Programmed Cell Death DuringCaenorhabditis elegansDevelopment

Abstract

Programmed cell death is an integral component of Caenorhabditis elegans development. Genetic and reverse genetic studies in C. elegans have led to the identification of many genes and conserved cell death pathways that are important for the specification of which cells should live or die, the activation of the suicide program, and the dismantling and removal of dying cells. Molecular, cell biological, and biochemical studies have revealed the underlying mechanisms that control these three phases of programmed cell death. In particular, the interplay of transcriptional regulatory cascades and networks involving multiple transcriptional regulators is crucial in activating the expression of the key death-inducing gene egl-1 and, in some cases, the ced-3 gene in cells destined to die. A protein interaction cascade involving EGL-1, CED-9, CED-4, and CED-3 results in the activation of the key cell death protease CED-3, which is tightly controlled by multiple positive and negative regulators. The activation of the CED-3 caspase then initiates the cell disassembly process by cleaving and activating or inactivating crucial CED-3 substrates; leading to activation of multiple cell death execution events, including nuclear DNA fragmentation, mitochondrial elimination, phosphatidylserine externalization, inactivation of survival signals, and clearance of apoptotic cells. Further studies of programmed cell death in C. elegans will continue to advance our understanding of how programmed cell death is regulated, activated, and executed in general.KEYWORDS Caenorhabditis elegans; activation phase; execution phase; programmed cell death; specification phase; WormBook

Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors

“…C. elegans is an excellent model as apoptotic machinery is highly conserved, but lacks expression of either COX isoform (Lesa et al, 2003; Yuan et al, 1993). We performed cell death analysis using the ced-1(e1735) mutant that is defective in cell corpse engulfment process, which sensitized the cell death assay (Conradt et al, 2016; Nakagawa et al, 2010). With 100 μM fenbufen or indoprofen treatment, we observed statistically significant decrease of cell death starting at 2-fold, whereas 0.5% DMSO did not cause any effect (Figure 5B, Figure S4C).…”

miRNAs cooperate in apoptosis regulation during C. elegans development

“…It is well established that EGL-1 activity is controlled at the transcriptional level (for review, see Nehme and Conradt 2008;Conradt et al 2016), and it has been proposed that transcription factors that are critical for differentiation in a particular lineage may be used in that same lineage to also cause transcriptional up-regulation of egl-1 in the daughter that is programmed to die. For example, in the ABalappaap lineage, the COE transcription factor UNC-3 of C. elegans is required for both the complete differentiation of the daughter programmed to survive (ABalappaapa) and the death of the daughter that is programmed to die [ABalappaapp (X)] (Wang et al 2015).…”

“…In addition, transcriptional reporters have demonstrated that the egl-1 gene is most highly expressed in cells programmed to die (Conradt and Horvitz 1999;Thellmann et al 2003;Liu et al 2006;Potts et al 2009;Hirose et al 2010;Winn et al 2011;Hirose and Horvitz 2013;Jiang and Wu 2014;Wang et al 2015). Furthermore, genetic studies revealed that egl-1 transcription is governed by lineage-specific transcription factors, which control the death of individual, often bilaterally symmetric, cells (for review, see Conradt et al 2016). For example, a heterodimer of the basic helix-loop-helix (bHLH) transcription factors HLH-2 Daughterless and HLH-3 Achaete-scute (HLH-2/HLH-3) binds to a specific cis-acting element of the egl-1 locus [referred to as B(egl-1)] and is required for egl-1 transcriptional activation in the left and right NSM sister cells, which are programmed to die (Thellmann et al 2003).…”

Programmed cell clearance: From nematodes to humans

“…The nematode C. elegans is a well-established model organism to study cell death [23]. The origin and fate of each cell has been described in detail and several key modulators of the cell clearance process have been shown to have homologs in mammals [24].…”