Hormone Triggers Mass Cell Death During Drosophila Metamorphosis

Conducting experiments on Drosophila salivary glands, researchers at the University of Utah (Salt Lake City) and Massachusetts Institute of Technology (MIT; Cambridge) have discovered how the hormone ecdysone triggers programmed cell death, or apoptosis, in immature insect tissues during metamorphosis, clearing the way for the formation of adult organs. The group's findings, reported in the March 24 issue of Molecular Cell, could eventually lead to a better understanding of how apoptosis operates in mammalian cells.

According to Carl Thummel, a Howard Hughes Medical Institute (HHMI) investigator at the University of Utah, studying the process of programmed cell death during development is nearly impossible in most animals, because the cells that are affected are scattered throughout the organism. As fruit flies develop, however, whole larval organs undergo rapid, mass cell death in order to make room for adult tissues. "Using a model system in which cell death is so easily detectable, we are able to see how a hormone triggers this process," Thummel said.

The researcher team—which also included Utah researcher Changan Jiang, HHMI investigator Hermann Steller at MIT, and Anne-Francoise Lamblin, a former MIT researcher now at the National Institutes of Health—decided to study Drosophila salivary glands because they contain large chromosomes that form easily observable "puffs" when genes are activated. These puffs allowed the scientists to easily trace the pathway between the hormone trigger and the transcriptional activation of target genes that kill the cells.

The experiments revealed key components of a "death cascade" of biochemical signals initiated by ecdysone as it plugs into its receptor. Once this receptor is activated, the death-inhibiting gene diap2 is repressed, and the death-activating genes reaper and hid are turned on.

To their surprise, however, the scientists witnessed a burst of protective diap2 expression that occurred right before reaper and hid were activated. "This burst of activity does support models that diap2 normally holds back the death response," Thummel commented. "But we still don't know why the salivary gland really cares that it's only got a couple of more hours to live. We do know that the ecdysone pulse induces many genes in the gland, and it's possible that the burst of diap2 activity right before its death preserves an important final function it's trying to hold onto."

The pathways, on the other hand, turned out to be relatively simple. "We unexpectedly found that the hormone receptor directly regulates transcription of the reaper gene," Thummel said. "It's quite a shallow pathway. We couldn't ask for a simpler circuit."

Next the researchers will tackle a far more complicated question: Why do pulses of ecdysone that occur throughout metamorphosis have different effects depending on the developmental stage of the fly? Thummel believes that since the process is so stage-specific, it can't be as simple as it seems. "There must be other components in this hierarchy that we haven't found yet."

The researchers believe that their findings in fruit flies may lead to a deeper understanding of mammalian cell death programs, because inserting either reaper or hid genes into mammalian cells also triggers apoptosis, just as if the switch had been thrown by a mammalian apoptosis gene.

"It will likely be very tricky to find the mammalian genes because they have very short regions of homology," Thummel said. "However, so far we do know that many components of the vertebrate cell death pathway have homologs in flies. And with the publication of the full sequence of the Drosophila genome, many other aspects of this critical pathway will soon become clear."

To learn more about the completion of the Drosophila sequence, read Drosophila is Done.

For more information: Howard Hughes Medical Institute, 4000 Jones Bridge Rd., Chevy Chase, MD 20815-6789. Tel: 301-215-8500.

Edited by Jim Pomager