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Review
. 2021 Feb;22(2):77-91.
doi: 10.1038/s41583-020-00407-7. Epub 2020 Dec 7.

The functional organization of axonal mRNA transport and translation

Irene Dalla Costa #  1 , Courtney N Buchanan #  1 , Matthew D Zdradzinski #  1 , Pabitra K Sahoo  1 , Terika P Smith  1 , Elizabeth Thames  1 , Amar N Kar  1 , Jeffery L Twiss  2
Affiliations
Review

The functional organization of axonal mRNA transport and translation

Irene Dalla Costa et al. Nat Rev Neurosci. 2021 Feb.

Abstract

Axons extend for tremendously long distances from the neuronal soma and make use of localized mRNA translation to rapidly respond to different extracellular stimuli and physiological states. The locally synthesized proteins support many different functions in both developing and mature axons, raising questions about the mechanisms by which local translation is organized to ensure the appropriate responses to specific stimuli. Publications over the past few years have uncovered new mechanisms for regulating the axonal transport and localized translation of mRNAs, with several of these pathways converging on the regulation of cohorts of functionally related mRNAs - known as RNA regulons - that drive axon growth, axon guidance, injury responses, axon survival and even axonal mitochondrial function. Recent advances point to these different regulatory pathways as organizing platforms that allow the axon's proteome to be modulated to meet its physiological needs.

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Conflict of interest statement

Competing interests

J,L.T. and P.K.S. have a US Patent for G3BP1 as a target for accelerating axon regeneration (US Patent 10,668,128). A.N.K., P.K.S. and J.L.T. have applied for a US patent for G3BP1 as a target for preventing neurodegeneration.

