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Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons

Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arra... Full description

Journal Title: Neuron (Cambridge Mass.), 2017-06-21, Vol.94 (6), p.1142-1154.e6
Main Author: Welsbie, Derek S
Other Authors: Mitchell, Katherine L , Jaskula-Ranga, Vinod , Sluch, Valentin M , Yang, Zhiyong , Kim, Jessica , Buehler, Eugen , Patel, Amit , Martin, Scott E , Zhang, Ping-Wu , Ge, Yan , Duan, Yukan , Fuller, John , Kim, Byung-Jin , Hamed, Eman , Chamling, Xitiz , Lei, Lei , Fraser, Iain D.C , Ronai, Ze’ev A , Berlinicke, Cynthia A , Zack, Donald J
Format: Electronic Article Electronic Article
Language: English
Subjects:
RNA
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/28641113
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title: Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons
format: Article
creator:
  • Welsbie, Derek S
  • Mitchell, Katherine L
  • Jaskula-Ranga, Vinod
  • Sluch, Valentin M
  • Yang, Zhiyong
  • Kim, Jessica
  • Buehler, Eugen
  • Patel, Amit
  • Martin, Scott E
  • Zhang, Ping-Wu
  • Ge, Yan
  • Duan, Yukan
  • Fuller, John
  • Kim, Byung-Jin
  • Hamed, Eman
  • Chamling, Xitiz
  • Lei, Lei
  • Fraser, Iain D.C
  • Ronai, Ze’ev A
  • Berlinicke, Cynthia A
  • Zack, Donald J
subjects:
  • Activating transcription factor 2
  • Amino acids
  • Analysis
  • Animals
  • Apoptosis
  • Article
  • Cell activation
  • Cell Death
  • cell death signaling
  • Cell Survival - drug effects
  • Cell Survival - genetics
  • Cellular signal transduction
  • Disease
  • Disease Models, Animal
  • DLK (dual leucine zipper kinase)
  • DNA binding proteins
  • Drug approval
  • Flow Cytometry
  • Gene expression
  • Genetic screening
  • genetic structures
  • Genomes
  • Genomics
  • Glaucoma
  • Human Embryonic Stem Cells - cytology
  • Humans
  • Immunoprecipitation
  • Kinases
  • Leucine
  • Leucine zipper proteins
  • Libraries
  • LZK (leucine zipper kinase)
  • MAP Kinase Kinase Kinases - genetics
  • MAP Kinase Kinase Kinases - metabolism
  • Medical colleges
  • Medical screening
  • Mice
  • Mice, Knockout
  • Nervous system diseases
  • Neurites
  • Neurodegenerative diseases
  • Neurological diseases
  • Neurons
  • Neuroprotection
  • Neurosciences
  • Ophthalmology
  • Optic nerve
  • Optic Nerve Injuries - genetics
  • Optic Nerve Injuries - pathology
  • Piperazines - pharmacology
  • Prevention
  • Protein Kinase Inhibitors - pharmacology
  • Proteins
  • Real-Time Polymerase Chain Reaction
  • Research institutes
  • Retina
  • Retina - cytology
  • Retinal ganglion cells
  • Retinal Ganglion Cells - drug effects
  • Retinal Ganglion Cells - metabolism
  • Retinal Ganglion Cells - pathology
  • RGC (retinal ganglion cell)
  • RNA
  • RNAi screen
  • sense organs
  • Signal transduction
  • siRNA
  • Stem cells
  • Transcription factors
ispartof: Neuron (Cambridge, Mass.), 2017-06-21, Vol.94 (6), p.1142-1154.e6
description: Dual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. •Arrayed, whole-genome siRNA screening identifies RGC cell death mediators•LZK cooperates with DLK to promote RGC cell death in response to axon injury•FDA-approved inhibitor of DLK/LZK prevents human RGC cell death•DLK/LZK-mediated cell death involves SOX11, JUN, ATF2, and MEF2A Welsbie et al. use high-throughput whole-genome siRNA-based screening in primary retinal ganglion cells to identify novel pathway members of DLK-mediated axon injury signaling, including the related kinase LZK and the transcription factors, MEF2A and SOX11.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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titleEnhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons
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creatorWelsbie, Derek S ; Mitchell, Katherine L ; Jaskula-Ranga, Vinod ; Sluch, Valentin M ; Yang, Zhiyong ; Kim, Jessica ; Buehler, Eugen ; Patel, Amit ; Martin, Scott E ; Zhang, Ping-Wu ; Ge, Yan ; Duan, Yukan ; Fuller, John ; Kim, Byung-Jin ; Hamed, Eman ; Chamling, Xitiz ; Lei, Lei ; Fraser, Iain D.C ; Ronai, Ze’ev A ; Berlinicke, Cynthia A ; Zack, Donald J
creatorcontribWelsbie, Derek S ; Mitchell, Katherine L ; Jaskula-Ranga, Vinod ; Sluch, Valentin M ; Yang, Zhiyong ; Kim, Jessica ; Buehler, Eugen ; Patel, Amit ; Martin, Scott E ; Zhang, Ping-Wu ; Ge, Yan ; Duan, Yukan ; Fuller, John ; Kim, Byung-Jin ; Hamed, Eman ; Chamling, Xitiz ; Lei, Lei ; Fraser, Iain D.C ; Ronai, Ze’ev A ; Berlinicke, Cynthia A ; Zack, Donald J
descriptionDual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. •Arrayed, whole-genome siRNA screening identifies RGC cell death mediators•LZK cooperates with DLK to promote RGC cell death in response to axon injury•FDA-approved inhibitor of DLK/LZK prevents human RGC cell death•DLK/LZK-mediated cell death involves SOX11, JUN, ATF2, and MEF2A Welsbie et al. use high-throughput whole-genome siRNA-based screening in primary retinal ganglion cells to identify novel pathway members of DLK-mediated axon injury signaling, including the related kinase LZK and the transcription factors, MEF2A and SOX11.
