germ-cell nuclei are only partially enclosed by a plasma membrane and are thus part
of a syncytium. Until the onset of diakinesis, these nuclei are characterized by a high
nuclear to cytoplasmic volume ratio, a ratio that is reversed when oozytes are formed.
After dying, apoptotic cells separate from the germ-line syncytium and extrude most
of their cytoplasm to be used by growing oocytes in the germ-line syncytium. Only
oocytes have to accumulate a high volume of cytoplasm; accordingly, male meiotic
cells do not undergo apoptosis. Alternatively, germ-cell apoptosis could also be
explained by developmental checkpoints that lead to the demise of naturally occurring
compromised germ cells. Similarly, simple alterations in the metabolism of germ cells
could also lead to programmed cell death. Indeed, this hypothesis is supported by the
fact that a large number of genetic loci lead to excessive germ-cell apoptosis (S.
Milstein, Anton Gartner, Pawel Pasierbeck and Michael Hengartner, unpublished
observation). Besides the above-considered basal level of germ-cell death, germ-cell
apoptosis can also be initiated by bacterial infection as well as by meiotic defects and
genotoxic stress. The best case for biologic significance can be made for bacterially
induced cell death, as worms defective in programmed cell death have a dramatically
reduced live span as compared to their wild-type counterparts (Aballay and Ausubel,
2001). As to DNA damage-induced programmed cell death, it seems that the
induction of programmed cell death by DNA damage checkpoints has only a minor
biologic function. mrt-2, rad-5, and cep-1 checkpoint mutants, as well as the general
cell-death mutants ced-3 and ced-4, are equally defective in inducing DNA damage-
induced programmed cell death, but in contrast to the strong radiation sensitivity of
mrt-2 mutants, rad-5 radiation sensitivity is very low, and cep-1 as well as ced-4 and
ced-3 animals are almost as radiation resistant as wild-type animals (Gartner et al.,
2000; Ahmed et al., 2001; Schumacher et al., 2001). Given that cep-1 animals as well
as ced-3 and ced-4 animals are able to undergo checkpoint induced cell cycle arrest,
whereas rad-5 animals are defective in both DNA damage-induced programmed cell
death and cell-cycle arrest, it seems that DNA damage checkpointinduced DNA
repair (defective in mrt-2) is the most important damage response, and damage-
induced apoptosis is the least important damage response (Gartner et al., 2000;
Ahmed et al., 2001; Schumacher et al., 2001). It is unclear why C. elegans evolved
damage-induced programmed cell death. It is likely that the biologic significance of
this response is to eliminate meiotic cells with defects in the regulation of meiotic
recombination, a suggestion supported by the finding that checkpoint mutants, as
well as the cep-1 mutants, have a weak meiotic chromosome segregation defect (Derry
et al., 2001).
14.
ConclusionC. elegans has proved to be an invaluable model system for the study of programmed
cell death. However, many key problems concerning the regulation of programmed
cell death still have to be solved. It will be interesting to determine further key targets
of the ced-3 caspase. The various upstream pathways that lead to the activation of the
182 GENETICS OF APOPTOSIS