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The MAP3Ks DLK and LZK direct diverse responses to axon damage in zebrafish peripheral neurons

Kadidia Pemba Adula, Mathew Shorey, Vasudha Chauhan, Khaled Nassman, Shu-Fan Chen, View ORCID ProfileMelissa M Rolls, View ORCID ProfileAlvaro Sagasti
doi: https://doi.org/10.1101/2021.07.03.450951
Kadidia Pemba Adula
1Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, CA 90095
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Mathew Shorey
2Department of Biochemistry and Molecular Biology and the Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802
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Vasudha Chauhan
1Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, CA 90095
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Khaled Nassman
1Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, CA 90095
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Shu-Fan Chen
1Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, CA 90095
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Melissa M Rolls
2Department of Biochemistry and Molecular Biology and the Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802
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  • ORCID record for Melissa M Rolls
Alvaro Sagasti
1Molecular, Cell and Developmental Biology Department and Molecular Biology Institute, University of California, Los Angeles, CA 90095
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  • ORCID record for Alvaro Sagasti
  • For correspondence: sagasti@mcdb.ucla.edu
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Abstract

The MAP3Ks Dual Leucine Kinase (DLK) and Leucine Zipper Kinase (LZK) are essential mediators of axon damage responses, but their responses are varied, complex, and incompletely understood. To characterize their functions in axon injury, we generated zebrafish mutants of each gene, labeled motor neurons (MN) and touch-sensing neurons in live zebrafish, precisely cut their axons with a laser, and assessed the ability of mutant axons to regenerate. DLK and LZK were required redundantly and cell autonomously for axon regeneration in MNs, but not in larval Rohon-Beard (RB) or adult dorsal root ganglion (DRG) sensory neurons. Surprisingly, in dlk lzk double mutants, the spared branches of wounded RB axons grew excessively, suggesting that these kinases inhibit regenerative sprouting in damaged axons. Uninjured trigeminal sensory axons also grew excessively in mutants when neighboring neurons were ablated, indicating that these MAP3Ks are general inhibitors of sensory axon growth. These results demonstrate that zebrafish DLK and LZK promote diverse injury responses, depending on the neuronal cell identity and type of axonal injury.

Significance statement The MAP3Ks DLK and LZK are damage sensors that promote diverse outcomes to neuronal injury, including axon regeneration. Understanding their context-specific functions is a prerequisite to considering these kinases as therapeutic targets. To investigate DLK and LZK cell-type specific functions, we created zebrafish mutants in each gene. Using mosaic cell labeling and precise laser injury we found that both proteins were required for axon regeneration in motor neurons, but, unexpectedly, were not required for axon regeneration in Rohon-Beard or dorsal root ganglion (DRG) sensory neurons, and negatively regulated sprouting in the spared axons of touch-sensing neurons. These findings emphasize that animals have evolved distinct mechanisms to regulate injury site regeneration and collateral sprouting, and identify differential roles for DLK and LZK in these processes.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 03, 2021.
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The MAP3Ks DLK and LZK direct diverse responses to axon damage in zebrafish peripheral neurons
Kadidia Pemba Adula, Mathew Shorey, Vasudha Chauhan, Khaled Nassman, Shu-Fan Chen, Melissa M Rolls, Alvaro Sagasti
bioRxiv 2021.07.03.450951; doi: https://doi.org/10.1101/2021.07.03.450951
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The MAP3Ks DLK and LZK direct diverse responses to axon damage in zebrafish peripheral neurons
Kadidia Pemba Adula, Mathew Shorey, Vasudha Chauhan, Khaled Nassman, Shu-Fan Chen, Melissa M Rolls, Alvaro Sagasti
bioRxiv 2021.07.03.450951; doi: https://doi.org/10.1101/2021.07.03.450951

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