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3PMID: 28641113
languageeng
publisherUnited States: Elsevier Inc
subjectActivating transcription factor 2 ; Amino acids ; Analysis ; Animals ; Apoptosis ; Article ; Cell activation ; Cell Death ; cell death signaling ; Cell Survival - drug effects ; Cell Survival - genetics ; Cellular signal transduction ; Disease ; Disease Models, Animal ; DLK (dual leucine zipper kinase) ; DNA binding proteins ; Drug approval ; Flow Cytometry ; Gene expression ; Genetic screening ; genetic structures ; Genomes ; Genomics ; Glaucoma ; Human Embryonic Stem Cells - cytology ; Humans ; Immunoprecipitation ; Kinases ; Leucine ; Leucine zipper proteins ; Libraries ; LZK (leucine zipper kinase) ; MAP Kinase Kinase Kinases - genetics ; MAP Kinase Kinase Kinases - metabolism ; Medical colleges ; Medical screening ; Mice ; Mice, Knockout ; Nervous system diseases ; Neurites ; Neurodegenerative diseases ; Neurological diseases ; Neurons ; Neuroprotection ; Neurosciences ; Ophthalmology ; Optic nerve ; Optic Nerve Injuries - genetics ; Optic Nerve Injuries - pathology ; Piperazines - pharmacology ; Prevention ; Protein Kinase Inhibitors - pharmacology ; Proteins ; Real-Time Polymerase Chain Reaction ; Research institutes ; Retina ; Retina - cytology ; Retinal ganglion cells ; Retinal Ganglion Cells - drug effects ; Retinal Ganglion Cells - metabolism ; Retinal Ganglion Cells - pathology ; RGC (retinal ganglion cell) ; RNA ; RNAi screen ; sense organs ; Signal transduction ; siRNA ; Stem cells ; Transcription factors
ispartofNeuron (Cambridge, Mass.), 2017-06-21, Vol.94 (6), p.1142-1154.e6
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1Mitchell, Katherine L
2Jaskula-Ranga, Vinod
3Sluch, Valentin M
4Yang, Zhiyong
5Kim, Jessica
6Buehler, Eugen
7Patel, Amit
8Martin, Scott E
9Zhang, Ping-Wu
10Ge, Yan
11Duan, Yukan
12Fuller, John
13Kim, Byung-Jin
14Hamed, Eman
15Chamling, Xitiz
16Lei, Lei
17Fraser, Iain D.C
18Ronai, Ze’ev A
19Berlinicke, Cynthia A
20Zack, Donald J
title
0Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons
1Neuron (Cambridge, Mass.)
addtitleNeuron
descriptionDual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. •Arrayed, whole-genome siRNA screening identifies RGC cell death mediators•LZK cooperates with DLK to promote RGC cell death in response to axon injury•FDA-approved inhibitor of DLK/LZK prevents human RGC cell death•DLK/LZK-mediated cell death involves SOX11, JUN, ATF2, and MEF2A Welsbie et al. use high-throughput whole-genome siRNA-based screening in primary retinal ganglion cells to identify novel pathway members of DLK-mediated axon injury signaling, including the related kinase LZK and the transcription factors, MEF2A and SOX11.
