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Seminars in Cell & Developmental Biology 18 (2007) 171–177

Review

Why cells move messages: The biologicalfunctions of mRNA localization

Tung-Gia Du, Maria Schmid, Ralf-Peter Jansen ∗Department of Chemistry and Biochemistry, Gene Center, Ludwig-Maximilians-University Munich,

Feodor-Lynen-Str. 25, D-81377 Munich, Germany

Available online 6 February 2007

bstract

RNA localization is a widespread mechanism that allows cells to spatially control protein function by determining their sites of synthesis. Inmbryos, localized mRNAs are involved in morphogen gradient formation or the asymmetric distribution of cell fate determinants. In somatic cellypes, mRNA localization contributes to local assembly of protein complexes or facilitates protein targeting to organelles. Long-distance transportf specific mRNAs in plants allows coordination of developmental processes between different plant organs. In this review, we will discuss theiological significance of different patterns of mRNA localization.

2007 Elsevier Ltd. All rights reserved.

eywords: Morphogen; Cell fate determinant; �-Actin; RNA transport; Asymmetric cell division

ontents

1. mRNA localization and the formation of protein gradients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1722. mRNA localization and asymmetric distribution of cell fate determinants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1723. mRNA localization and local assembly of protein complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1734. mRNA localization to the vicinity of organelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174

5. Long distance transport of mRNAs and small RNAs in plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1756. Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Why do cells target specific mRNAs to particular cytoplas-ic domains? It seems obvious even to the non-specialist that

ocalization of an mRNA should result in local synthesis of thencoded protein at the target site. However, experimental evi-ence for the necessity to target a certain mRNA to a distinctite has been achieved only for a limited number of cases. Thiss in part due to the use of high-throughput methods to identifyocalized mRNAs [1,2]. For many localized mRNAs that weredentified in high-throughput approaches or by co-purificationith known RNA-localizing proteins we still lack functionalata, mainly because disturbing their localization did not result

∗ Corresponding author. Tel.: +49 89 2180 76903; fax: +49 89 2180 76948.E-mail address: rjansen@lmb.uni-muenchen.de (R.-P. Jansen).

mpm

084-9521/$ – see front matter © 2007 Elsevier Ltd. All rights reserved.oi:10.1016/j.semcdb.2007.01.010

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175

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n a detectable phenotype (e.g. Ref. [3]). In other cases, localizedRNAs were identified in organisms in which the biological

unction of RNA localization cannot easily be addressed becausehey miss the elaborate genetic tools that are at hand in modelrganisms. Due to these restrictions most – but not all – of ournowledge on the function of mRNA localization stems fromnalysis of localized mRNAs in mouse, Drosophila or yeast.

In this review, we will focus on the functional significance ofRNA localization. For detailed description of the mechanisms

f mRNA localization or signals that confer localization we refero the review articles by Palacios (page 163) and Bullock (page94) in this issue.

Why localize mRNAs? In his first survey of intracellularRNA localization, Daniel St Johnston has already given several

ossible answers [4]. Reducing transport costs is one of them. Inultiple rounds of translation, one mRNA molecule can give rise

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72 T.-G. Du et al. / Seminars in Cell & D

o several protein molecules. Therefore, localization of mRNAhould be more cost-efficient than protein transport. This mightxplain why e.g. specific mRNAs have been detected in cyto-lasmic areas surrounding the nucleus (perinuclear region) oritochondria (perimitochondrial region; see below). Another

eason why mRNA rather than protein is localized is that therotein must not be translated at any other location than the tar-et site. One such example is myelin basic protein (MBP), aomponent of the myelin sheath of oligodendrocytes that wrapsround axons of neurons [5]. As MBP sticks to membranes,ransport of the protein via the secretory pathway would resultn a collapse of the intracellular membrane system. Local trans-ation of MBP from its mRNA that has been targeted to the cell’s

yelinating processes circumvents this problem. Localized ver-us non-localized translation also allows spatial fine-tuning ofrotein synthesis and distribution. This might be especially use-ul if protein synthesis has to respond rapidly to signals, as it ishe case for postsynaptic sites in dendrites of neurons (see Dahmt al. in this issue). Furthermore, mRNA localization can serveo set up protein gradients, or to establish and maintain cellularolarity or cell diversification.

