title: A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors.
abstract: 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.
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, New York, United States of America.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Schwendeman
authors.affiliation: Laboratory of Developmental Genetics, The Rockefeller University, New York, New York, United States of America.
authors.forename: Shai
authors.initials: S
authors.lastname: Shaham
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects* / Q000235:genetics; D004330:Drosophila / Q000187:drug effects; D008297:Male; D008322:Mammals / Q000235:genetics; D009154:Mutation / Q000187:drug effects; D009410:Nerve Degeneration / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D054852:Small Molecule Libraries