"By understanding how cell fusion works in a simple worm, we can begin to build our knowledge about how the process works in higher organisms, including humans," says co-author Dr. Benjamin Podbilewicz, assistant professor of biology at the Technion-Israel Institute of Technology.
"When cell fusion fails to occur in worms, we get birth defects and organs that do not function properly. In addition, if we understand the fusion mechanism, we may someday be able to stop the fusion of a sperm and an egg, thereby making a new form of contraceptive."
Co-author Dr. William Mohler, assistant professor of genetics and developmental biology at University of Connecticut Health Center in Farmington, adds that "the formation of giant cells through cell fusion is essential for the proper formation of skeletal muscle in humans, so down the road, our findings may contribute to increased understanding of muscle damage and repair in both normal human health and in muscle-related tissue disease.
Other researchers praised the study. Dr. Paul Sternberg, professor of biology at the California Institute of Technology, said that because cell fusion events are crucial in the development of animals, the newly discovered fusion-regulating gene "will become an important paradigm for studying both the mechanism of cell fusion and its regulation."
From their previous work, the researchers could predict the normal steps of cell fusion and development in the skin and vulva of C. elegans. They genetically altered the worms so that a protein that normally resides in the junctions between cells was fluorescent. The worms were then exposed to a chemical known to cause mutations in genes. The researchers used high-powered microscopes to look for mutated cells in the skin and the vulva of the offspring these worms produced.
The Israeli and U.S. teams independently identified two mutant forms of one gene that were responsible for cells’ failure to fuse. The normal gene produces at least two proteins present in cells of this roundworm just before and during cell fusion. The next step in their work will involve studying the behavior of these proteins.
By all criteria tested, the gene appears to specifically control the process of cell fusion. To rule out cell positioning as a possible cause of fusion failure, the researchers precisely analyzed the arrangements of unfused cells in mutant worms. These patterns were normal, thereby eliminating cell positioning as a cause of failure to fuse. In addition, they carefully demonstrated that mutant cells fail even in the earliest stages of cell fusion. Their membranes fail to open even tiny pores, not allowing movement of cell contents between neighboring cells.
After cloning the mutant gene, which had not previously been studied, the researchers determined exactly where on the gene the mutation occurred. They followed changes in the development of the skin and vulva cells to examine the effects of the mutations. The cells that failed to fuse looked normal during early embryonic development, but as development progressed, defects in the tissues they formed became evident. Worms containing mutant skin cells were shorter, fatter, and less mobile than normal worms. Those with mutant vulva cells produced fewer offspring or were completely infertile.
Dr. Podbilewicz predicts that the mutant worms probably would die in the wild. He also predicts that there could be proteins with similar functions but different makeups in other organisms, making the findings on C. elegans applicable to other organisms.
Dr. Podbilewicz, Dr. Mohler and their colleagues hope that future research will identify additional proteins that are essential to normal cell fusion. They also are developing a test for the presence of the essential protein, as a possible predictor for whether or not a cell will fuse properly.
The Technion-Israel Institute of Technology is Israel's leading scientific and technological center for applied research and education. It commands a worldwide reputation for its pioneering work in computer science, biotechnology, water-resource management, materials engineering, aerospace and medicine. The majority of the founders and managers of Israel’s high-tech companies are Technion graduates. The Technion’s 19 faculties and 30 research centers and institutes in Haifa are home to 13,000 students and 700 faculty members.
Based in New York City, the American Technion Society (ATS) is the leading American organization supporting higher education in Israel. The ATS has raised $868 million since its inception in 1940, more than half of that during the last eight years. A nationwide membership organization with more than 20,000 supporters and 17 offices around the country, the ATS is driven by the belief that the economic future of Israel is in high technology and the future of high technology in Israel is at the Technion. Technion societies are located in 24 countries around the world.
Journal
Developmental Cell