through the formation of cytoplasmic RNP complex during Drosophila oogenesis. Development 128, 3233–3242 (2001).
Berleth, T. et al. The role of localization of bicoid RNA in organizing the anterior pattern of the Drosophila embryo. EMBO J. 7, 1749–1756 (1988).
Schnorrer, F., Bohmann, K. & Nüsslein-Volhard, C. The molecular motor dynein is involved in targeting Swallow and bicoid RNA to the anterior pole of Drosophila oocytes. Nature Cell Biol. 2, 185–190 (2000).
Meng, J. & Stephenson, E. C. Oocyte and embryonic cytoskeletal defects caused by mutations in the Drosophila swallow gene. Dev. Genes Evol. 212, 239–247 (2002).
Schnorrer, F., Luschnig, S., Koch, I. & Nüsslein-Volhard, C. γ-Tubulin37C and γ-tubulin ring complex protein 75 are essential for bicoid RNA localization during Drosophila oogenesis. Dev. Cell 3, 685–696 (2002).
Ferrandon, D., Elphick, L., Nüsslein-Volhard, C. & St Johnston, D. Staufen protein associates with the 3′ UTR of bicoid mRNA to form particles which move in a microtubule-dependent manner. Cell 79, 1221–1232 (1994).
Martin, S. G., Leclerc, V., Smith-Litiere, K. & St Johnston, D. The identification of novel genes required for Drosophila anteroposterior axis formation in a germline clone screen using GFP–Staufen. Development 130, 4201–4215 (2003).
Ramos, A. et al. RNA recognition by a Staufen double-stranded RNA-binding domain. EMBO J. 19, 997–1009 (2000).
Brendza, R. P., Serbus, L. R., Duffy, J. B. & Saxton, W. M. A function for kinesin I in the posterior transport of oskar mRNA and Staufen protein. Science 289, 2120–2122 (2000). Provides the first clear proof of the role of kinesin in mRNA localization.
Clark, I., Jan, L. Y. & Jan, Y. N. Reciprocal localization of Nod and kinesin fusion proteins indicates microtubule polarity in the Drosophila oocyte, epithelium, neuron and muscle. Development 124, 461–470 (1997).
Glotzer, J. B., Saffrich, R., Glotzer, M. & Ephrussi, A. Cytoplasmic flows localize injected oskar RNA in Drosophila oocytes. Curr. Biol. 7, 326–337 (1997).
Palacios, I. M. & St Johnston, D. Kinesin light chain-independent function of the Kinesin heavy chain in cytoplasmic streaming, and posterior localization in the Drosophila oocyte. Development 129, 5473–5485 (2002).
Kim-Ha, J., Smith, J. L. & Macdonald, P. M. oskar mRNA is localized to the posterior pole of the Drosophila oocyte. Cell 66, 23–35 (1991).
Gunkel, N., Yano, T., Markussen, F. -H., Olsen, L. C. & Ephrussi, A. Localization-dependent translation requires a functional interaction between the 5′ and 3′ ends of oskar mRNA. Genes Dev. 12, 1652–1664 (1998).
Kim-Ha, J., Kerr, K. & Macdonald, P. M. Translational regulation of oskar messenger RNA by Bruno, an ovarian RNA binding protein, is essential. Cell 81, 403–412 (1995).
Hachet, O. & Ephrussi, A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428, 959–963 (2004). Shows that the splicing of the first intron of oskar mRNA is absolutely required for its subsequent transport to the posterior of the oocyte.
Li, M.-G., McGrail, M., Serr, M. & Hays, T. H. Drosophila cytoplasmic dynein, a microtubule motor that is asymmetrically localized in the oocyte. J. Cell Biol. 126, 1475–1494 (1994).
McGrail, M., Ludmann, S. & Hays, T. S. Analysis of cytoplasmic dynein function in Drosophila oogenesis. Mol. Biol. Cell 6, 886–886 (1995).
Polesello, C., Delon, I., Valenti, P., Ferrer, P. & Payre, F. Dmoesin controls actin-based cell shape and polarity during Drosophila melanogaster oogenesis. Nature Cell Biol. 4, 782–789 (2002).
