High-content genome-wide rnai screen reveals ccr3 as a key mediator of neuronal cell death

Jianmin Zhang, Huaishan Wang, Omar Sherbini, Emily Ling Lin Pai, SungUng Kang, Ji Sun Kwon, Jia Yang, Wei He, Hong Wang, Stephen Eacker, Zhikai Chi, Xiaobo Mao, Jinchong Xu, Haisong Jiang, Shaida A. Andrabi, Ted M Dawson, Valina Dawson

Research output: Contribution to journalArticle

Abstract

Neuronal loss caused by ischemic injury, trauma, or disease can lead to devastating consequences for the individual. With the goal of limiting neuronal loss, a number of cell death pathways have been studied, but there may be additional contributors to neuronal death that are yet unknown. To identify previously unknown cell death mediators, we performed a high-content genome-wide screening of short, interfering RNA (siRNA) with an siRNA library in murine neural stem cells after exposure to N-methyl-N-nitroso-N=-nitroguanidine (MNNG), which leads to DNA damage and cell death. Eighty genes were identified as key mediators for cell death. Among them, 14 are known cell death mediators and 66 have not previously been linked to cell death pathways. Using an integrated approach with functional and bioinformatics analysis, we provide possible molecular networks, interconnected pathways, and/or protein complexes that may participate in cell death. Of the 66 genes, we selected CCR3 for further evaluation and found that CCR3 is a mediator of neuronal injury. CCR3 inhibition or deletion protects murine cortical cultures from oxygen-glucose deprivation-induced cell death, and CCR3 deletion in mice provides protection from ischemia in vivo. Taken together, our findings suggest that CCR3 is a previously unknown mediator of cell death. Future identification of the neural cell death network in which CCR3 participates will enhance our understanding of the molecular mechanisms of neural cell death.

Original languageEnglish (US)
Article numbere0185-16.2016
JournaleNeuro
Volume3
Issue number5
DOIs
StatePublished - Sep 1 2016

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Cell Death
Genome
Small Interfering RNA
Wounds and Injuries
Neural Stem Cells
Computational Biology
Genes
DNA Damage
Ischemia
Oxygen
Glucose

Keywords

  • Excitotoxicity
  • Ischemia
  • Library screen
  • Stroke

ASJC Scopus subject areas

  • Medicine(all)

Cite this

High-content genome-wide rnai screen reveals ccr3 as a key mediator of neuronal cell death. / Zhang, Jianmin; Wang, Huaishan; Sherbini, Omar; Pai, Emily Ling Lin; Kang, SungUng; Kwon, Ji Sun; Yang, Jia; He, Wei; Wang, Hong; Eacker, Stephen; Chi, Zhikai; Mao, Xiaobo; Xu, Jinchong; Jiang, Haisong; Andrabi, Shaida A.; Dawson, Ted M; Dawson, Valina.

In: eNeuro, Vol. 3, No. 5, e0185-16.2016, 01.09.2016.

Research output: Contribution to journalArticle

Zhang, J, Wang, H, Sherbini, O, Pai, ELL, Kang, S, Kwon, JS, Yang, J, He, W, Wang, H, Eacker, S, Chi, Z, Mao, X, Xu, J, Jiang, H, Andrabi, SA, Dawson, TM & Dawson, V 2016, 'High-content genome-wide rnai screen reveals ccr3 as a key mediator of neuronal cell death', eNeuro, vol. 3, no. 5, e0185-16.2016. https://doi.org/10.1523/ENEURO.0185-16.2016
Zhang, Jianmin ; Wang, Huaishan ; Sherbini, Omar ; Pai, Emily Ling Lin ; Kang, SungUng ; Kwon, Ji Sun ; Yang, Jia ; He, Wei ; Wang, Hong ; Eacker, Stephen ; Chi, Zhikai ; Mao, Xiaobo ; Xu, Jinchong ; Jiang, Haisong ; Andrabi, Shaida A. ; Dawson, Ted M ; Dawson, Valina. / High-content genome-wide rnai screen reveals ccr3 as a key mediator of neuronal cell death. In: eNeuro. 2016 ; Vol. 3, No. 5.
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