Noncanonical cell death programs in the nematode Caenorhabditis elegans

Abstract

Genetic studies of the nematode Caenorhabditis elegans have uncovered four genes, egl-1 (BH3 only), ced-9 (Bcl-2 related), ced-4 (apoptosis protease activating factor-1), and ced-3 (caspase), which function in a linear pathway to promote developmental cell death in this organism. While this core pathway functions in many cells, recent studies suggest that additional regulators, acting on or in lieu of these core genes, can promote or inhibit the onset of cell death. Here, we discuss the evidence for these noncanonical mechanisms of C. elegans cell death control. We consider novel modes for regulating the core apoptosis genes, and describe a newly identified cell death pathway independent of all known C. elegans cell death genes. The existence of these noncanonical cell death programs suggests that organisms have evolved multiple ways to ensure appropriate cellular demise during development.

Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism

“…However, we never observed the complete suppression of the cell-death phenotype, even when apoptotic genes were absent. The presence of residual cell death even in ced-9, ced-4 and ced-3 mutants suggests that the apoptotic pathway is only one of the cell death mechanisms activated after smn-1 knock-down, and that it may require additional caspase or non-apoptotic/alternative death mechanisms (50,51). We therefore suggest that CED-4/Apaf-1 is also activated by an alternative upstream mechanism and that CED-4/Apaf-1 itself activates other downstream effectors, in addition to CED-3/ICE-caspase (Supplementary Material, Fig.…”

Programmed cell death in the nervous system—a programmed cell fate?

“…Transcriptional regulation of egl-1 expression has been shown to be combinatorial, at least in the case of the posterior ventral nerve cord progeny, where a complex between the Hox protein MAB-5 and the Pbx homologue CEH-20 directly regulates egl-1 transcription [41]. However, recent evidence suggests there are also EGL-1-independent ways to activate PCD in C. elegans, and these may be more relevant to the more infrequent late deaths [48]. An alternative to this model would involve different transcription factors regulating expression of different cell death genes.…”

Non-caspase proteases: triggers or amplifiers of apoptosis?

“…CED-3 is also required for physiological and DNA damageinduced cell death in the worm germline [12]. Caspase-like proteins and caspase-independent mediators have been identified in worms [13], but these enzymes may amplify rather than execute CED-3 mediated death signaling as we propose for higher eukaroytes (see below). Nevertheless, C. elegans also exhibits a caspase-independent, necrotic program to eliminate neuronal cells by hyperactive ion channels [14].…”