. mRNA localization and the formation of proteinradients

Gradients of morphogens pattern the embryo body plan [6].hey can act as regulators of gene expression that switch onifferent sets of genes dependent on their concentration alongdefined embryonic axis. The first molecularly defined mor-

hogen, Bicoid in Drosophila embryos is encoded by a localizedRNA (for a recent review see Ref. [7]). Bicoid mRNA is local-

zed during oogenesis to the anterior tip of the oocyte wheret is anchored. After fertilization, it is translated and a gradi-nt of Bicoid protein forms with the highest concentration athe anterior. Bicoid can then enter the nuclei in the anteriorart of the embryo and switch on its target genes [8]. Propericoid mRNA targeting is of crucial importance in this sys-em since all mutants with affected bicoid localization showefects in embryonic patterning [7]. While bicoid localiza-ion specifies the anterior end of the embryo, localization ofskar mRNA to the opposite pole initiates formation of polelasm at the posterior of the embryo [9]. The pole plasm con-ains several other localized mRNAs that are essential for laterevelopment of the primordial germ cells [10]. One of the poste-iorly localized mRNAs is nanos mRNA, which upon translationives rise to a second morphogen gradient that defines pos-erior structures of the embryo [11]. However, in contrast toicoid, nanos mRNA is not exclusively localized to the posteriornd gradient formation is mainly achieved by restricting nanosranslation to the posterior end [12]. A third localized mRNA,urken, defines the dorsoventral axis of the embryo (reviewedn Ref. [13]). gurken encodes a transforming growth factor �TGF�) like signalling protein. During late oocyte development

urken is targeted by a two-step mechanism to the anteriodor-al corner of the oocyte adjacent to the cell nucleus. Secretionf the protein made from gurken mRNA at the anteriodor-al corner induces a secondary signal in the adjacent follicle

pna

pmental Biology 18 (2007) 171–177

ells that eventually establishes the dorsoventral axis of theocyte.

Localized mRNAs cannot only induce the formation of intra-ellular protein gradients but can also facilitate the formation ofxtracellular signal gradients. In the Drosophila embryo, Wing-ess is a secreted glycoprotein that functions to establish cellates during segmentation of the ventral epidermis [14]. Inter-stingly, in cells that express wingless (wg), the mRNA localizesust below the surface of the apical membrane [15]. Mistargetingf wg mRNA to the basal cell membrane results in an embry-nic phenotype similar to that observed upon loss of wg function15]. This suggests that mRNA localization to the apical side ofhe cell facilitates proper secretion and extracellular gradientormation.

. mRNA localization and asymmetric distribution ofell fate determinants

Asymmetric cell divisions are widespread in the bacte-ial and eukaryotic kingdoms [16–18]. Generally this achievesnequal distribution of different cellular components includingucleic acids and proteins. Numerous mRNAs are asymmet-ically distributed upon cell division, especially during earlymbryogenesis. For many, however, the reason for their asym-etric partitioning is not understood (see, e.g., Ref. [19]). Even

n cases where the encoded protein functions as a cell fateeterminant, the biological significance of the localization ofts mRNA localization is not immediately obvious [20].

The currently best-understood example that provides a directunctional link between mRNA localization and cell fate deter-ination can be found in the budding yeast Saccharomyces

erevisisae (Fig. 1A). Here, the Ash1 protein has a key functionn the regulation of mating-type switching [21]. This occurs afterell division in only one of the two resulting cells and is initiatedy the site-specific restriction endonuclease HO that cleaves inhe actively expressed mating type locus. HO expression is con-rolled temporally and spatially [21]. The protein is made onlyn mother (i.e. the cell that has given rise to the bud) but notn daughter cells (i.e. the mature buds). Ash1p is a transcrip-ional repressor that blocks expression of HO in the daughterell and thus controls spatial distribution of HO protein. ASH1s expressed prior to cell division and accumulates in daughterell nuclei due to the localization of its mRNA to the daughterell tip [21–23]. ASH1 mRNA mis-localization results in equalistribution of the protein in nuclei of mother and daughter cellsnd, consequently, both cells acquire an identical fate [21,22]. Inontrast to ASH1 there are a series of localized mRNAs whoseeason for localization we do not understand. In total, 25 mRNAsre localized to the bud or daughter cell tip by a common machin-ry [3,24]. However, for most of them targeting to the bud tips not necessary to achieve asymmetric protein distribution [3].his indicates that mRNA localization in these cases might either