Rongo, C., Gavis, E. R. & Lehmann, R. Localization of oskar RNA regulates Oskar translation and requires Oskar protein. Development 121, 2737–2746 (1995).
Babu, K., Cai, Y., Bahri, S., Yang, X. & Chia, W. Roles of Bifocal, Homer, and F-actin in anchoring Oskar to the posterior cortex of Drosophila oocytes. Genes Dev. 18, 138–143 (2004).
Ainger, K. et al. Transport and localization of exogenous myelin basic protein mRNA microinjected into oligodendrocytes. J. Cell Biol. 123, 431–441 (1993). The first use of fluorescent RNA injection to visualize mRNA movement in living cells.
Carson, J. H., Worboys, K., Ainger, K. & Barbarese, E. Translocation of myelin basic protein mRNA in oligodendrocytes requires microtubules and kinesin. Cell Motil. Cytoskeleton 38, 318–328 (1997).
Rook, M. S., Lu, M. & Kosik, K. S. CaMKIIα 3′ untranslated region-directed mRNA translocation in living neurons: visualization by GFP linkage. J. Neurosci. 20, 6385–6393 (2000).
Huang, Y. S., Carson, J. H., Barbarese, E. & Richter, J. D. Facilitation of dendritic mRNA transport by CPEB. Genes Dev. 17, 638–653 (2003).
Kanai, Y., Dohmae, N. & Hirokawa, N. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43, 513–525 (2004). Reports that the tail region of kinesin can be used to purify a high-molecular-weight complex that contains many RNA-binding proteins and several dendritically localized mRNAs.
Mallardo, M. et al. Isolation and characterization of Staufen-containing ribonucleoprotein particles from rat brain. Proc. Natl Acad. Sci. USA 100, 2100–2105 (2003).
Köhrmann, M. et al. Microtubule-dependent recruitment of Staufen–green fluorescent protein into large RNA-containing granules and subsequent dendritic transport in living hippocampal neurons. Mol. Cell. Biol. 10, 2945–2953 (1999).
Tiruchinapalli, D. M. et al. Activity-dependent trafficking and dynamic localization of zipcode binding protein 1 and β-actin mRNA in dendrites and spines of hippocampal neurons. J. Neurosci. 23, 3251–6321 (2003).
Fusco, D. et al. Single mRNA molecules demonstrate probabilistic movement in living mammalian cells. Curr. Biol. 13, 161–167 (2003). The first analysis of the movement of single mRNA molecules in living cells.
Yoon, Y. J. & Mowry, K. L. Xenopus Staufen is a component of a ribonucleoprotein complex containing Vg1 RNA and kinesin. Development 131, 3035–3045 (2004).
Betley, J. N. et al. Kinesin II mediates Vg1 mRNA transport in Xenopus oocytes. Curr. Biol. 14, 219–224 (2004).
Pfeiffer, D. C. & Gard, D. L. Microtubules in Xenopus oocytes are oriented with their minus-ends towards the cortex. Cell Motil. Cytoskeleton 44, 34–43 (1999).
Chartrand, P., Meng, X. H., Huttelmaier, S., Donato, D. & Singer, R. H. Asymmetric sorting of ASH1p in yeast results from inhibition of translation by localization elements in the mRNA. Mol. Cell 10, 1319–1330 (2002).
Capri, M., Santoni, M. J., Thomas-Delaage, M. & Ait-Ahmed, O. Implication of a 5′ coding sequence in targeting maternal mRNA to the Drosophila oocyte. Mech. Dev. 68, 91–100 (1997).
Serano, J. & Rubin, G. M. The Drosophila synaptotagmin-like protein bitesize is required for growth and has mRNA localization sequences within its open reading frame. Proc. Natl Acad. Sci. USA 100, 13368–13373 (2003).
Prakash, N., Fehr, S., Mohr, E. & Richter, D. Dendritic localization of rat vasopressin mRNA: ultrastructural analysis and mapping of targeting elements. Eur. J. Neurosci. 9, 523–532 (1997).
