1. Neuroscience

Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength

  1. Yunbo Li
  2. Erin M Ritchie
  3. Christopher L Steinke
  4. Cai Qi
  5. Lizhen Chen
  6. Binhai Zheng
  7. Yishi Jin  Is a corresponding author
  1. University of California, San Diego, United States
https://doi.org/10.7554/eLife.63509
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Cite this article
  1. Yunbo Li
  2. Erin M Ritchie
  3. Christopher L Steinke
  4. Cai Qi
  5. Lizhen Chen
  6. Binhai Zheng
  7. Yishi Jin
(2021)
Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength
eLife 10:e63509.
https://doi.org/10.7554/eLife.63509
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Abstract

The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

Data availability

This study does not generate sequencing data, proteomic data, or diffraction data. Source data for immunofluorescence quantification, cell counts, and animal behaviors have been provided for Figures 1-7.

Article and author information

Author details

  1. Yunbo Li

    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.

  2. Erin M Ritchie

    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 L Steinke

    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.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1663-9971

  4. Cai Qi

    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. Lizhen Chen

    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. Binhai Zheng

    Department of Neurosciences, School of Medicine,, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. 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

Howard Hughes Medical Institute

  • Yishi Jin

Craig H. Neilsen Foundation

  • Yishi Jin

Kavli Institute for Brain and Mind, University of California, San Diego

  • Yishi Jin

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

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Yunbo Li
  2. Erin M Ritchie
  3. Christopher L Steinke
  4. Cai Qi
  5. Lizhen Chen
  6. Binhai Zheng
  7. Yishi Jin
(2021)
Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength
eLife 10:e63509.
https://doi.org/10.7554/eLife.63509

Share this article

https://doi.org/10.7554/eLife.63509

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