Novel Programs of Caspase Independent Cell Death

During development and morphogenesis of multicellular organisms, programmed cell death controls cell number and also shapes organs (Vaux and Korsmeyer 1999). The most common type of cell death in this context is caspase-dependent apoptosis (Edinger and Thompson 2004). Recent research in C. elegans and Drosophila has revealed that specific cells also die in a caspase-independent manner (Kumar and Rothman 2007). Cell corpses are subsequently removed through engulfment by neighboring or specialized phagocytic cells in both C. elegans and Drosophila. The process of engulfment in the nematode assists apoptotic cell killing itself and is also involved in the clearance of necrotic cells (Zhou et al. 2004). In Drosophila, cells dying in a caspase-independent manner are removed by a similar mechanism

(Mergliano and Minden 2003). Interestingly, observations in cell-death deficient H99 Drosophila embryos revealed removal of cells in the epidermis via caspase-independent cell death that may involve engulfment of living cells (Mergliano and Minden 2003).

A nonapoptotic, caspase-independent cell death mechanism is involved in the removal of the linker cell of C. elegans, which is born during the second larval stage (L2) and is essential for male gonadal development in the nematode (Sulston et al. 1983). As the linker cell migrates it directs the extension of the male gonad and mediates the fusion of the vas deferens and cloaca. The linker cell finally dies at L4/adult stage. Death was thought to be dependent on the neighboring engulfing cells (Sulston et al. 1980). However, after laser ablation of the grandparental precursor engulfing cells the linker cell still dies, which hints at a linker cell intrinsic death program. Cell death is independent of genes typically involved in developmental timing, engulfment, and all types of cell death characterized in C. elegans, such as necrosis, apoptosis, and autophagy (Abraham et al. 2007). Some morphological features of the linker cell death such as nuclear crenellation, the absence of chromatin compaction and cytoplasmic changes such as dilation of cell organelles are reminiscent of caspase-independent cell death in other organisms (Clarke 1990). Thus, the linker cell death program in C. elegans may represent a conserved caspase-independent mode of cell death in diverse species (Abraham et al. 2007).

In Drosophila, 15 nurse cells assure the development of one growing oocyte each, by supplying it with essential macromolecules, such as proteins, mRNA, and organelles. Finally they die after extruding all their remaining cytoplasmic contents into the oocyte (McCall 2004). This type of cell death was thought to be classical, caspase-dependent apoptosis but recent research illuminated that nurse cells die in a caspase-independent manner (Mazzalupo and Cooley 2006). Visualization and inhibition of caspase activity demonstrates that caspases do not play a role during the death of the nurse cells. While the possibility of necrosis cannot be excluded, no signs of autophagic or apoptotic cell death have been detected (Mazzalupo and Cooley 2006). Similar to the linker cell death in C. elegans, a yet unidentified cell death mechanism likely underlies the demise of nurse cells.

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