Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

Abstract

Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.

Data availability

RNA-sequencing data associated with this manuscript has been deposited on the GEO database (identifier GSE135338).All proteomics data associated with this manuscript has been uploaded to the PRIDE online repository (identifier: PXD015650).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Max Koppers

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Roberta Cagnetta

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Toshiaki Shigeoka

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Lucia CS Wunderlich

    Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7200-1713
  5. Pedro Vallejo-Ramirez

    Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Julie Qiaojin Lin

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Sixian Zhao

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Maximilian AH Jakobs

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0879-7937
  9. Asha Dwivedy

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Michael S Minett

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  11. Anaïs Bellon

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Clemens F Kaminski

    Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5194-0962
  13. William A Harris

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9995-8096
  14. John Flanagan

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Christine E Holt

    Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    ceh33@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2829-121X

Funding

Netherlands Organization for Scientific Research (Rubicon 019.161LW.033)

  • Max Koppers

Wellcome Trust (085314/Z/08/Z)

  • Christine E Holt

Wellcome Trust (203249/Z/16/Z)

  • Christine E Holt

European Research Council (Advanced Grant 322817)

  • Christine E Holt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the University of Cambridge Ethical Review Committee in compliance with the University of Cambridge Animal Welfare Policy. This research has been regulated under the Animals (Scientific Procedures) Act 1986 Amendment Regulations 2012 following ethical review by the University of Cambridge Animal Welfare and Ethical Review Body (AWERB) and under project license PPL80/2198.

Reviewing Editor

  1. Carol A Mason, Columbia University, United States

Publication history

  1. Received: May 23, 2019
  2. Accepted: November 19, 2019
  3. Accepted Manuscript published: November 20, 2019 (version 1)
  4. Version of Record published: December 5, 2019 (version 2)

Copyright

© 2019, Koppers et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Max Koppers
  2. Roberta Cagnetta
  3. Toshiaki Shigeoka
  4. Lucia CS Wunderlich
  5. Pedro Vallejo-Ramirez
  6. Julie Qiaojin Lin
  7. Sixian Zhao
  8. Maximilian AH Jakobs
  9. Asha Dwivedy
  10. Michael S Minett
  11. Anaïs Bellon
  12. Clemens F Kaminski
  13. William A Harris
  14. John Flanagan
  15. Christine E Holt
(2019)
Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons
eLife 8:e48718.
https://doi.org/10.7554/eLife.48718

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