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1Amino acids
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4Apoptosis
5Article
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9Cell Survival - drug effects
10Cell Survival - genetics
11Cellular signal transduction
12Disease
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14DLK (dual leucine zipper kinase)
15DNA binding proteins
16Drug approval
17Flow Cytometry
18Gene expression
19Genetic screening
20genetic structures
21Genomes
22Genomics
23Glaucoma
24Human Embryonic Stem Cells - cytology
25Humans
26Immunoprecipitation
27Kinases
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29Leucine zipper proteins
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31LZK (leucine zipper kinase)
32MAP Kinase Kinase Kinases - genetics
33MAP Kinase Kinase Kinases - metabolism
34Medical colleges
35Medical screening
36Mice
37Mice, Knockout
38Nervous system diseases
39Neurites
40Neurodegenerative diseases
41Neurological diseases
42Neurons
43Neuroprotection
44Neurosciences
45Ophthalmology
46Optic nerve
47Optic Nerve Injuries - genetics
48Optic Nerve Injuries - pathology
49Piperazines - pharmacology
50Prevention
51Protein Kinase Inhibitors - pharmacology
52Proteins
53Real-Time Polymerase Chain Reaction
54Research institutes
55Retina
56Retina - cytology
57Retinal ganglion cells
58Retinal Ganglion Cells - drug effects
59Retinal Ganglion Cells - metabolism
60Retinal Ganglion Cells - pathology
61RGC (retinal ganglion cell)
62RNA
63RNAi screen
64sense organs
65Signal transduction
66siRNA
67Stem cells
68Transcription factors
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5Kim, Jessica
6Buehler, Eugen
7Patel, Amit
8Martin, Scott E
9Zhang, Ping-Wu
10Ge, Yan
11Duan, Yukan
12Fuller, John
13Kim, Byung-Jin
14Hamed, Eman
15Chamling, Xitiz
16Lei, Lei
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titleEnhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons
authorWelsbie, Derek S ; Mitchell, Katherine L ; Jaskula-Ranga, Vinod ; Sluch, Valentin M ; Yang, Zhiyong ; Kim, Jessica ; Buehler, Eugen ; Patel, Amit ; Martin, Scott E ; Zhang, Ping-Wu ; Ge, Yan ; Duan, Yukan ; Fuller, John ; Kim, Byung-Jin ; Hamed, Eman ; Chamling, Xitiz ; Lei, Lei ; Fraser, Iain D.C ; Ronai, Ze’ev A ; Berlinicke, Cynthia A ; Zack, Donald J
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1Amino acids
2Analysis
3Animals
4Apoptosis
5Article
6Cell activation
7Cell Death
8cell death signaling
9Cell Survival - drug effects
10Cell Survival - genetics
11Cellular signal transduction
12Disease
13Disease Models, Animal
14DLK (dual leucine zipper kinase)
15DNA binding proteins
16Drug approval
17Flow Cytometry
18Gene expression
19Genetic screening
20genetic structures
21Genomes
22Genomics
23Glaucoma
24Human Embryonic Stem Cells - cytology
25Humans
26Immunoprecipitation
27Kinases
28Leucine
29Leucine zipper proteins
30Libraries
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32MAP Kinase Kinase Kinases - genetics
33MAP Kinase Kinase Kinases - metabolism
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42Neurons
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45Ophthalmology
46Optic nerve
47Optic Nerve Injuries - genetics
48Optic Nerve Injuries - pathology
49Piperazines - pharmacology
50Prevention
51Protein Kinase Inhibitors - pharmacology
52Proteins
53Real-Time Polymerase Chain Reaction
54Research institutes
55Retina
56Retina - cytology
57Retinal ganglion cells
58Retinal Ganglion Cells - drug effects
59Retinal Ganglion Cells - metabolism
60Retinal Ganglion Cells - pathology
61RGC (retinal ganglion cell)
62RNA
63RNAi screen
64sense organs
65Signal transduction
66siRNA
67Stem cells
68Transcription factors
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0Lead Contact
1Present address: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080, USA
abstractDual leucine zipper kinase (DLK) has been implicated in cell death signaling secondary to axonal damage in retinal ganglion cells (RGCs) and other neurons. To better understand the pathway through which DLK acts, we developed enhanced functional genomic screens in primary RGCs, including use of arrayed, whole-genome, small interfering RNA libraries. Explaining why DLK inhibition is only partially protective, we identify leucine zipper kinase (LZK) as cooperating with DLK to activate downstream signaling and cell death in RGCs, including in a mouse model of optic nerve injury, and show that the same pathway is active in human stem cell-derived RGCs. Moreover, we identify four transcription factors, JUN, activating transcription factor 2 (ATF2), myocyte-specific enhancer factor 2A (MEF2A), and SRY-Box 11 (SOX11), as being the major downstream mediators through which DLK/LZK activation leads to RGC cell death. Increased understanding of the DLK pathway has implications for understanding and treating neurodegenerative diseases. •Arrayed, whole-genome siRNA screening identifies RGC cell death mediators•LZK cooperates with DLK to promote RGC cell death in response to axon injury•FDA-approved inhibitor of DLK/LZK prevents human RGC cell death•DLK/LZK-mediated cell death involves SOX11, JUN, ATF2, and MEF2A Welsbie et al. use high-throughput whole-genome siRNA-based screening in primary retinal ganglion cells to identify novel pathway members of DLK-mediated axon injury signaling, including the related kinase LZK and the transcription factors, MEF2A and SOX11.
copUnited States
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pmid28641113
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