Claussen, M., Horvay, K. & Pieler, T. Evidence for overlapping, but not identical, protein machineries operating in vegetal RNA localization along early and late pathways in Xenopus oocytes. Development 131, 4263–4273 (2004).
Hoek, K. S., Kidd, G. J., Carson, J. H. & Smith, R. hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Biochemistry 37, 7021–7029 (1998).
Munro, T. P. et al. Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking. J. Biol. Chem. 274, 34389–34395 (1999).
Ainger, K. et al. Transport and localization elements in myelin basic protein mRNA. J. Cell Biol. 138, 1077–1087 (1997).
Kim-Ha, J., Webster, P., Smith, J. & Macdonald, P. Multiple RNA regulatory elements mediate distinct steps in localization of oskar mRNA. Development 119, 169–178 (1993).
Kloc, M., Bilinski, S., Pui-Yee Chan, A. & Etkin, L. D. The targeting of Xcat2 mRNA to the germinal granules depends on a cis-acting germinal granule localization element within the 3′ UTR. Dev. Biol. 217, 221–229 (2000).
Serano, T. & Cohen, R. S. A small predicted stem loop structure mediates oocyte localization of Drosophila K10 messenger RNA. Development 121, 3809–3818 (1995).
Long, R. M. et al. An exclusively nuclear RNA-binding protein affects asymmetric localization of ASH1 mRNA and Ash1p in yeast. J. Cell Biol. 153, 307–318 (2001).
Bergsten, S. E., Huang, T., Chatterjee, S. & Gavis, E. R. Recognition and long-range interactions of a minimal nanos RNA localization signal element. Development 128, 427–435 (2001).
Crucs, S., Chatterjee, S. & Gavis, E. R. Overlapping but distinct RNA elements control repression and activation of nanos translation. Mol. Cell 5, 457–467 (2000).
Gavis, E. R., Lunsford, L., Bergsten, S. E. & Lehmann, R. A conserved 90 nucleotide element mediates translational repression of nanos RNA. Development 122, 2791–2800 (1996).
Chan, A. P., Kloc, M. & Etkin, L. D. fatvg encodes a new localized RNA that uses a 25-nucleotide element (FVLE1) to localize to the vegetal cortex of Xenopus oocytes. Development 126, 4943–4953 (1999).
Bubunenko, M., Kress, T. L., Vempati, U. D., Mowry, K. L. & King, M. L. A consensus RNA signal that directs germ layer determinants to the vegetal cortex of Xenopus oocytes. Dev. Biol. 248, 82–92 (2002).
Cote, C. A. et al. A Xenopus protein related to hnRNP I has a role in cytoplasmic RNA localization. Mol. Cell 4, 431–437 (1999).
Deshler, J. O., Highett, M. I., Abramson, T. & Schnapp, B. J. A highly conserved RNA-binding protein for cytoplasmic mRNA localization in vertebrates. Curr. Biol. 8, 489–496 (1998).
Deshler, J. O., Highett, M. I. & Schnapp, B. J. Localization of Xenopus Vg1 mRNA by Vera protein and the endoplasmic reticulum. Science 276, 1128–1131 (1997).
Gautreau, D., Cote, C. A. & Mowry, K. L. Two copies of a subelement from the Vg1 RNA localization sequence are sufficient to direct vegetal localization in Xenopus oocytes. Development 124, 5013–5020 (1997).
Havin, L. et al. RNA-binding protein conserved in both microtubule- and microfilament- based RNA localization. Genes Dev. 12, 1593–1598 (1998).
Kwon, S. et al. UUCAC- and Vera-dependent localization of VegT RNA in Xenopus oocytes. Curr. Biol. 12, 558–564 (2002).
Lewis, R. A. et al. Conserved and clustered RNA recognition sequences are a critical feature of signals directing RNA localization in Xenopus oocytes. Mech. Dev. 121, 101–109 (2004).
Betley, J. N., Frith, M. C., Graber, J. H., Choo, S. & Deshler, J. O. A ubiquitous and conserved signal for RNA localization in chordates. Curr. Biol. 12, 1756–1761 (2002).
