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...

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Veröffentlicht in:Neuron (Cambridge, Mass.) Jg. 94; H. 6; S. 1142
Hauptverfasser: 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
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 21.06.2017
Schlagworte:
Animals
Cell Death
Cell Survival - drug effects
Cell Survival - genetics
Disease Models, Animal
Flow Cytometry
Human Embryonic Stem Cells - cytology
Humans
Immunoprecipitation
MAP Kinase Kinase Kinases - genetics
MAP Kinase Kinase Kinases - metabolism
Mice
Mice, Knockout
Neurites
Neurons
Optic Nerve Injuries - genetics
Optic Nerve Injuries - pathology
Piperazines - pharmacology
Protein Kinase Inhibitors - pharmacology
Real-Time Polymerase Chain Reaction
Retina - cytology
Retinal Ganglion Cells - drug effects
Retinal Ganglion Cells - metabolism
Retinal Ganglion Cells - pathology
LZK (leucine zipper kinase)
Neuroprotection
RGC (retinal ganglion cell)
RNAi screen
glaucoma
cell death signaling
DLK (dual leucine zipper kinase)
ISSN:1097-4199, 1097-4199
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1097-4199
1097-4199
DOI:10.1016/j.neuron.2017.06.008