Genetics of Apoptosis

the huge excess of cells, most of these embryos develop and hatch into larvae, although
at a slower rate of development. Examination of cell death in these embryos shows
that hyperplasia induced by cyclin E overexpression is largely counteracted by
increased apoptosis. The excess cells are removed in a pattern-specific fashion rather
than randomly, and the doomed cells express Rpr prior to their death. Increased cell
number in developing adult structures can also be compensated for by increased
apoptosis. Expression of activated Ras can result in increased cell division, followed
by increased cell death (Karim and Rubin, 1998).
In both embryonic and larval tissues, disruptions in pattern can also be
counteracted by increased apoptosis. This ‘pattern repair’ can involve changes both
in levels of apoptosis and in cell division. A nice example of this is provided by studies
examining the effects of misexpressing the anterior morphogen bicoid. Increased
bicoid in the anterior of the embryo results in an expansion of embryonic head
structures (Driever and Nüsslein-Volhard, 1988). Surprising, a large number of these
bicoid-overexpressing embryos develop into normal adults. Analysis of cell death in
these embryos shows increased death in the anterior regions of the embryos, and
decreased death in the posterior regions (Namba et al., 1997). The anterior death is
accompanied by increased Rpr expression. Thus, defects in global patterning can be
accomplished by modulation of the normal cell-death pathway.
Within a single developing tissue or organ, the regulation of cell number is essential
to producing a properly proportioned structure. In the developing wing, ectopically
generated death on one side of the wing is counteracted by increased death on the
opposite side, and by increased division on the smaller side (Milán et al., 1997). If
the ectopic death is not too extensive, the wing develops into a correctly proportioned
adult wing of normal size. As in embryos, if the number of cells in a developing tissue
is reduced below a threshold—for example, by a cell-cycle block—the ability of the
tissue to compensate is insufficient, and defects in adult structures occur (de Nooij
and Hariharan, 1995).

9.

Conclusions

Drosophila provides a powerful model system to investigate how apoptosis is regulated
and executed during development. Genetic screens have proven to be invaluable for
identifying genes important for this process. In addition, the genetic and molecular
tools available in this system allow the validation of findings generated in other
systems. For example, loss-of-function genetics can be used to test the importance of
interactions detected in overexpression studies.
Studies on the developmental regulation of cell death in Drosophila are greatly
aided by the substantial information available on the regulation of other aspects of
development. There is likely to be substantial overlap between the regulation of cell
division, cell differentiation, and cell survival. Understanding how these processes are
coordinately regulated will be critical to full understanding of patterning and
organogenesis. In addition, the contribution of apoptosis must be considered to fully

196 GENETICS OF APOPTOSIS