Researcher discover new cell death program
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Cell death during animal development acts like an eraser — sculpting organs, the nervous system, fingers and toes — by removing unnecessary or unneeded cells. There are a few different processes that regulate how and when cells die, but research from Rockefeller University identifies a new type of programmed cell death that does not depend on the normal family of executioner proteins.
“Caspases are proteases; they are the key executioners of cell death,” says Mary Abraham, a graduate student in Shai Shaham’s lab. “And much of the work that has been done on cell death has been on these caspases and the type of cell death they regulate called apoptosis. But we wanted to know if they are the only way to kill a cell, and we found that they aren’t.”
Looking back over the literature, Abraham and Shaham had seen hints that there was a caspase-independent type of programmed cell death, but never any conclusive evidence. They saw C. elegans, where the lineage and fate of every single cell is known, as the perfect model system to answer the question. They focused in on one cell in particular, called the linker cell.
“I think everyone knew there was something a little off about the linker cell,” says Shaham, head of the Laboratory of Developmental Genetics. “It undergoes a very complex migration in the male animal while the gonad develops behind it. At the end of the migration, the linker cell dies and the gonad fuses with an exit channel, linking it with the outside environment. If you kill the cell too early, the gonad doesn’t grow properly. And we noticed that if the cell doesn’t die, it interferes with the fusion and sperm build up in the gonad.”
Abraham studied all of the genes known to be involved in cell death, systematically disrupting them in the animal. She used broad-spectrum caspase inhibitors to try to stop the linker cell from dying, but nothing worked. “Even after all this, I still wasn’t able to block linker cell death, which really suggested to me that this cell was dying using a different mechanism.”
Support for this idea came when she took a closer look at the morphology of a dying linker cell. She saw an accumulation of vesicles, like bubbles, in the linker cell, and swollen organelles, but apart from some nuclear membrane ruffling, the nucleus looked normal. None of these characteristics fit with the morphology of apoptosis, the type of cell death controlled by caspases. “I have been in the cell death field for 17 years, and I had never seen anything like it,” says Shaham.
Once again, Abraham went back to the literature. In a 1976 Journal of Cell Biology paper, she found what she was looking for. Electron micrographs of cells dying in the developing mouse nervous system showed all the same traits as her linker cell. “At that time, characterization of programmed cell death was primarily morphological. Apoptotic cell death had specific morphology, like chromosome condensation. One type of cell death they identified, which hasn’t received a lot of attention, had exactly the same features — the accumulation of cytoplasmic vesicles, the absolute lack of anything major going on in the nucleus — that we saw in the linker cell.”
“When you look at mice where cell death genes have been knocked out,” says Shaham, “the phenotypes you get are unbelievably mild when you consider the huge numbers of cells that die during development. This suggests either that redundant mechanisms ensure that apoptosis can still occur in these mutants, or that another pathway might play a role. If the latter is true, perhaps the other pathway they use is the same one that leads to linker cell death.”
