The requirement for <i>Phr1</i> in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons

Bloom, A. Joseph; Miller, Bradley R.; Sanes, Joshua R.; DiAntonio, Aaron

doi:10.1101/gad.1592107

Cited by 131 publications

(163 citation statements)

References 41 publications

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“…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). Furthermore, knockdown of PHR1 in our RGC cultures did not affect DLK levels, suggesting that either PHR1 regulates DLK levels only in certain settings/ neuronal subtypes or that DLK levels in vertebrates are regulated by another as-yet-unidentified protein.…”

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.

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229

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: 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.

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229

307

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“…Cite this article as Cold Spring Harb Perspect Biol 2010;2:a001925 contexts during neuronal development, including: axonal pruning (Watts et al 2004); various aspects of axon guidance (Campbell and Holt 2001;DiAntonio et al 2001;Bloom et al 2007;Lewcock et al 2007); synapse formation (DiAntonio et al 2001;Nakata et al 2005); synapse maintenance (DiAntonio et al 2001;Aravamudan and Broadie 2003;Ehlers 2003;Speese et al 2003); and synapse elimination (Ding et al 2007) (reviewed in DiAntonio and Hicke 2004). Acute treatment with the proteosome inhibitor lactacystin blocks axogenesis in dorsal root ganglion cells (Klimaschewski et al 2006).…”

Section: Initiating and Growing An Axonmentioning

confidence: 99%

Initiating and Growing an Axon

Polleux¹,

Snider²

2010

Cold Spring Harbor Perspectives in Biology

161

127

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The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.

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“…The PHR proteins regulate various events in neuronal development, including synapse formation (3)(4)(5)(6), axon guidance (6 -9), and axon termination (7, 10 -13). In C. elegans, defects in neuronal development caused by loss of RPM-1 result in mild defects in locomotion and severe defects in short-term learning (14).…”

mentioning

confidence: 99%

Defining Minimal Binding Regions in Regulator of Presynaptic Morphology 1 (RPM-1) Using Caenorhabditis elegans Neurons Reveals Differential Signaling Complexes

Baker

Grill

2017

Journal of Biological Chemistry

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The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons

Cited by 131 publications

References 41 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

Initiating and Growing an Axon

Defining Minimal Binding Regions in Regulator of Presynaptic Morphology 1 (RPM-1) Using Caenorhabditis elegans Neurons Reveals Differential Signaling Complexes

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