acilitate protein sorting or functions as backup mechanism.

A similar backup strategy seems to exist in the case of

rospero and inscuteable mRNAs in asymmetrically dividingeuroblasts in Drosophila embryos [20,25]. Neuroblasts usu-lly divide along the apical-basal axis into a ganglion mother

T.-G. Du et al. / Seminars in Cell & Develo

Fig. 1. Functions of mRNA localization. (A) Asymmetric distribution of cellfate determinants. Yeast ASH1 mRNA is localized to the daughter cell tip priorto cell division. Local translation of the encoded Ash1 protein results in anenrichment of Ash1 in the daughter cell nucleus where the protein repressesmating type switching. (B) Long-distance signalling. FT mRNA is transcribedin leafs of Arabidopsis and transported through the plant vascular system tothe shoot apical meristem, where the encoded protein acts as transcriptionalactivator inducing flowering. (C) Protein isoform sorting and local assemblyof protein complexes. �-Actin but not �-actin mRNA localizes to the leadingedge of chicken embryonic fibroblasts. Local expression of �-actin results in theassembly of this isoform into actin filaments. (D) Facilitated protein targeting.Mgp

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etallothionein-1 (MT-1) mRNA localizes to the perinuclear cytoplasm. Tar-eting of the mRNA to this region results in a considerably more efficient MT-1rotein import into the nucleus.

ell (GMC) and a new neuroblast. The GMC divides once morento two postmitotic neurons or glia precursors, while the neu-

oblast continues to divide in a stem cell-like fashion. Duringitosis, prospero mRNA is sorted to the cell cortex of the basal

ide, which will subsequently become part of the GMC [18,20].n the GMC, Prospero protein acts as a cell fate determinant.

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pmental Biology 18 (2007) 171–177 173

ocalization of prospero is mediated by the double-strandedNA-binding protein Staufen and the adaptor Miranda that teth-rs Staufen to the cell cortex [26,27]. Loss of Staufen functionesults in symmetric distribution of prospero mRNA but doesot block asymmetric distribution of Prospero protein. This isue to a direct interaction of the cortical protein Miranda withrospero that is independent of its binding to prospero mRNAediated via Staufen [26]. Thus, Miranda serves to localize bothrospero protein and its mRNA. In contrast to Prospero, Inscute-ble protein is part of an apically sorted protein complex that isequired to coordinate mitotic spindle orientation and sorting ofhe basal sorting machinery [18]. Inscuteable mRNA is trans-orted to the apical cortex in a dynein-dependent process butailure to localize the mRNA results in only a modest defect ofsymmetric division [25]. Both examples suggest that mRNAocalization in the Drosophila neuroblast serves to facilitate butot accomplish asymmetric protein distribution.

During Xenopus development, localization of mRNAs con-ributes to embryonic patterning [28]. Several mRNAs areocalized to the vegetal pole or the vegetal hemisphere of theocyte and are later asymmetrically inherited by the cellu-ar progeny that arises from this region. Two main pathwaysave been described that result in vegetal RNA localizationn Xenopus [29]. During the early pathway, mRNAs associatend move with the so-called message transport organizer regionMETRO), which is part of the mitochondrial cloud that formsuring early oocyte development [29]. Most of these mRNAsre incorporated into the germ plasm and encode proteins thatre required for germ cell development [28]. The late localiza-ion pathway in Xenopus oocytes is used to deposit germ layereterminants in the vegetal hemisphere [28,29]. This hemispheres a repository of mesodermal and endodermal determinants.

well-characterized example for the importance of localizingRNAs to this region is VegT mRNA that encodes a T-box tran-

cription factor required for mesendodermal development [30].ocalization of another mRNA, Vg1, has also been implicated inpecification of both mesodermal and endodermal tissues [31].

