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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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2016
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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. |
format | Online Article Text |
id | pubmed-5055323 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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