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Enhanced Functional Genomic Screening Identifies Novel Mediators of Dual Leucine Zipper Kinase-Dependent Injury Signaling in Neurons.
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.
Afiliação
  • Welsbie DS; 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.
  • Mitchell KL; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Jaskula-Ranga V; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Sluch VM; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Yang Z; 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.
  • Kim J; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Buehler E; National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
  • Patel A; 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.
  • Martin SE; National Center for Advancing Translational Sciences, NIH, Bethesda, MD 20892, USA.
  • Zhang PW; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Ge Y; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Duan Y; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Fuller J; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Kim BJ; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Hamed E; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Chamling X; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Lei L; Department of Biology, University of New England, Biddeford, ME 04005, USA.
  • Fraser IDC; Signaling Systems Unit, Laboratory of Systems Biology, National Institute for Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
  • Ronai ZA; Signal Transduction Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
  • Berlinicke CA; Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
  • Zack DJ; 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
Neuron ; 94(6): 1142-1154.e6, 2017 Jun 21.
Article em En | MEDLINE | ID: mdl-28641113
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Ganglionares da Retina / Sobrevivência Celular / Traumatismos do Nervo Óptico / MAP Quinase Quinase Quinases Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Células Ganglionares da Retina / Sobrevivência Celular / Traumatismos do Nervo Óptico / MAP Quinase Quinase Quinases Tipo de estudo: Diagnostic_studies / Prognostic_studies / Screening_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2017 Tipo de documento: Article