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High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death

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 identif...

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Autores principales: Zhang, Jianmin, Wang, Huaishan, Sherbini, Omar, Ling-lin Pai, Emily, Kang, Sung-Ung, Kwon, Ji-Sun, Yang, Jia, He, Wei, Wang, Hong, Eacker, Stephen M., Chi, Zhikai, Mao, Xiaobo, Xu, Jinchong, Jiang, Haisong, Andrabi, Shaida A., Dawson, Ted M., Dawson, Valina L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075945/
https://www.ncbi.nlm.nih.gov/pubmed/27822494
http://dx.doi.org/10.1523/ENEURO.0185-16.2016
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author Zhang, Jianmin
Wang, Huaishan
Sherbini, Omar
Ling-lin Pai, Emily
Kang, Sung-Ung
Kwon, Ji-Sun
Yang, Jia
He, Wei
Wang, Hong
Eacker, Stephen M.
Chi, Zhikai
Mao, Xiaobo
Xu, Jinchong
Jiang, Haisong
Andrabi, Shaida A.
Dawson, Ted M.
Dawson, Valina L.
author_facet Zhang, Jianmin
Wang, Huaishan
Sherbini, Omar
Ling-lin Pai, Emily
Kang, Sung-Ung
Kwon, Ji-Sun
Yang, Jia
He, Wei
Wang, Hong
Eacker, Stephen M.
Chi, Zhikai
Mao, Xiaobo
Xu, Jinchong
Jiang, Haisong
Andrabi, Shaida A.
Dawson, Ted M.
Dawson, Valina L.
author_sort Zhang, Jianmin
collection PubMed
description 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.
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spelling pubmed-50759452016-11-07 High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death Zhang, Jianmin Wang, Huaishan Sherbini, Omar Ling-lin Pai, Emily Kang, Sung-Ung Kwon, Ji-Sun Yang, Jia He, Wei Wang, Hong Eacker, Stephen M. Chi, Zhikai Mao, Xiaobo Xu, Jinchong Jiang, Haisong Andrabi, Shaida A. Dawson, Ted M. Dawson, Valina L. eNeuro New Research 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. Society for Neuroscience 2016-10-24 /pmc/articles/PMC5075945/ /pubmed/27822494 http://dx.doi.org/10.1523/ENEURO.0185-16.2016 Text en Copyright © 2016 Zhang et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle New Research
Zhang, Jianmin
Wang, Huaishan
Sherbini, Omar
Ling-lin Pai, Emily
Kang, Sung-Ung
Kwon, Ji-Sun
Yang, Jia
He, Wei
Wang, Hong
Eacker, Stephen M.
Chi, Zhikai
Mao, Xiaobo
Xu, Jinchong
Jiang, Haisong
Andrabi, Shaida A.
Dawson, Ted M.
Dawson, Valina L.
High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title_full High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title_fullStr High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title_full_unstemmed High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title_short High-Content Genome-Wide RNAi Screen Reveals CCR3 as a Key Mediator of Neuronal Cell Death
title_sort high-content genome-wide rnai screen reveals ccr3 as a key mediator of neuronal cell death
topic New Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075945/
https://www.ncbi.nlm.nih.gov/pubmed/27822494
http://dx.doi.org/10.1523/ENEURO.0185-16.2016
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