Expanded genetic screening in C. elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration

Abstract

The mechanisms underlying axon regeneration in mature neurons are relevant to the understanding of normal nervous system maintenance and for developing therapeutic strategies for injury. Here, we report novel pathways in axon regeneration, identified by extending our previous function-based screen using the C. elegans mechanosensory neuron axotomy model. We identify an unexpected role of the nicotinamide adenine dinucleotide (NAD+) synthesizing enzyme, NMAT-2/NMNAT, in axon regeneration. NMAT-2 inhibits axon regrowth via cell-autonomous and non-autonomous mechanisms. NMAT-2 enzymatic activity is required to repress regrowth. Further, we find differential requirements for proteins in membrane contact site, components and regulators of the extracellular matrix, membrane trafficking, microtubule and actin cytoskeleton, the conserved Kelch-domain protein IVNS-1, and the orphan transporter MFSD-6 in axon regrowth. Identification of these new pathways expands our understanding of the molecular basis of axonal injury response and regeneration.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Kyung Won Kim

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    For correspondence
    kwkim@hallym.ac.kr
    Competing interests
    The authors declare that no competing interests exist.
  2. Ngang Heok Tang

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Christopher A Piggott

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew G Andrusiak

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Seungmee Park

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ming Zhu

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Naina Kurup

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Salvatore J Cherra III

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Zilu Wu

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Andrew D Chisholm

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    For correspondence
    adchisholm@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
  11. Yishi Jin

    Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, United States
    For correspondence
    yijin@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9371-9860

Funding

American Heart Association (13POST14800057)

  • Kyung Won Kim

Canadian Institutes of Health Research (MFE-146808)

  • Matthew G Andrusiak

National Institutes of Health (NS057317)

  • Yishi Jin

National Institutes of Health (NS093588)

  • Yishi Jin

Hallym University Research Fund (HRF-201809-014)

  • Kyung Won Kim

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

Reviewing Editor

  1. Kang Shen, Stanford University, United States

Publication history

  1. Received: July 2, 2018
  2. Accepted: November 19, 2018
  3. Accepted Manuscript published: November 21, 2018 (version 1)
  4. Version of Record published: December 5, 2018 (version 2)

Copyright

© 2018, Kim 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. Kyung Won Kim
  2. Ngang Heok Tang
  3. Christopher A Piggott
  4. Matthew G Andrusiak
  5. Seungmee Park
  6. Ming Zhu
  7. Naina Kurup
  8. Salvatore J Cherra III
  9. Zilu Wu
  10. Andrew D Chisholm
  11. Yishi Jin
(2018)
Expanded genetic screening in C. elegans identifies new regulators and an inhibitory role for NAD+ in axon regeneration
eLife 7:e39756.
https://doi.org/10.7554/eLife.39756
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