Figures

Fig. 1 |
Fig. 1 |. ribonucleoprotein (rNP)-coupled transport of mRNAs into axons.
a | Schematic of a neuron showing the anterograde transport of RNPs that are engaged with motor proteins directly (known as transport RNPs) or indirectly (through binding to vesicles) for microtubule-based transport along the axon shaft. Although it is not clear whether transport RNPs also move in a retrograde direction, retrograde vesicle-based RNA transport has been reported recently. b | Some RNA-binding proteins (RBPs) initially interact with newly transcribed RNAs in the nucleus to form an RNP. Drawing from studies in other systems, these nuclear RNPs are thought to exit the nucleus through the nuclear pore, after which they are remodelled through the addition of some new RBPs and the removal of others, with some of the released RBPs returning to the nucleus,. c,d | RNPs can bind kinesin motor proteins as a ‘transport RNP’ (panel c) or can bind to vesicles (endosomes or lysosomes) through molecular tether proteins (panel d). RNPs may also utilize adaptor proteins for binding to kinesin (not shown). Pre-microRNAs (pre-miRNAs) and mature miRNAs have also been shown to associate with vesicles for transport into axons. In addition, the RNA-induced silencing complex (RISC), which is needed for miRNA processing, has been shown to associate with vesicles,, although it is not clear whether it functions directly on or adjacent to the vesicle for processing co-trafficked pre-miRNAs or whether it acts on different pre-miRNAs that already resided in the axon.
Fig. 2 |
Fig. 2 |. Defining axonal mRNA regulons.
An RNA-binding protein (RBP) can interact with multiple axonal mRNAs that encode proteins with complementary functions, thereby defining an axonal RNA regulon,. The schematic depicts three axonal RNA regulons in which related mRNAs (depicted in different shades of blue, red or purple) are bound by a single shared RBP. Additional RBPs bind to this complex, either in the nucleus or in the cytoplasm, to establish a ribonucleoprotein (RNP) for axonal localization. The regulon-defining RBP is shown here as a nuclear RBP, on the basis of the finding that heterogeneous nuclear RNPs bind to axonal mRNAs that are associated with axon growth. This does not exclude the possibility of a regulon defined by cytoplasmic RBPs. Axonal RNA regulons for axon growth and mitochondrial function (axon survival) have been reported, while a regulon for injury signalling in the axon was inferred from work showing that nucleolin is needed for the axonal localization of both Kpnb1 and Mtor mRNAs,.
Fig. 3 |
Fig. 3 |. The fate of mRNAs on reaching their axonal destinations.
a | Schematic of a neuron showing the transport of mRNA and pre-microRNAs (pre-miRNAs) to their axonal destinations. Ribosomes and translation factors accumulate in growth cones and at spots along the axon shaft, including at branch points in cultured neurons,,; these regions have been referred to as ‘hotspots’ for translation in axons. Axonal mRNAs are presumably released from a transport ribonucleoprotein (RNP) or vesicle (endosome or lysosome) at or near those hotspots. However, axonal translation is likely not limited to these regions. The released mRNAs can be translated or sequestered into axonal mRNA storage depots. b | mRNAs in the transport granule are thought to be translationally suppressed during their transport, and single RNA-binding proteins (RBPs) have been shown to prevent mRNA translation when bound. On arrival in axons and release from RBPs, mRNAs can be immediately translated or they can be stored in stress granule-like compartments as seen for G3BP1 granules in rodents and TIAR-2 granules in Caenorhabditis elegans,. c | Vesicle-coupled mRNAs are thought to be similarly translationally repressed by RBPs during their transport. On release of the RNP from the vesicle and subsequent release of RBPs, the mRNA can be immediately translated or stored in axonal stress granule-like compartments. RNPs bound to lysosomes include G3BP1 (REF.), which has also been shown to store mRNAs in axons, suggesting that the transport RBP may be remodelled on release to become a storage depot for axonal mRNAs. d | RNA-induced silencing complex (RISC) components have been shown to associate with vesicles,, suggesting that vesicle co-transported pre-miRNAs may provide a second means to suppress the translation of local mRNAs until needed. That is, an ‘on demand’ maturation of the pre-miRNA that happens before or after its release from the vesicle could place it and RISC components in close proximity to the released mRNAs and allow translational silencing.
Fig. 4 |
Fig. 4 |. Distinct axonal translational control mechanisms have different functional outcomes.
The concept of RNA regulons (FIG. 2) can be extended to encompass groups of axonal mRNAs that exhibit translational regulation on the basis of the functional effects of the encoded proteins. The schematic illustrates examples of these regulatory mechanisms. a | Late endosome-coupled mRNA transport has been linked to several mRNAs involved in the support of mitochondrial function, which is needed for collateral branching of axons,,. b | Some axonal mRNAs that encode injury response-associated and axon regeneration-associated proteins are translationally silenced by storage in G3BP1 granules (stress granule-like structures) in mammalian peripheral nervous system axons; phosphorylation of G3BP1 (G3BP1PS) triggers disassembly of these granules and the release of the mRNAs for translation,,. TIAR-2 granules have similarly been linked to the storage of growth-associated axonal mRNAs in the axons of Caenorhabditis elegans, with phosphorylation of TIAR-2 favouring granule disassembly. c | Cell surface receptors can sequester mRNAs and ribosome subunits in the axoplasm, releasing these for synthesis of proteins presumably needed for axon guidance on the receptor binding to those guidance cues,. d | Increased levels of axoplasmic Ca2+ following injury can trigger endoplasmic reticulum (ER) stress-associated phosphorylation of eukaryotic translation initiation factor 2A (EIF2A), which can suppress generalized protein synthesis but paradoxically upregulate the synthesis of proteins needed for response to injury,,,,. Motifs in both the 5′ untranslated region (UTR) and the 3′ UTR of axonal mRNAs have been shown to modulate both their transport into axons and their translation within axons; these post-transcriptional mechanisms are mediated by RNA-binding proteins and by translation initiation factors interacting with those motifs. Such a mechanism could therefore underlie the injury response. Notably, signals activated by trophic and tropic stimuli can converge on translation initiation factors to regulate axonal mRNA translation in addition to the receptor-mediated storage mechanism depicted in panel d. e | Although not as clearly linked to RNA regulons, the repression of translation in axons as well as potentially ‘on demand’ degradation of some axonal mRNAs can be regulated through microRNAs (miRNAs). Thus far, this regulatory mechanism has been linked to mitochondrial function,. f | Several of the axonally translated proteins that are regulated by these mechanisms can contribute to axon-to-soma signalling to further regulate gene expression.
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