Zhao, W. M., Jiang, C., Kroll, T. T. & Huber, P. W. A proline-rich protein binds to the localization element of Xenopus Vg1 mRNA and to ligands involved in actin polymerization. EMBO J. 20, 2315–2325 (2001).
Kroll, T. T., Zhao, W. M., Jiang, C. & Huber, P. W. A homolog of FBP2/KSRP binds to localized mRNAs in Xenopus oocytes. Development 129, 5609–5619 (2002).
Czaplinski, K. et al. Identification of 40LoVE, a Xenopus hnRNP D family protein involved in localizing a TGF-β related mRNA during oogenesis. Dev. Cell (in press).
Micklem, D. R., Adams, J., Grünert, S. & St Johnston, D. Distinct roles of two conserved Staufen domains in oskar mRNA localisation and translation. EMBO J. 19, 1366–1377 (2000).
Brunel, C. & Ehresmann, C. Secondary structure of the 3′ UTR of bicoid mRNA. Biochimie 86, 91–104 (2004).
Macdonald, P. M. & Struhl, G. Cis-acting sequences responsible for anterior localization of bicoid mRNA in Drosophila embryos. Nature 336, 595–598 (1988).
Macdonald, P. M. bicoid mRNA localization signal: phylogenetic conservation of function and RNA secondary structure. Development 110, 161–171 (1990).
Macdonald, P. M., Kerr, K., Smith, J. L. & Leask, A. RNA regulatory element BLE1 directs the early steps of bicoid mRNA localization. Development 118, 1233–1243 (1993).
Macdonald, P. M. & Kerr, K. Mutational analysis of an RNA recognition element that mediates localization of bicoid mRNA. Mol. Cell. Biol. 18, 3788–3795 (1998).
Macdonald, P. M. & Kerr, K. Redundant RNA recognition events in bicoid mRNA localization. RNA 3, 1413–1420 (1997).
Arn, E. A., Cha, B. J., Theurkauf, W. E. & Macdonald, P. M. Recognition of a bicoid mRNA localization signal by a protein complex containing Swallow, Nod, and RNA binding proteins. Dev. Cell 4, 41–51 (2003). Describes the identification of a protein complex that binds to the bicoid localization signal. None of the RNA-binding proteins in the complex interact specifically with bicoid mRNA on their own, which indicates that the complex is formed by low-affinity interactions.
Ferrandon, D., Koch, I., Westhof, E. & Nüsslein-Volhard, C. RNA–RNA interaction is required for the formation of specific bicoid mRNA 3′ UTR–STAUFEN ribonucleoprotein complexes. EMBO J. 16, 1751–1758 (1997).
Wagner, C. et al. Dimerization of the 3′ UTR of bicoid mRNA involves a two-step mechanism. J. Mol. Biol. 313, 511–524 (2001).
Wagner, C., Ehresmann, C., Ehresmann, B. & Brunel, C. Mechanism of dimerization of bicoid mRNA: initiation and stabilization. J. Biol. Chem. 279, 4560–4569 (2004).
Tange, T. O., Nott, A. & Moore, M. J. The ever-increasing complexities of the exon junction complex. Curr. Opin. Cell Biol. 16, 279–284 (2004).
Mohr, S. E., Dillon, S. T. & Boswell, R. E. The RNA-binding protein Tsunagi interacts with Mago Nashi to establish polarity and localize oskar mRNA during Drosophila oogenesis. Genes Dev. 15, 2886–2899 (2001).
Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674 (2001).
Newmark, P. A. & Boswell, R. E. The mago nashi locus encodes an essential product required for germ plasm assembly in Drosophila. Development 120, 1303–1313 (1994).
Palacios, I. M., Gatfield, D., St Johnston, D. & Izaurralde, E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757 (2004).
van Eeden, F. J. M., Palacios, I. M., Petronczki, M., Weston, M. J. D. & St Johnston, D. Barentsz is essential for the posterior localization of oskar mRNA and colocalizes with it to the posterior. J. Cell Biol. 154, 511–524 (2001).
St Johnston, D., Beuchle, D. & Nüsslein-Volhard, C. Staufen, a gene required to localize maternal RNAs in the Drosophila egg. Cell 66, 51–63 (1991).
