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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.<\/jats:p>","DOI":"10.1073\/pnas.1211284110","type":"journal-article","created":{"date-parts":[[2013,2,20]],"date-time":"2013-02-20T01:56:59Z","timestamp":1361325419000},"page":"4045-4050","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":252,"title":["Functional genomic screening identifies dual leucine zipper kinase as a key mediator of retinal ganglion cell death"],"prefix":"10.1073","volume":"110","author":[{"given":"Derek S.","family":"Welsbie","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"},{"name":"Glaucoma Center of Excellence, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"},{"name":"The Key Laboratory of Pathobiology, Ministry of Education, Changchun 130000, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"},{"name":"Department of Ophthalmology, Harbin Medical University, The Second Affiliated Hospital, Harbin, Heilongjiang 150086, China;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Martin","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health (NIH), Bethesda, MD 20892;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia A.","family":"Berlinicke","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Laszlo","family":"Hackler","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Fuller","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287;"},{"name":"Center for Nanomedicine at the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21231;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-hui","family":"Cao","sequence":"additional","affiliation":[{"name":"Solomon H. 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