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The functional organization of axonal mRNA transport and translation

Nature Reviews Neuroscience volume 22, pages 77–91 (2021)Cite this article

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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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Fig. 1: Ribonucleoprotein (RNP)-coupled transport of mRNAs into axons.
Fig. 2: Defining axonal mRNA regulons.
Fig. 3: The fate of mRNAs on reaching their axonal destinations.
Fig. 4: Distinct axonal translational control mechanisms have different functional outcomes.

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Acknowledgements

The authors are supported by the following funding sources for work related to the topic of this Review: US National Institutes of Health (R01-NS089633 and R01-NS041596 to J.L.T.; K01-NS105879 to T.P.S.), US National Science Foundation (MCB-1020970 to J.L.T.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to J.L.T), South Carolina Spinal Cord Injury Research Fund (2019-PD-02 to P.K.S.), South Carolina EPSCoR Stimulus Research Program (18-SR04 to J.L.T.) and the University of South Carolina Research Office ASPIRE programme (to J.L.T. and A.N.K.). J.L.T. is the incumbent SmartState Chair of Childhood Neurotherapeutics at the University of South Carolina.

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  1. These authors contributed equally: Irene Dalla Costa, Courtney N. Buchanan, Matthew Zdradzinski.

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  1. Department of Biological Sciences, University of South Carolina, Columbia, SC, USA

    Irene Dalla Costa, Courtney N. Buchanan, Matthew D. Zdradzinski, Pabitra K. Sahoo, Terika P. Smith, Elizabeth Thames, Amar N. Kar & Jeffery L. Twiss

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Contributions

All of the authors made substantial contributions to the discussion of the content of the article. I.D.C., C.N.B., M.Z. and J.L.T. researched data for the article. I.D.C., C.N.B., M.Z., J.L.T. and P.K.S. wrote the article. I.D.C., C.N.B., J.L.T., P.K.S., T.P.S., E.T. and A.N.K. reviewed and edited the manuscript before submission.

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Correspondence to Jeffery L. Twiss.

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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.

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Nature Reviews Neuroscience thanks G. Bassell, U. Hengst and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Ribosomes

RNA–protein complexes composed of 60S and 40S subunits that are responsible for translating mRNAs into protein.

RNA profiling

The measurement of the identities and abundances of RNAs across different cell or tissue populations or subcellular sites and in different physiological conditions or growth states.

RNA-binding proteins

(RBPs). Proteins that can bind RNA via RNA structures (‘motifs’) and that are involved in RNA processing, trafficking, stability and translational regulation.

Ribonucleoproteins

(RNPs). Complexes of RNA-binding proteins and RNAs that associate, often in the form of a granule or organelle-like structures.

Motor proteins

Proteins that bind to microtubules or microfilaments and transport cargos from one site in a cell to another.

Nuclear pore complex

A protein complex that transects the nuclear membrane and controls the exchange of many components between the nucleus and the cytoplasm.

Nonsense-mediated decay

A mechanism for the selective degradation of mRNAs that contain premature stop codons within, or have exon–exon junctions within, their 3′ untranslated regions.

Interactomes

Sets of molecular interactions; for example, an RNA-binding protein has both an ‘RNA interactome’ and a ‘protein interactome’ that define the macromolecules that it interacts with.

Adaptor proteins

Proteins containing specific protein-binding sites that facilitate interactions between protein binding partners (for example, proteins linking cargos to motor proteins).

Transport granule

An RNA-protein complex, or ribonucleoprotein, that is needed for transport of mRNAs to subcellular sites.

Liquid–liquid phase separation

(LLPS). A process in which solutions of macromolecules (proteins and nucleic acids) transition to form a membraneless phase-separated cytoplasmic condensate.

Polysome

A complex of multiple ribosomes bound to an mRNA that is typically regarded as a site of active translation.

Unfolded protein response

A molecular response that occurs when levels of unfolded proteins increase in the endoplasmic reticulum; this reduces overall protein synthesis to decrease continued load of unfolded proteins and allows the cell to respond to different types of stress.

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Dalla Costa, I., Buchanan, C.N., Zdradzinski, M.D. et al. The functional organization of axonal mRNA transport and translation. Nat Rev Neurosci 22, 77–91 (2021). https://doi.org/10.1038/s41583-020-00407-7

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