. mRNA localization and local assembly of proteinomplexes

In polarized somatic cells, localized mRNAs can serve asemplate for spatially restricted synthesis of proteins to maintainellular asymmetry. In some cases, mRNA localization mightlso help to facilitate the compartmentalized assembly ofultifactor complexes. One of the best-characterized examples

or this aspect of mRNA localization is �-actin mRNA inotile cells (Fig. 1C). In several motile cell types, �-actinRNA is targeted to the leading edge of lamellipodia [32].hese flattened cytoplasmic extensions are actin rich andolymerizing actin filaments provide the protrusive force forhe extension of lamellipodia during cell motility. Cis-actingocalization elements within the 3′-UTR (untranslated region)

ncluding the ‘zipcode’ sequence are essential for the sortingf �-actin mRNA [33]. The zipcode binding protein 1 (ZBP1)s required for the transport of �-actin mRNA [34] and inhibitsranslation until the message reaches its final destination [35].

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hese results are consistent with a recent publication which forhe first time showed directly that �-actin protein is translatedrimarily at the sites of mRNA localization [36].

The first indications for a physiological function of �-actinRNA targeting came from studies in which motile cells were

reated with antisense oligonucleotides directed against the zip-ode. Treatment resulted not only in loss of mRNA localizationut also in impaired cell morphology and motility [37]. Pointutations in the mRNA zipcode or over-expression of domi-

ant negative ZBP1 fragments had the same effect [32,34]. Whyoes �-actin mRNA delocalization cause loss of cell morphol-gy and motility? A decreased local concentration of �-actin athe leading edge due to mislocalized �-actin mRNA could havewo possible consequences. Reduced efficiency of actin filamentolymerization could slow down the formation of new cell pro-rusions. Alternatively, the rate of actin polymerization itself

ight be unaffected yet the location of actin synthesis may beltered. That indeed the second suggested mechanism is respon-ible for cell polarity and directional motility was suggested byn elegant series of experiments [38]. Loss of cell polarizationue to impaired �-actin mRNA targeting can have other dele-erious effects such as the gain of metastatic potential in tumorells [39–41].

It is evident from the observations discussed above that mis-argeting of �-actin mRNA results in abnormal cell phenotypes.ut this does not directly address the question why �-actinRNA instead of �-actin protein is localized. RNA localization

an create a microenvironment in which the newly synthesizedctin monomers are available at much higher concentration.s �-actin translation occurs in a restricted cell compartment

ike the thin lamellipodium [36], high local levels of �-actinonomers can considerably enhance the dynamics of actin poly-erization [32]. Additionally, mRNA localization can easily

llow for sorting of specific actin isoforms. Since only �-actin,ut not �- or �-actin mRNAs, is targeted to the cell periph-ry in moving cells [33], its local translation might preventormation of unwanted isoform heteromers. Interestingly, somectin-binding proteins that are believed to function at the leadingdge preferentially interact with the �-isoform and its specificnrichment might consequently support these interactions (foretailed discussion see Ref. [32]). Recently, another exampleor protein isoform specific sorting on the level of mRNA wasescribed. Integrin �3 but not other integrin � isoform mRNAs or-subunit mRNAs localize to focal adhesion sites [42]. However,s integrins form obligate �/�-heterodimers, the physiologicalelevance for �3 mRNA localization remains unclear.

�-Actin mRNA is not the only transcript targeted to theeading edge in migrating cells. Several other mRNAs encod-ng motility-related proteins contain the consensus sequence ofhe �-actin zipcode element and are likely to be localized asell [38]. The actin-related protein 2/3 (ARP2/3) complex is

ssential for the nucleation of actin filament assembly and isocated at leading protrusions in crawling cells [43]. A recent

tudy demonstrated that the mRNAs of all seven subunits ofhe ARP2/3 complex are localized to lamellipodia in fibroblasts44]. Importantly, this study provides the first case in which allranscripts encoding a multimeric complex are targeted to its

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pmental Biology 18 (2007) 171–177

lace of function and potential assembly site. The advantage foretero-multimer assembly offered by mRNA localization is evi-ent since high local concentrations of all subunits can facilitateomplex assembly. Such compartmentalized synthesis wouldlso avoid any random and unwanted protein interactions.

