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

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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.

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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.

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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.
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.
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.

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

"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.