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. 2016 Aug;203(4):1533-62.
doi: 10.1534/genetics.115.186247.

Programmed Cell Death During Caenorhabditis elegans Development

Barbara Conradt  1 , Yi-Chun Wu  2 , Ding Xue  3
Affiliations

Programmed Cell Death During Caenorhabditis elegans Development

Barbara Conradt et al. Genetics. 2016 Aug.

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; WormBook; activation phase; execution phase; programmed cell death; specification phase.

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Figures

Figure 1
Figure 1
Nomarski image of an embryo with apoptotic cells. Three cells indicated by arrows underwent programmed cell death in a bean/comma stage embryo and exhibit a refractile, raised-button-like appearance. Bar, 5 μm.
Figure 2
Figure 2
Genes involved in the activation and the execution phases of programmed cell death in C. elegans. Genes involved in two critical phases of programmed cell death, (A) activation and (B) execution, are shown. In the execution phase, four cell death execution events (fragmentation and degradation of chromosomal DNA, mitochondrial elimination, engulfment of apoptotic cell corpses, and inactivation of survival signals) are directly activated by the proteolytic cleavage of the CED-3 caspase. Three partially-redundant pathways, colored in pink, red, and green, respectively, mediate recognition and removal of apoptotic cell corpses. The activation of CED-10 and CDC-42 small GTPases leads to cytoskeletal reorganization required for pseudopod extension around an apoptotic cell. Arrows indicate confirmed activation and dashed arrows indicate proposed activation.
Figure 3
Figure 3
Cell death specification. (A) cis-elements and transcription factors regulating the transcription of egl-1. egl-1 transcription unit as well as transcription units located upstream and downstream of the egl-1 transcription unit are shown. The gray bar represents part of chromosome V and green regions represent sequences that are outside of coding regions and that are conserved in other Caenorhabditis species. Many of these regions have been shown to be required for egl-1 transcriptional control in specific cells or lineages, and hence, represent cis-regulatory elements of the egl-1 locus. Indicated above the schematic of the egl-1 locus are transcription factors that have been shown to directly control egl-1 transcription by binding to specific cis-regulatory elements. (B) Model for the transcriptional upregulation of egl-1 in the NSM sister cell. In the NSM neuroblast, the activity of the Snail-like gene ces-1 is negatively controlled by the HLF-like transcription factor gene ces-2 and the MIDA1-like gene dnj-11. ces-1 activity in the NSM neuroblast can affect NSM neuroblast polarity through targets of ces-1 that are currently unknown. It also can affect cell cycle progression by suppressing the activity of the cdc-25.2 gene, which is required for cell cycle progression. After the asymmetric division of the NSM neuroblast, ces-1 activity is detected in the larger NSM but not in the smaller NSM sister cell. This asymmetry in ces-1 results in the ces-1-dependent repression of egl-1 transcription in the NSM but not in the NSM sister cell. In the NSM sister cell, egl-1 transcription can occur and this is dependent on the HLH genes hlh-2 and hlh-3. (C) Model for the killing function of the engulfment pathways in the NSM lineage. In the NSM neuroblast, the central cell death pathway is activated to a certain degree through a mechanism that remains to be determined. ced-3 activity generated in the NSM neuroblast leads to the activation of the engulfment pathways in neighbors of the NSM neuroblast. The engulfment pathways subsequently promote the polarization of the NSM neuroblast and the formation of a gradient of ced-3 activity along the cell division axis. As a result of this gradient, the smaller NSM sister cell inherits more ced-3 activity than the larger NSM and this facilitates the killing of the NSM sister cell.
Figure 4
Figure 4
The formation and maturation of a phagosome containing a cell corpse. Key proteins that act during (A) formation and (B) maturation of a phagosome are shown. Arrows and block arrows indicate activation or inhibition, respectively, and the dashed line indicates a proposed function.
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