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A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors

Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely i...

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Detalles Bibliográficos
Autores principales: Schwendeman, Andrew R., Shaham, Shai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055323/
https://www.ncbi.nlm.nih.gov/pubmed/27716809
http://dx.doi.org/10.1371/journal.pone.0164595
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author Schwendeman, Andrew R.
Shaham, Shai
author_facet Schwendeman, Andrew R.
Shaham, Shai
author_sort Schwendeman, Andrew R.
collection PubMed
description Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely important. Recent work in the nematode Caenorhabditis elegans identified a non-apoptotic cell death form mediating the demise of the male-specific linker cell. This cell death process (LCD, linker cell-type death) is morphologically conserved, and its molecular effectors also mediate axon degeneration in mammals and Drosophila. To develop reagents to manipulate LCD, we established a simple high-throughput screening protocol for interrogating the effects of small molecules on C. elegans linker cell death in vivo. From 23,797 compounds assayed, 11 reproducibly block linker cell death onset. Of these, five induce animal lethality, and six promote a reversible developmental delay. These results provide proof-of principle validation of our screening protocol, demonstrate that developmental progression is required for linker cell death, and suggest that larger scale screens may identify LCD-specific small-molecule regulators that target the LCD execution machinery.
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spelling pubmed-50553232016-10-27 A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors Schwendeman, Andrew R. Shaham, Shai PLoS One Research Article Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely important. Recent work in the nematode Caenorhabditis elegans identified a non-apoptotic cell death form mediating the demise of the male-specific linker cell. This cell death process (LCD, linker cell-type death) is morphologically conserved, and its molecular effectors also mediate axon degeneration in mammals and Drosophila. To develop reagents to manipulate LCD, we established a simple high-throughput screening protocol for interrogating the effects of small molecules on C. elegans linker cell death in vivo. From 23,797 compounds assayed, 11 reproducibly block linker cell death onset. Of these, five induce animal lethality, and six promote a reversible developmental delay. These results provide proof-of principle validation of our screening protocol, demonstrate that developmental progression is required for linker cell death, and suggest that larger scale screens may identify LCD-specific small-molecule regulators that target the LCD execution machinery. Public Library of Science 2016-10-07 /pmc/articles/PMC5055323/ /pubmed/27716809 http://dx.doi.org/10.1371/journal.pone.0164595 Text en © 2016 Schwendeman, Shaham http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Schwendeman, Andrew R.
Shaham, Shai
A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title_full A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title_fullStr A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title_full_unstemmed A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title_short A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors
title_sort high-throughput small molecule screen for c. elegans linker cell death inhibitors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055323/
https://www.ncbi.nlm.nih.gov/pubmed/27716809
http://dx.doi.org/10.1371/journal.pone.0164595
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