Programmed cell death is an evolutionarily conserved process that plays critical roles in development. During programmed cell death, proteases known as “caspases” are activated in the dying cell, which is engulfed by a neighboring cell and degraded. Almost all C. elegans cell deaths are believed to be “suicides” — e.g., they are caspase-dependent and do not require engulfment. However, the death of the cell B.al/rapaav has been considered a potential “murder,” based on reports that this death depends on engulfment genes and the presence of the engulfing cell. B.alapaav and B.arapaav are generated in the male tail during the late L3 stage. During the early L4 stage one of these cells dies, and the other survives and adopts an epithelial fate. The decision of which cell dies and which survives is stochastic. The cell that dies is engulfed by the neighboring cell P12.pa.
That the B.al/rapaav cell death is engulfment-dependent contrasts with most C. elegans cell deaths. We and others have found that mutations in the engulfment pathway cause both B.alapaav and B.arapaav to survive. However, we found that if the engulfing cell P12.pa is ablated, the B.al/rapaav death still occurs in 39% of animals. We discovered that the dying B.al/rapaav can be engulfed by other neighboring cells in the absence of P12.pa.
The B.al/rapaav cell death is known to be caspase-dependent, leading to the suggestion that cell-interactions might activate the cell-death pathway in the dying cell and hence that this death might be an “induced suicide.” We observed that when the B.al/rapaav cell death is blocked by engulfment defects or P12.pa ablation, the undead cell still initiates the cell-death pathway. Similar to cells that are about to die, the undead cells in engulfment mutants look round and cytoplasmically refractile as seen using Nomarski microscopy and expose phosphatidylserine on their surfaces. By contrast, the undead cell in mutants of the suicide pathway genes egl-1, ced-9, ced-4 or ced-3 appear healthy, suggesting that in engulfment mutants the B.alrapaav death process fails at a point after caspase activation. egl-1 and ced-3 are expressed in the dying or undead cell in wild-type and engulfment-defective worms, and these genes are required for the B.al/rapaav cell death, suggesting that the core cell-death pathway is necessary but not sufficient for this cell death. We conclude that this death is an “assisted suicide.” Studies of this assisted suicide should facilitate understanding of cell-autonomous and cell non-autonomous mechanisms that sensitize cells to death not only in C. elegans but also in other animals including humans, in whom cancer cells are more sensitive than non-cancer cells to the cell-death process.
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