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Neuron. 2017 Jun 21;94(6):1142-1154.e6. doi: 10.1016/j.neuron.2017.06.008.

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

Author information

1
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dwelsbie@ucsd.edu.
2
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
3
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Shiley Eye Institute, University of California, San Diego, La Jolla, CA 92093, USA.
4
National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
5
Department of Biology, University of New England, Biddeford, ME 04005, USA.
6
Signaling Systems Unit, Laboratory of Systems Biology, National Institute for Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
7
Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
8
Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Solomon H. Snyder Department of Neuroscience, Department of Molecular Biology and Genetics, Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: donzack@gmail.com.

Abstract

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.

KEYWORDS:

DLK (dual leucine zipper kinase); LZK (leucine zipper kinase); Neuroprotection; RGC (retinal ganglion cell); RNAi screen; cell death signaling; glaucoma

PMID:
28641113
PMCID:
PMC5553555
DOI:
10.1016/j.neuron.2017.06.008
[Indexed for MEDLINE]
Free PMC Article

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