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  • Review Article
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Moving messages: the intracellular localization of mRNAs

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.

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Figure 1: Examples of localized mRNAs.
Figure 2: Localization of gurken, bicoid and oskar mRNAs along different populations of microtubules in the Drosophila melanogaster oocyte.

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Acknowledgements

D.St J. is supported by a Principal Research Fellowship from the Wellcome Trust.

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DATABASES

Entrez Gene

CaMKIIα

hnRNPA2

MBP

ZBP1

FlyBase

BicD

bicoid

BTZ

CUP

EGL

eIF4AIII

gurken

hairy

HRP48

inscuteable

Jaguar

LGL

Mago nashi

Miranda

nanos

oskar

prospero

Staufen

vasa

Y14

Zipper

FURTHER INFORMATION

Daniel St Johnston's homepage

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.

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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

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