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On the wings of knowledge

Master-slave relationship of cell growth and cell cycle underlies fruit-fly research in the lab of Bruce Edgar
Dr. Bruce Edgar with a bottle of fruit-flies.
Dr. Bruce Edgar of the Basic Sciences Division displays a bottle of fruit-flies, useful in understanding the genetics involved when cell cycles go awry. Photo by Clay Eals

Fruit flies buzz about Dr. Bruce Edgar's Ba- sic Sciences Division laboratory, but no one moves toward the fly swatter.

Instead, these tiny creatures are under intense scrutiny, and a glimpse through the microscope provides evidence supporting one of the main themes of research in the Edgar lab.

"The cell cycle is the slave, and cell growth is the master," Edgar said, summing up the premise of his work.

Cancer can result from a cell cycle spinning out of control. Labs such as Edgar's have found Drosophila fruit flies useful in understanding the genetics behind the wheel when cell cycles go awry.

The first inklings of cellular growth's role in cell-cycle control came from experiments in the 1970s by work in yeast carried out by Drs. Lee Hartwell (now center president and director) and Murdoch Mitchison (while at the University of Edinburgh in Scotland). "But the way growth is coupled to cell-cycle progression has remained obscure ever since," Edgar said.

Choreographed switches

Edgar turned to Drosophila to dissect the genetics behind the connection between cell growth and the cell cycle. A precisely choreographed series of genetic switches governs the progress from a cluster of cells to a fully patterned wing in Drosophila.

"The methods for genetic manipulation are fantastic," Edgar said. "Their development includes lots of growing cell types and growth-regulated cell cycles."

Genetic triggers outside the cell cycle itself could maintain cell-cycle control or, alternatively, spiral a cell toward cancer. Edgar hypothesized that the cell cycle is dominated by cell growth, in such a way that "cells divide because they are allowed to grow more." Conversely, he posited that the "slave" cannot switch roles with the "master," as an increased rate of cell-cycle progression does not necessarily translate into accelerated growth.

In an experiment to test this hypothesis, Edgar and colleagues sped up the cell cycle in half of a Drosophila wing, leaving the other half untouched. In the portion speeding through the cell cycle, the team found twice the number of cells, but the wing itself was still in the proper proportions because the cells were smaller. Then the team did the opposite experiment, putting the brakes on the cell-cycle rate. Cells doubled in size, but there were half as many. Again, the wing itself looked normal.

Clear conclusion

In both experiments, the number and size of cells had changed without significant alteration in mass accumulation and overall growth, so the conclusion was clear.

"We had de-coupled growth from proliferation," Edgar said.

These results were published in Cell in 1998, co-authored by Edgar lab postdoctoral fellows Dr. Thomas Neufeld and Dr. Laura Johnston and technician Aida Flor de la Cruz.

Importantly, speeding up or slowing down the cell cycle had no effect on the proportions of the developing wing. This meant that other signals must be important in shaping the wing into a custom fit for Drosophila.

"In development, the number of cells is plastic," Edgar said.

And the same could be said for human development. "The size of a finger, for example, is not determined by counting the number of cells from one end of the finger to the other," he said, "but by something else."

What signals serve as tailors in wing design in Drosophila?

A tightly controlled developmental program establishes a gradient of secreted cell-signaling molecules known as morphogens along the head-to-tail and back-to-belly axes, with morphogen microgradients fine-tuning the patterning process locally. Key morphogens are Decapentaplegic (Dpp), Epidermal Growth Factor homologs, and Wingless (Wg) in Drosophila.

"The level of signals, such as those from the molecule Dpp along the wing axis, determines the wing's overall shape," he said.

When postdoctoral fellow Dr. Cristina Martin-Castellanos inhibited Dpp signaling, for example, cells divided more slowly, and the wing was misshapen and dwarfed in size. The opposite was true when Dpp was enhanced.

Edgar said these and other experiments serve as evidence that morphogens double as both wing designer and growth master as well, though distinguishing between these functions has proven an experimental enigma.

"It has been quite a challenge to separate growth from cell identity signals," he said.

One way morphogens might control cell growth is by regulating other genes that are dedicated to metabolic control, Edgar said. A possible candidate in Drosophila is myc, first cloned in Dr. Robert Eisenman's Basic Sciences Division lab.

"The myc gene stimulates protein synthesis, and that controls cell growth," Edgar said, "but it doesn't change the identity of the cell."

Insulins critical players

A recent study led by graduate student Jessica Britton and published in the February edition of Developmental Cell indicates that nutrient intake can control cell growth as well. Insulins, for example, are critical players in regulating energy balance in the fly.

When insulin-signaling components were hyperactivated in cells of the Drosophila "fat body" (fat tissue which functions similarly to the human liver), these cells ballooned in size. "Insulins promote nutrient import into the cell," Edgar said. "Cells become gluttonous and don't stop eating."

Interestingly, when an animal is nutrient-deprived, "these rebel cells continue to grow, at the expense of the entire animal," said postdoctoral fellow Dr. Leslie Saucedo. All tissues are stressed, except the fat body, which is overexpressing insulin pathway components, she said. Saucedo is studying a gene that may be a novel component of the insulin-signaling pathway.

Components of insulin signaling are similar between humans and flies, Edgar said. Understanding how insulins can drive cell growth in the fly wing, then, may lead to better understanding of how faulty growth-factor signaling can bypass control mechanisms and lead to cancer, he said.

Signaling components activated by growth factors such as insulin are of particular relevance to cancer, Edgar said, since mutations in components of nearly all growth-factor signaling paths can be oncogenic, or cancer-causing.

"Cancer cells ignore negative growth signals," he said. "Some types of cancer are associated with growth-factor signaling components."

'First hit' in cancer

Mutations in growth control might be the "first hit" in the generation of cancer. Another hit is needed for the cell identity to change and for cells to cycle out of control. However, "the second hit you would expect is something that alters cell specification," Edgar said, "not something that affects nutrition."

Could nutrition-related signals like growth-factor pathway components act in concert with patterning signals? If so, where do the two pathways intersect? The Edgar lab seeks to understand how patterning and nutrient-dependent growth signals join forces to crack the whip over the cell cycle.

"We expect that the growth and cell identity pathways converge, but we don't know where at this point," Edgar said. "Insulin signaling promotes nutrient import to cause cells to grow. There is no evidence of patterning genes affecting nutrient import, but they do affect protein synthesis, affecting the cell's ability to utilize nutrients."

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