. mRNA localization to the vicinity of organelles

mRNA localization can also facilitate protein sorting torganelles. Generally, protein sorting is based on peptide signalsithin the protein to be sorted. However, increasing evidence

uggests that localization of mRNAs encoding proteins destinedo organelles like ER, mitochondria or nuclei supports proteinargeting or allows refined targeting that cannot occur on therotein level (see also Dahm et al., this issue).

Vimentin, �-actin, and �-actin mRNAs display perinuclearocalization [33,45,46]. In addition, transcripts coding for

etallothionein-1 (MT-1), cellular retinoic acid binding protein ICRABPI) and transcription factors c-FOS and c-MYC accumu-ate at the nuclear periphery and associate with the perinuclearytoskeleton [47–50]. The physiological role of perinuclearRNA localization might be to enhance the efficiency of nuclear

mport of proteins encoded by these mRNAs (Fig. 1D). MT-is a predominantly cytosolic protein that is imported into

he nucleus upon G1/S phase transition of the cell cycle. In atudy where cells were transfected with MT-1 mRNA whose′UTR was replaced by a heterologous RNA, the hybrid MT-1essage did no longer take up a perinuclear position. Simultane-

usly, MT-1 protein did not localize to the nucleus during G1/Shase transition [51]. Interestingly, cells with non-localizingT-1 mRNA were more susceptible to stress, DNA damage

nd showed increased apoptosis after exposure to mutagens [52].hese observations indicate that perinuclear localization of MT-mRNA is necessary for the protein to be fully functional, whichight also be true for c-FOS, c-MYC or CRABPI. It is, how-

ver, not yet clear to what extent this functional model can beeneralized.

A number of mRNAs are targeted to the rough ER throughhe nascent chain emanating from a translating ribosome. Onop of this general targeting, certain transcripts are directed topecific subcompartments of the ER. In developing rice seeds,his is the case for two mRNAs encoding different seed storageroteins, prolamines and globulin-like glutelins [53]. ProlamineRNAs localize to the surface of ER containing prolamine pro-

ein bodies, so called PB-ER. In contrast, glutelin RNAs arereferentially targeted to cisternal ER (C-ER). Both storage pro-eins are synthesized on the surface of cortical ER, translocatednto the ER lumen and then further sorted. Targeting of stor-ge protein mRNAs in the rice seeds provides an interestingechanism that facilitates trafficking of their corresponding pro-

eins to distinct endomembrane compartments. Consequently,his allows a spatial separation of protein synthesis to preventnon-productive mixing of the two disparate storage proteins

54–56].During the evolution of the eukaryotic cell, mitochondria

ave lost the majority of their initial genome, which rendershese organelles dependent on the delivery of proteins encoded

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y nuclear genes. Although there is a large body of evidence thathese proteins are targeted to mitochondria post-translationally,ew data suggest that sorting of a subset of nuclear-encodedroteins to mitochondria involves mRNA localization. In yeast,or instance, the 3′-UTR of ATM1 [57] and ATP2 mRNAs58] direct these transcripts to the vicinity of mitochondria.he latter transcript encodes a subunit of the mitochondrialTP synthase. Interestingly, impaired ATP2 mRNA sorting cor-

elates with a severe respiratory deficiency, indicating a linketween mRNA localization and protein function. However, theechanistic details underlying the transport of mitochondrially-

argeted mRNAs remain elusive. Local enrichment of transcriptst mitochondrial-bound polysomes may ensure an effective co-ranslational import into these organelles [59].

