Embryos that are homozygous for a deletion that removes Rpr, Grim, and Hid
lack all developmental apoptosis, and are lethal at the end of embryogenesis. The
most obvious phenotypes in these embryos are a block in a morphogenetic movement
required for proper head development, and a large number of excess cells in the central
nervous system (White et al., 1994; Zhou et al., 1995; Nassif et al., 1998). This latter
defect indicates that in flies, as in mammals, excess neurons are generated during
development, to be eliminated by apoptosis. The defects in head development may
arise from excess cells interfering in tissue involution.
Animals mutant for Hid are viable to adult stages, although short-lived (Abbott
and Lengyel, 1991; Grether et al., 1995). They have increased numbers of midline
glia cells at the end of embryogenesis, and excess interommatidial cells in the adult
eye. The viability of both of these cell types is known to be regulated by the activity
of the EGF receptor (EGFR) (Freeman, 1996; Scholz et al., 1997; Stemerdink and
Jacobs, 1997; Bergmann et al., 1998; Kurada and White, 1998; Miller and Cagan,
1998; Sawamoto et al., 1998; Bergmann et al., 2002). EGFR, acting through the Ras/
Raf/MAPK pathway, downregulates Hid activity, as described above. Cell survival is
favored when cells are exposed to high levels of EGFR activity, and cells undergo Hid-
induced apoptosis in the absence of this activity. Hid mutants also show other defects
in development—for example, in the developing wing—that have not yet been
ascribed to defects in cell death.
Mutants that selectively remove Rpr have recently been described (Peterson et al.,
2002). Again these mutants are viable, and show relatively specific defects in cell
death. Surprisingly, despite the demonstration that the ecdysone receptor and p53
directly regulate Rpr expression (Brodsky et al., 2000; Jiang et al., 2000; Ollmann et
al., 2000), no defects have been detected in hormone—or p53-induced apoptosis in
the Rpr mutant. Ecdysone-induced expression of other proapoptotic proteins, such
as Hid, is likely to be sufficient for apoptosis in the absence of Rpr. Interestingly,
apoptosis induced by ionizing radiation is reduced in the Rpr mutants. Taken
together, these data indicate that Rpr function is important for the full response to
DNA damage, but is not rate limiting in the context of p53 overexpression.
Two populations of cells in the nervous system are increased in Rpr mutants. One
is a group of neurons that normally die during metamorphosis, but survive in the
Rpr-mutant adult, and the other is a subset of neuroblasts, or neural stem cells. Some
neuroblasts are normally destined to undergo apoptosis at the end of embryonic
development. In the Rpr mutant, these deaths do not occur, and the neuroblasts
continue to divide, giving rise to a very enlarged nervous system. It is not known why
the elimination of these populations of cells is so dependent on Rpr activity.
The generation of excess cells and their elimination by apoptosis provides the
organism with significant flexibility in development. Studies where normal
development is perturbed illustrate this point dramatically. Disruptions both in organ
patterning and in the total number of cells in a tissue or in the whole organism can
be compensated by increased cell death, as described below.
Ectopic expression of cyclin E in the embryo results in an extra round of cell
division, nearly doubling the cell density in the embryo (Li, Q. et al., 1999). Despite
APOPTOSIS IN DROSOPHILA 195