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

Li, Yunbo; Ritchie, Erin M; Steinke, Christopher L; Cai, Qingsong; Chen, Lizhen; Zheng, Binhai; Jin, Yishi

doi:10.7554/elife.63509

Cited by 13 publications

(9 citation statements)

References 76 publications

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“…Conditional knock-out (cKO) mice were generated in which exon 2 of the DLK or LZK gene is flanked by loxP sites (Chen et al, 2016(Chen et al, , 2018Li et al, 2021). The DLK conditional allele was generously provided by Lawrence B. Holzman (University of Pennsylvania).…”

Section: Experimental Micementioning

confidence: 99%

“…Because CST axons normally do not exhibit significant regeneration after spinal cord injury, we used PTEN deletion to attain an elevated baseline level of CST regeneration (Liu et al, 2010) so that a reduction in regeneration could be readily detected. Accordingly, we bred previously validated DLK fl/fl and LZK fl/fl conditional alleles (Chen et al, 2016(Chen et al, , 2018Li et al, 2021; Figs. 1A, 2A) to PTEN fl/fl mice to obtain various combinations of homozygous double and triple conditional mutants, all in C57BL/6 background.…”

Section: Establishing and Validating Inducible Gene Ko Micementioning

confidence: 99%

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A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

Saikia¹,

Chavez‐Martinez²,

Kim³

et al. 2022

J. Neurosci.

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The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from Caenorhabditis elegans to mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled. Together with our previous study implicating LZK in astrocytic reactivity and scar formation, these data illustrate the multicellular function of this pair of MAP3Ks in both neurons and glia in the injury response of the mammalian spinal cord. Significance StatementFunctional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucinezipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated.

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Section: Experimental Micementioning

confidence: 99%

Section: Establishing and Validating Inducible Gene Ko Micementioning

confidence: 99%

A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

Saikia¹,

Chavez‐Martinez²,

Kim³

et al. 2022

J. Neurosci.

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“…DLK-1 promotes axon regeneration in C. elegans through a p38/MAPK-like pathway [ 65 , 66 , 67 ]. However, overexpressed DLK-1 in Purkinje cells caused both rapid and slow degeneration or apoptosis through the JNK/MAPK pathway [ 68 ]. The same is true for Erk/MAPK signaling.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomes of Injured Lamprey Axon Tips: Single-Cell RNA-Seq Suggests Differential Involvement of MAPK Signaling Pathways in Axon Retraction and Regeneration after Spinal Cord Injury

Jin

Zhou

Li³

et al. 2022

Cells

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Axotomy in the CNS activates retrograde signals that can trigger regeneration or cell death. Whether these outcomes use different injury signals is not known. Local protein synthesis in axon tips plays an important role in axon retraction and regeneration. Microarray and RNA-seq studies on cultured mammalian embryonic or early postnatal peripheral neurons showed that axon growth cones contain hundreds to thousands of mRNAs. In the lamprey, identified reticulospinal neurons vary in the probability that their axons will regenerate after axotomy. The bad regenerators undergo early severe axon retraction and very delayed apoptosis. We micro-aspirated axoplasms from 10 growing, 9 static and 5 retracting axon tips of spinal cord transected lampreys and performed single-cell RNA-seq, analyzing the results bioinformatically. Genes were identified that were upregulated selectively in growing (n = 38), static (20) or retracting tips (18). Among them, map3k2, csnk1e and gtf2h were expressed in growing tips, mapk8(1) was expressed in static tips and prkcq was expressed in retracting tips. Venn diagrams revealed more than 40 components of MAPK signaling pathways, including jnk and p38 isoforms, which were differentially distributed in growing, static and/or retracting tips. Real-time q-PCR and immunohistochemistry verified the colocalization of map3k2 and csnk1e in growing axon tips. Thus, differentially regulated MAPK and circadian rhythm signaling pathways may be involved in activating either programs for axon regeneration or axon retraction and apoptosis.

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“…The copyright holder for this preprint (which this version posted July 3, 2021. ; https://doi.org/10.1101/2021.07.03.450951 doi: bioRxiv preprint (Xiong et al, 2010;Stone et al, 2014). In mammals, the outcomes of DLK and LZK activation in response to axon damage are varied and context-dependent: DLK or LZK can promote neurite branching (Chen et al, 2016b), axon elongation (Shin et al, 2012), inhibition of axon regeneration (Dickson et al, 2010), axon degeneration of the distal stump (Miller et al, 2009;Summers et al, 2018), cell death (Ghosh et al, 2011;Watkins et al, 2013;Yin et al, 2017;Welsbie et al, 2019;Li et al, 2021), or microglial and astrocyte responses to injury (Chen et al, 2018;Wlaschin et al, 2018). In mice with a DLK gene-trap, downstream responses were reduced after sciatic nerve injury, and explant cultures of DRG grew shorter axons than controls (Itoh et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

The MAP3Ks DLK and LZK Direct Diverse Responses to Axon Damage in Zebrafish Peripheral Neurons

et al. 2022

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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.

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

Cited by 13 publications

References 76 publications

A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord

Transcriptomes of Injured Lamprey Axon Tips: Single-Cell RNA-Seq Suggests Differential Involvement of MAPK Signaling Pathways in Axon Retraction and Regeneration after Spinal Cord Injury

The MAP3Ks DLK and LZK Direct Diverse Responses to Axon Damage in Zebrafish Peripheral Neurons

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