The St. Jude study is the first to show that Scythe plays a critical role during development of mammals by selectively regulating when and where specific cells either proliferate or undergo apoptosis, the process by which cells self-destruct. Understanding exactly how Scythe balances apoptosis with cell proliferation could provide significant insights into how organs develop in the growing embryo, researchers said.
The St. Jude team showed in laboratory models that in the absence of Scythe the lungs, kidneys and brains develop abnormally and the embryos cannot survive. These defects were caused by the loss of control over both the multiplication of some cells and the process of apoptosis, in which cells self-destruct.
Normally, there is a balance between life and death in the embryo as the various parts of specific organs get "sculpted" out of the growing mass of cells and some cells are eliminated, according to Peter McKinnon, Ph.D., an associate member of the St. Jude Department of Genetics and Tumor Cell Biology. But cells in certain organs of models lacking both copies of the Scythe gene (Scythe-/-) either failed to receive or failed to respond to signals triggering proliferation or apoptosis. The resulting organs were malformed and unable to function properly, he said. McKinnon is the senior author of a report on this work that appears in the December issue of Molecular and Cellular Biology.
"Scythe is critical to the embyro's ability to survive and develop normally," McKinnon said. "The protein appears to regulate both apoptosis and the multiplication of cells in a way that we don't yet understand."
Previous work by other researchers suggests that the Scythe protein might work by regulating the folding and activity of the molecules that make up the signaling pathway that controls apoptosis. Scythe was also known to interact with another protein called Reaper to control development of the fruit fly. Therefore, the St. Jude team developed laboratory models lacking both copies of Scythe to study what happens in the gene's absence. The scientists discovered that major defects in lung development appeared late in the process of embryo development.
Specifically, the lungs were very small and their branching airways were underdeveloped. In addition, there were almost no alveoli--the small air sacs at the end of the smallest airways. Moreover, the kidneys failed to form properly or did not form at all. This showed that Scythe is required for development of both the lung and kidney. The Scythe-/- model also often failed to develop a normal brain. In the absence of Scythe some parts of the brain grew abnormally large and contained excessive amounts of water.
Finally, the St. Jude team showed that cells from the Scythe-/- model responded to ionizing radiation and hydrogen peroxide by undergoing apoptosis like normal cells. However, these cells were more resistant to menadiaone and thapsigarin--two chemicals known to trigger apoptosis. But when the investigators put Scythe genes back into the cells, they became sensitive to these treatments and underwent apoptosis.
"These chemicals affect the movement of calcium inside a special structure where proteins are made," McKinnon said. "This showed that Scythe helps trigger apoptosis in specific circumstances. Further studies are currently underway to elucidate this process."
Part of the Scythe molecule resembles that of molecules known to be involved with protein destruction, according to Fabienne Desmots, the postdoctoral researcher in the Department of Genetics and Tumor Cell Biology who did much of the work on this project. This finding suggests that Scythe might help to regulate the signaling molecules that are involved in either apoptosis or cell proliferation.
"By having a hand in controlling the levels of key proteins involved in these processes, Scythe appears to indirectly balance life and death decisions in the growing embryo," said Desmots, who is the first author of the paper. Desmots is now at the University of Rennes in France.
Other authors of the study include Helen R. Russell, Youngsoo Lee and Kelli Boyd. This work was supported in part by the National Institutes of Health and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization. For more information, please visit www.stjude.org.