Highwire Restrains Synaptic Growth by Attenuating a MAP Kinase Signal

Collins, Catherine A.; Wairkar, Yogesh P.; Johnson, Sylvia L.; DiAntonio, Aaron

doi:10.1016/j.neuron.2006.05.026

Cited by 323 publications

(577 citation statements)

References 52 publications

Supporting

Mentioning

543

Contrasting

Unclassified

Order By: Relevance

“…3A), indicating that increased translation and/or decreased protein turnover must underlie the mechanism of DLK up-regulation. In Drosophila melanogaster, Wallenda/DLK is posttranslationally regulated by the E3 ubiquitin ligase Highwire (36,37). However, mice with a brain-specific conditional knockout of Phr1 (Pam/Highwire/RPM-1 1, the vertebrate Highwire homolog) show no difference in the overall brain levels of DLK protein (38).…”

Section: Axonal Injury Up-regulates Dlk Expression Through a Posttranmentioning

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.

Self Cite

239

307

View full text Add to dashboard Cite

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...

show abstract

Section: Axonal Injury Up-regulates Dlk Expression Through a Posttranmentioning

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.

Self Cite

239

307

View full text Add to dashboard Cite

show abstract

“…Inactivation of the DLK-1 pathway suppresses RPM-1 loss of function phenotypes, whereas overexpression of DLK-1 causes synaptic aberrations resembling RPM-1 mutations (Nakata et al 2005). In Drosophila, the downstream target of highwire is a MAPKKK encoded by a gene called wallenda (Collins et al 2006). Although the downstream effectors of DLK-1 and the wallenda proteins are different, attenuation of the signaling mediated by these proteins inhibits synaptic growth in similar ways (Fulga and Van Vactor 2008).…”

Section: E3smentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

131

123

View full text Add to dashboard Cite

Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

show abstract

“…9) (Ikeda et al, 2001). In Drosophila, the protein wallenda is homologous to vertebrate DLK and LZK, and overexpression of wallenda in Drosophila results in an increase in synaptic formation due to increased JNK-Fos activation (Collins et al, 2006). Further understanding of signaling through DLK and LZK will increase our knowledge of these MAP3Ks contribution to neuronal development.…”

Section: Dlk and Lzk (Omim#*600447 *604915)mentioning

confidence: 99%