DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Watkins, Trent A.; Wang, Bei; Huntwork‐Rodriguez, Sarah; Yang, Jing; Jiang, Zhiyu; Eastham-Anderson, Jeffrey; Modrušan, Zora; Kaminker, Joshua S.; Tessier‐Lavigne, Marc; Lewcock, Joseph W.

doi:10.1073/pnas.1211074110

Cited by 291 publications

(473 citation statements)

References 42 publications

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“…The work by Watkins et al suggests that DLK is also involved in the regeneration of optic nerve axons after optic nerve crush (49). It remains to be determined whether DLK is involved in glaucoma-related axonal degeneration.…”

Section: Discussionmentioning

confidence: 99%

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Welsbie

Yang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

237

307

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Glaucoma, a major cause of blindness worldwide, is a neurodegenerative optic neuropathy in which vision loss is caused by loss of retinal ganglion cells (RGCs). To better define the pathways mediating RGC death and identify targets for the development of neuroprotective drugs, we developed a high-throughput RNA interference screen with primary RGCs and used it to screen the full mouse kinome. The screen identified dual leucine zipper kinase (DLK) as a key neuroprotective target in RGCs. In cultured RGCs, DLK signaling is both necessary and sufficient for cell death. DLK undergoes robust posttranscriptional up-regulation in response to axonal injury in vitro and in vivo. Using a conditional knockout approach, we confirmed that DLK is required for RGC JNK activation and cell death in a rodent model of optic neuropathy. In addition, tozasertib, a small molecule protein kinase inhibitor with activity against DLK, protects RGCs from cell death in rodent glaucoma and traumatic optic neuropathy models. Together, our results establish a previously undescribed drug/drug target combination in glaucoma, identify an early marker of RGC injury, and provide a starting point for the development of more specific neuroprotective DLK inhibitors for the treatment of glaucoma, nonglaucomatous forms of optic neuropathy, and perhaps other CNS neurodegenerations.G laucoma is the leading cause of irreversible blindness worldwide (1). It is a neurodegenerative disease in which vision loss is caused by the axonal injury and death of retinal ganglion cells (RGCs) (2), the projection neurons that process and transmit vision from the retina to the brain. Current therapies (i.e., surgery, laser, and eye drops) all act by lowering intraocular pressure (IOP). However, pressure reduction can be difficult to achieve, and even with significant pressure lowering, RGC loss can continue. Efforts have therefore been made to develop neuroprotective agents that would complement IOP-lowering therapies by directly inhibiting the RGC cell death process (3, 4). However, no neuroprotective agent has yet been approved for clinical use.Protein kinases provide attractive targets for the development of neuroprotective agents. A number of kinases, including cyclindependent kinases, death-associated protein kinases, JNK1-3, MAPKs, and glycogen synthase kinase-3β, are involved in neuronal cell death (5-12). An additional attraction is that protein kinases are readily druggable. The pharmacology and medicinal chemistry of kinase inhibitors are well-developed, with kinases now being the most important class of drug targets after G protein-coupled receptors (13). Although the primary clinical use of kinase inhibitors continues to be as antineoplastic agents, increasing attention is being paid to their use in other areas (14,15).To identify, in a comprehensive and unbiased manner, kinases that could serve as targets for neuroprotective glaucoma therapy, we screened the entire mouse kinome for kinases whose inhibition promotes RGC survival. For this screen, we develope...

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Section: Discussionmentioning

confidence: 99%

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Welsbie

Yang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

237

307

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“…DLK activates transcription of both apoptotic and regenerative genes in mammalian neurons (37). In the tubulin mutants, overextension of the primary neurite paralleled elimination of the synaptic branch.…”

Section: Discussionmentioning

confidence: 99%

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

Chen

Lee

Liao

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.axon retraction | axon regeneration | Rho signaling | DLK | microtubules T he connectivity of neuronal circuits is established first through a highly dynamic phase of addition or elimination of axon branches and synapses, followed by a maintenance phase in which axon and dendritic branches show remarkable stability during the lifetime of postmitotic neurons. Disruption of neuronal circuits elicits remodeling responses that eliminate dysfunctional neurites or synapses and may stimulate the regeneration of injured axons. To enable these remodeling responses, neurons need to sense the insults and signal to the effectors that execute either retraction or extension of the neuronal structures. A well-studied effector for neuronal remodeling is the dual leucine-zipper kinase DLK, whose activation is required for both Wallerian degeneration and axon regeneration after injury, depending on the species and contexts examined (1-4). The DLK protein level is primarily controlled by proteasomal turnover that depends on Highwire/RPM-1, a ubiquitin E3 ligase that targets DLK for degradation (5). The Caenorhabditis elegans DLK, DLK-1, is activated by calcium influx during axon injury that triggers the dissociation of an inhibitory DLK-1 isoform (6). A recent report suggests that C. elegans dlk-1 is a direct transcriptional target of the FoxO transcription factor DAF-16 in axon regeneration (7). Despite the extensive characterization of DLK, little is known about how neurons sense various insults and translate them into DLK-activating signals.Microtubules are a major neuronal cytoskeleton component that shapes and maintains synapses and axons (8, 9). Mutations in Ankyrin and α-spectrin, two membrane skeletal proteins that organize microtubules at presynaptic sites, triggered synaptic bouton shrinkage and axon terminal retraction at Drosophila neuromuscular junction, highlighting the central importance of microtubules in the maintenance of synapses and axon b...

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“…Recent work has identified the neuron-enriched kinase dual leucine zipper kinase (DLK) as an integrator of many types of neuronal injury, suggesting that this kinase may be a conserved driver of neuronal degeneration (3)(4)(5)(6)(7)(8). DLK is required for initiation of the c-Jun N-terminal kinase (JNK)-dependent stress response in neurons and broadly regulates injury-induced transcriptional changes (3,5).…”

Section: Introductionmentioning

confidence: 99%

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

Pichon¹,

Meilandt²,

Domínguez³

et al. 2017

Sci. Transl. Med.

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DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury

Cited by 291 publications

References 42 publications

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death

RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

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