St Johnston, D., Brown, N. H., Gall, J. G. & Jantsch, M. A conserved double-stranded RNA-binding domain. Proc. Natl Acad. Sci. USA 89, 10979–10983 (1992).
Huynh, J. R., Munro, T. P., Smith-Litiere, K., Lepesant, J. A. & St Johnston, D. The Drosophila hnRNPA/B homolog, Hrp48, is specifically required for a distinct step in osk mRNA localization. Dev. Cell 6, 625–635 (2004).
Yano, T., de Quinto, S. L., Matsui, Y., Shevchenko, A. & Ephrussi, A. Hrp48, a Drosophila hnRNPA/B homolog, binds and regulates translation of oskar mRNA. Dev. Cell 6, 637–648 (2004).
Matunis, E. L., Matunis, M. J. & Dreyfuss, G. Association of individual hnRNP proteins and snRNPs with nascent transcripts. J. Cell Biol. 121, 219–228 (1993).
Burnette, J. M., Hatton, A. R. & Lopez, A. J. Trans-acting factors required for inclusion of regulated exons in the Ultrabithorax mRNAs of Drosophila melanogaster. Genetics 151, 1517–1529 (1999).
Hammond, L. E., Rudner, D. Z., Kanaar, R. & Rio, D. C. Mutations in the hrp48 gene, which encodes a Drosophila heterogeneous nuclear ribonucleoprotein particle protein, cause lethality and developmental defects and affect P-element third-intron splicing in vivo. Mol. Cell. Biol. 17, 7260–7267 (1997).
Goodrich, J. S., Clouse, K. N. & Schupbach, T. Hrb27C, Sqd and Otu cooperatively regulate gurken RNA localization and mediate nurse cell chromosome dispersion in Drosophila oogenesis. Development 131, 1949–1958 (2004).
Mouland, A. J. et al. RNA trafficking signals in human immunodeficiency virus type 1. Mol. Cell. Biol. 21, 2133–2143 (2001).
Knowles, R. B. et al. Translocation of RNA granules in living neurons. J. Neurosci. 16, 7812–7820 (1996).
Krichevsky, A. M. & Kosik, K. S. Neuronal RNA granules. A link between RNA localization and stimulation-dependent translation. Neuron 32, 683–696 (2001).
Gu, W., Deng, Y., Zenklusen, D. & Singer, R. H. A new yeast PUF family protein, Puf6p, represses ASH1 mRNA translation and is required for its localization. Genes Dev. 18, 1452–1465 (2004).
Wilhelm, J. E., Hilton, M., Amos, Q. & Henzel, W. J. Cup is an eIF4E binding protein required for both the translational repression of oskar and the recruitment of Barentsz. J. Cell Biol. 163, 1197–1204 (2003).
Nakamura, A., Sato, K. & Hanyu-Nakamura, K. Drosophila cup is an eIF4E binding protein that associates with Bruno and regulates oskar mRNA translation in oogenesis. Dev. Cell 6, 69–78 (2004).
Gillespie, D. E. & Berg, C. E. homeless is required for RNA localization in Drosophila oogenesis and encodes a new member of the DE-H family of RNA-dependent ATPases. Genes Dev. 9, 2495–2508 (1995).
Cook, H. A., Koppetsch, B. S., Wu, J. & Theurkauf, W. E. The Drosophila SDE3 homolog armitage is required for oskar mRNA silencing and embryonic axis specification. Cell 116, 817–829 (2004).
Tomari, Y. et al. RISC assembly defects in the Drosophila RNAi mutant armitage. Cell 116, 831–841 (2004).
Webster, P. J., Liang, L., Berg, C. A., Lasko, P. & Macdonald, P. M. Translational repressor bruno plays multiple roles in development and is widely conserved. Genes Dev. 11, 2510–2521 (1997).
Vanzo, N. F. & Ephrussi, A. Oskar anchoring restricts pole plasm formation to the posterior of the Drosophila oocyte. Development 129, 3705–3714 (2002).
Salles, F. J., Lieberfarb, M. E., Wreden, C., Gergen, J. P. & Strickland, S. Coordinate initiation of Drosophila development by regulated polyadenylation of maternal messenger RNAs. Science 266, 1996–1999 (1994).
