Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength
- University of California, San Diego, United States
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
Christopher L Steinke
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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