Changes in Gene Expression in Experimental Glaucoma and Optic Nerve Transection: The Equilibrium between Protective and Detrimental Mechanisms

Yang, Zhiyong; Quigley, Harry A.; Pease, Mary Ellen; Yang, Yanqin; Jiao, Qian; Valenta, Danielle; Zack, Donald J.

doi:10.1167/iovs.07-0542

Cited by 155 publications

(169 citation statements)

References 50 publications

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“…Acute isolation of RNA from whole retina avoids stimulation of a stress response during retinal dissociation yet still detects many of the expression changes found in purified RGCs after nerve crush (1,22). In agreement with these previous studies, optic nerve injury in DLK lox :Cre neg controls induced widespread changes in the retinal expression profile, with 342 genes up-or down-regulated (P < 0.01; Fig.…”

Section: G K O and R)supporting

confidence: 90%

“…For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3).…”

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confidence: 99%

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

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

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

290

427

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The cell intrinsic factors that determine whether a neuron regenerates or undergoes apoptosis in response to axonal injury are not well defined. Here we show that the mixed-lineage dual leucine zipper kinase (DLK) is an essential upstream mediator of both of these divergent outcomes in the same cell type. Optic nerve crush injury leads to rapid elevation of DLK protein, first in the axons of retinal ganglion cells (RGCs) and then in their cell bodies. DLK is required for the majority of gene expression changes in RGCs initiated by injury, including induction of both proapoptotic and regeneration-associated genes. Deletion of DLK in retina results in robust and sustained protection of RGCs from degeneration after optic nerve injury. Despite this improved survival, the number of axons that regrow beyond the injury site is substantially reduced, even when the tumor suppressor phosphatase and tensin homolog (PTEN) is deleted to enhance intrinsic growth potential. These findings demonstrate that these seemingly contradictory responses to injury are mechanistically coupled through a DLK-based damage detection mechanism.A xonal damage results in significant neuronal cell death and axon degeneration, often leading to permanent functional deficits. For example, optic nerve crush rapidly induces a stress response in retinal ganglion cells (RGCs) that includes profound alterations in gene expression patterns (1) and ultimately leads to apoptosis of these neurons (2). As axon injury may occur a significant distance from the cell body, it has been proposed that retrograde molecular motors play a critical role in conveying damage signals to the nucleus, allowing the cell to respond to damage (3). Attenuation of this transport mechanism has been shown to reduce degeneration, suggesting that the ability of the nucleus to detect an insult is an essential component of the injury response (4).Recent data suggest that dual leucine zipper kinase (DLK) is an essential component of the neuronal response to axon damage. DLK protein is present in axons, and protein levels are increased in response to axonal injury (5). Loss of DLK has been shown to protect distal axons from Wallerian degeneration (6) and to abrogate stress-induced retrograde c-Jun N-terminal kinase (JNK) signaling through interaction with the scaffolding protein JNK-interacting protein 3 (JIP3) (7-9). In many instances, injury-induced JNK activation in neurons results in apoptosis through phosphorylation of activator protein 1 (AP-1) transcription factors such as c-Jun, which initiates a proapoptotic gene expression program (10, 11). Consistent with this, genetic deletion of JNK2 and/or JNK3 is sufficient to protect neurons from degeneration in a range of CNS injury models, including axotomy (12-14), although the role of DLK in these contexts is not known.In contrast, DLK has been shown to regulate axon regeneration after axonal injury in adult peripheral nerves (9) and invertebrate systems (5, 15). The mechanism underlying the divergence between these apoptotic and reg...

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Section: G K O and R)supporting

confidence: 90%

mentioning

confidence: 99%

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

Watkins¹,

Wang²,

Huntwork‐Rodriguez³

et al. 2013

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

290

427

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show abstract

“…Axonal injury typically reduces the expression of many RGCspecific markers secondary to the down-regulation of the Brn3 family of transcription factors (30). However, in RGCs with DLK knockdown, Brn3 continued to be expressed (Fig.…”

Section: Dlk Down-regulation Promotes Long-term Survival and Function Ofmentioning

confidence: 97%

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.

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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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“…The putative mechanisms of how this occurs are legion. They include pressureinduced injury of the ONH, leading to retinal gene expression alterations, 44,141 astrocyte response to changes in IOP, 142 oxidative stress, mitochondrial dysfunction, neurotrophic factors, 143,144 and autoimmunity. 145 Identifying validated genetic mutations that are replicated in multiple populations perhaps offers the best hope of correct identification of the most important pathways, which result in RGC death.…”

Section: Therapeutic Implications Of Genetics For Poagmentioning

confidence: 99%

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

Gemenetzi

Yang

Lotery

2011

Eye

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Changes in Gene Expression in Experimental Glaucoma and Optic Nerve Transection: The Equilibrium between Protective and Detrimental Mechanisms

Cited by 155 publications

References 50 publications

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

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

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

Current concepts on primary open-angle glaucoma genetics: a contribution to disease pathophysiology and future treatment

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