Otero, L. J., Devaux, A. & Standart, N. A 250-nucleotide UA-rich element in the 3′ untranslated region of Xenopus laevis Vg1 mRNA represses translation both in vivo and in vitro. RNA 7, 1753–1767 (2001).
Kolev, N. G. & Huber, P. W. VgRBP71 stimulates cleavage at a polyadenylation signal in Vg1 mRNA, resulting in the removal of a cis-acting element that represses translation. Mol. Cell 11, 745–755 (2003).
Forrest, K. M., Clark, I. E., Jain, R. A. & Gavis, E. R. Temporal complexity within a translational control element in the nanos mRNA. Development 131, 5849–5857 (2004).
Smibert, C. A., Lie, Y. S., Shillinglaw, W., Henzel, W. J. & Macdonald, P. M. Smaug, a novel and conserved protein, contributes to repression of nanos mRNA translation in vitro. RNA 5, 1535–1547 (1999).
Smibert, C. A., Wilson, J. E., Kerr, K. & Macdonald, P. M. Smaug protein represses translation of unlocalized nanos mRNA in the Drosophila embryo. Genes Dev. 10, 2600–2609 (1996).
Dahanukar, A., Walker, J. A. & Wharton, R. P. Smaug, a novel RNA-binding protein that operates a translational switch in Drosophila. Mol. Cell 4, 209–218 (1999).
Nelson, M. R., Leidal, A. M. & Smibert, C. A. Drosophila Cup is an eIF4E-binding protein that functions in Smaug-mediated translational repression. EMBO J. 23, 150–159 (2004).
Bratu, D. P., Cha, B. J., Mhlanga, M. M., Kramer, F. R. & Tyagi, S. Visualizing the distribution and transport of mRNAs in living cells. Proc. Natl Acad. Sci. USA 100, 13308–13313 (2003).
Zhang, H. L. et al. Neurotrophin-induced transport of a β-actin mRNP complex increases β-actin levels and stimulates growth cone motility. Neuron 31, 261–275 (2001).
Atlas, R., Behar, L., Elliott, E. & Ginzburg, I. The insulin-like growth factor mRNA binding-protein IMP-1 and the Ras-regulatory protein G3BP associate with tau mRNA and HuD protein in differentiated P19 neuronal cells. J. Neurochem. 89, 613–626 (2004).
Norvell, A., Kelley, R. L., Wehr, K. & Schüpbach, T. Specific isoforms of squid, a Drosophila hnRNP, perform distinct roles in Gurken localization during oogenesis. Genes Dev. 13, 864–876 (1999).
Kress, T. L., Yoon, Y. J. & Mowry, K. L. Nuclear RNP complex assembly initiates cytoplasmic RNA localization. J. Cell Biol. 165, 203–211 (2004).
Gu, W., Pan, F., Zhang, H., Bassell, G. J. & Singer, R. H. A predominantly nuclear protein affecting cytoplasmic localization of β-actin mRNA in fibroblasts and neurons. J. Cell Biol. 156, 41–51 (2002).
Lambert, J. D. & Nagy, L. M. Asymmetric inheritance of centrosomally localized mRNAs during embryonic cleavages. Nature 420, 682–686 (2002).
Acknowledgements
D.St J. is supported by a Principal Research Fellowship from the Wellcome Trust.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Supplementary information
Glossary
- SYNCYTIAL
-
Describes cells that contain multiple nuclei in a common cytoplasm.
- NURSE CELL
-
An auxiliary cell that supplies the Drosophila melanogaster oocyte with synthesized mRNAs and proteins during insect oogenesis through large cytoplasmic bridges, known as ring canals.
- MATING TYPE SWITCHING
-
The process by which the active mating type locus of a haploid yeast cell is replaced by one of the opposite mating type from a silent cassette elsewhere in the genome. Only mother cells switch mating type, because the transcription of the HO endonuclease, which initiates mating type switching, is repressed in daughter cells by ASH1.
- ACTIN STRESS FIBRE
-
Long, stable F-actin bundle that forms from focal adhesions in cells that are under mechanical tension.