. Long distance transport of mRNAs and small RNAsn plants

Less is known about RNA localization in the plant kingdomompared to animal cells but a role for RNAs as long-distancenformation molecules is emerging. The framework for such a

echanism is provided by the plant vascular system. In con-rast to animals, higher plants have evolved a unique vascularystem that consists of xylem and phloem. Xylem cells allowhe delivery of water and minerals, whereas phloem, which con-ists of living but enucleated sieve elements, transports photossimilates and nutrients to distantly located tissues and organs.ver the last decade, there is a growing body of evidence that

he phloem translocation stream also acts as an informationipeline, enabling coordination of developmental and physio-ogical processes at level of the whole plant. Plant phloem isnown to deliver a wide range of signalling molecules like pro-eins and phytohormones, but strikingly also RNA moleculesre transported. In terms of systemic RNA silencing, it hasong been known that RNA-based silencing signals are able toravel throughout the plant to spread systemically. Small inter-ering RNAs (siRNAs) are likely candidates to exert this form ofost-transcriptional gene silencing [60]. The phloem-dependentystemic transmission and amplification of RNA-based defenceignals may help to alert developing tissues to the presence ofnvasive and pathogenic genetic elements and is therefore ofteneferred to as the plant immune system [61]. In addition, longistance transport was also observed for non-coding microRNAsmiRNAs). In plants, miRNAs have emerged as important post-ranscriptional regulators and many of them have implicatedunctions in plant development or cell differentiation [62,63].ccordingly, the detection of a set of different miRNA species

n phloem sap suggests that in response to environmental cuesiRNAs may serve as bona fide systemic signals to exert non-

ell-autonomous control over diverse processes in plant growthnd development [64].

Support for the concept that also mRNAs are translocatedver long distances was initially provided by the identifica-

ion of a unique set of mRNAs isolated from phloem sap [65].rafting experiments and in situ RT-PCR analysis revealed that

he phloem stream has the capacity to mediate long distanceransport of several messenger RNAs to the apical meristem,

pmental Biology 18 (2007) 171–177 175

oving from the plant rootstock into a grafted scion [65–67].ong distance transport requires that mRNAs can traverse thearrow but dynamic channels of plasmodesmata (PD), whichre pores connecting adjacent cells. The passage via PD high-ights an important prerequisite for cell-to-cell movement ofNA [68]. The up- and unloading of RNAs into and out of

he phloem translocation stream, also appears to occur throughD [67,69]. How long-distance trafficking of mRNA is func-

ionally linked to developmental events was recently shownor the model plant Arabidopsis thaliana [70,71] (Fig. 1). Inrabidopsis day length is a major environmental determinant

hat controls the time of flowering, especially in spring, whenay length and ambient temperature increase. The photoperi-dic perception of day-length in the leaf leads to expressionf the mobile stimulus Flowering locus T (FT). Although tran-cribed in leafs, FT protein functions within the shoot apex, aistantly located meristematic region where floral developments stimulated. Here we can find a situation where expression of

signal and its site of function are spatially and temporarilyeparated. A mobile FT signal could solve the spatial paradox.

ovement of FT mRNA along the phloem was shown usingeat shock promoters to locally induce expression of FT in aingle Arabidopsis leaf [71]. After induction, increased levelsf the transgenic FT transcript appear at the shoot apex. Thisuggests that the pulse of FT expression can move from leaf tots destination where it triggers flowering. Although the compo-ition of the flowering signal is still elusive and specific proteinsediating the transport processes remain to be determined, FTRNA transport nicely demonstrates that mRNAs can serve as

ong-distance developmental signals in the plant kingdom.

. Outlook

mRNA localization serves as a sophisticated cellular toolo optimize protein expression on a post-transcriptional level.esides well-understood functions like generating morphogenradients or sorting determinants, mRNA localization seemso fulfil a variety of additional roles ranging from facilitatedssembly of protein complexes to long-distance signalling andoordination of developmental processes. In addition, newunctions have emerged like modulating synaptic plasticity ineurons or maximizing protein targeting to subcellular com-artments.

cknowledgements

R.P.J. and T.G.D. are supported by grants from the Deutscheorschungsgemeinschaft (DFG JA696/4-4 and SFB646 TPA5).

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