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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Podrobná bibliografie
Vydáno v:	Neuron (Cambridge, Mass.) Ročník 94; číslo 6; s. 1142
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 21.06.2017
Témata:	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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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4199 1097-4199
DOI:	10.1016/j.neuron.2017.06.008