- MOLECULAR BEACON
-
An oligonucleotide complementary to an mRNA of interest, with a fluorophore at one end and a quencher at the other. The ends of the beacon base pair in the free probe to bring the quencher next to the fluorophore, thereby preventing fluorescence, but this structure unwinds on hybridizing to the target mRNA and the fluorophore becomes active.
- PAIR-RULE GENE
-
A class of segmentation gene that divides the anterior–posterior axis of the fly embryo into segments. Each pair-rule gene is expressed in a stripe in every second segment (seven stripes in total) under the control of the Gap genes.
- MICROTUBULE ORGANIZING CENTRE
-
(MTOC). A large organelle that organizes most of the microtubules in the cell through the activity of the γ-tubulin ring complex, which nucleates new microtubules from their minus ends. In most somatic cells, the MTOC is the centrosome, which contains the paired centrioles, but the centrosomes disappear in female germ cells, which contain more diffuse MTOCs.
- HYPOMORPHIC ALLELE
-
An allele that reduces the level or activity of a gene product, without eliminating it entirely, often causing a less extreme phenotype than a loss-of-function (or null) allele.
- MACROMERES
-
The larger cells that are produced when early blastomeres undergo unequal divisions in invertebrate embryos.
- MICROMERES
-
The smaller cells that are produced when early blastomeres undergo unequal divisions in invertebrate embryos.
- COILED-COIL DOMAIN
-
A protein structural domain that mediates subunit oligomerization. Coiled coils contain between two and five α-helices that twist around each other to form a supercoil.
- RNA RECOGNITION MOTIF
-
This motif defines a domain found in many proteins that recognize single-stranded RNA sequences. The RNA-binding site is formed by a four-stranded β-sheet on one face of the domain that contains the highly conserved RNP1 and RNP2 motifs.
- KH DOMAIN
-
An evolutionary conserved RNA-binding domain, which was originally identified in the human hnRNPK protein, and that recognizes single-stranded RNA sequences. Many RNA-binding proteins contain multiple copies of the KH domain.
- MITOCHONDRIAL CLOUD
-
Also known as the Balbiani body. An aggregate of mitochondria surrounded by electron-dense material that forms next to the nucleus of pre-vitellogenic amphibian oocytes. It subsequently moves to the vegetal pole of the oocyte, where it is thought to have a central role in the assembly of germ plasm.
- RIBONUCLEOPROTEIN (RNP) COMPLEX
-
A complex of protein and RNA.
- EXON JUNCTION COMPLEX
-
(EJC). A protein complex that is deposited as a consequence of pre-mRNA splicing 20–24 nucleotides upstream of splicing-generated exon–exon junctions of newly synthesized mRNA. The EJC is required for efficient nuclear export, nonsense-mediated mRNA decay in mammals and the posterior localization of oskar mRNA.
- hnRNP
-
(Heterogeneous nuclear ribonucleoprotein). A group of >20 proteins that associate with high-molecular-weight nuclear RNA. Some hnRNP proteins, such as members of the hnRNPA/B family, shuttle in and out of the nucleus, whereas others are strictly nuclear.
Rights and permissions
About this article
Cite this article
St Johnston, D. Moving messages: the intracellular localization of mRNAs. Nat Rev Mol Cell Biol 6, 363–375 (2005). https://doi.org/10.1038/nrm1643
Issue Date:
DOI: https://doi.org/10.1038/nrm1643
This article is cited by
-
Functionalization of acyclic xenonucleic acid with modified nucleobases
Polymer Journal (2023)
-
Vasa nucleates asymmetric translation along the mitotic spindle during unequal cell divisions
Nature Communications (2022)
-
Walking the line: mechanisms underlying directional mRNA transport and localisation in neurons and beyond
Cellular and Molecular Life Sciences (2021)
-
Live cell imaging reveals 3′-UTR dependent mRNA sorting to synapses
Nature Communications (2019)
-
High-Sensitivity and High-Resolution In Situ Hybridization of Coding and Long Non-coding RNAs in Vertebrate Ovaries and Testes
Biological Procedures Online (2018)