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Scientists Discover How Genes Work Together To Control Neural Development

Penn State

Scientists have discovered how three genes work together to regulate the development of nerve cells--fundamental new knowledge that could boost efforts in other areas, including cancer research.

In the current issue of the journal Cell, published on August 8, two teams of researchers report that they independently made the same discovery. One team is led by Zhi-Chun Lai, assistant professor of biology, biochemistry, and molecular biology at Penn State, and Richard W. Carthew, assistant professor of biology at the University of Pittsburgh. The leader of the other research team is Gerald M. Rubin, of the University of California at Berkeley. The research is expected to contribute to the understanding of the nervous system and the brain, which is made up of billions of neurosn.

To make their discovery, Lai and Carthew's team studied fruit-fly eyes to figure out which genes regulate the development of photoreceptor neurons, which convert light signals into chemical signals that the brain can understand. The team used both genetic studies and cell-culture studies to complement and confirm their findings. "The fly genes we are studying are amazingly similar to their corresponding human genes and, at the very fundamental cellular level, there is no difference between the human cell and the fly cell," Lai explains. "Plus flies are a very good organism for genetic engineering."

During a fly's development, on about the fourth day of life, certain proto-eye cells receive instructions from the fly's genes to become either light-filtering cone cells or photoreceptor neurons. "That's when we dissect the eyes to look at them under the microscope," Lai says.

External signals tell the developing cells what kind of cell to become by initiating a cascade of internal molecular reactions called the "signal transduction pathway." "Cancer can result if errors occur in the signal-transduction pathway, giving a cell the signal to divide instead of the signal to become a neuron," Carthew explains. "These signal-transduction pathways are indispensible for life because they are critical for neural development, but they also can be a threat to life if a harmful error occurs somewhere along the pathway, resulting in uncontrolled cell division rather than controlled cell differentiation."

Last year Lai discovered an important clue about how a component of the signal-transduction pathway--a special kind of cell-growth regulator known as a neural inhibitor--works genetically. He found that proto-eye cells could become neurons only when the gene for making a protein known as Tramtrack was inactivated.

"Tramtrack is a kind of 'gatekeeper' protein that prevents the cell from differentiating into a neuron," Carthew explains. "When the cell receives a signal to become a neuron the signal-transduction pathway is activated, which induces the production of proteins that somehow get rid of Tramtrack." With that discovery pointing the way, Lai, Carthew, and their research team began a search to discover exactly which proteins were responsible for destroying Tramtrack.

The researchers genetically engineered strains of fruit flies to test a number of genes whose protein products they suspected would be good candidates. "There are two genetic directions you can take," Lai explains. "If you want to show that a gene is important for some function, you take it away and see what happens. Another thing you can do is to cause genes to overproduce their protein product in a cell and see what happens then."

Using this approach, the researchers narrowed down their list of candidate proteins to just two, known as Phyllopod and Sina, and demonstrated that they team up to target the Tramtrack protein for destruction. In the process, they also discovered the first known biochemical function for the Phyllopod and Sina proteins. "Our test-tube experiments demonstrated that Sina and Phyllopod bind to each other to form a partnership and that they also bind to Tramtrack to form a triad," Carthew says.

Using genetically engineered flies with either no Sina or with no Phyllopod proteins, Lai and Carthew discovered that the Tramtrack protein was able to be produced in the photoreceptor precursor cells, which later transform into cone cells. They also found, on the other hand, that overproduction of Phyllopod alone prevented accumulation of the Tramtrack protein as long as the Sina protein also was available in the same cell, which turned cone cells into photoreceptor cells. "We consider that to be a dramatic change," Lai remarks. "It tells us, as do our corresponding studies in cell culture, that together Phyllopod and Sina proteins are essential for targeting the Tramtrack protein for destruction."

"We are pretty confident that together Phyllopod and Sina bind to the gatekeeper protein, Tramtrack, which is the kiss of death that marks it for destruction by the cell's garbage-disposal enzymes," Carthew says. "Once the gatekeeper Tramtrack protein is removed, the cell is free to become a neuron."

"Up until a few years years ago, everyone thought developing cells always received positive signals, but now evidence is building at a rapid rate that the message often carried by the signal-transduction pathway is 'kill the gatekeeper,'" Carthew says.

"Many vertebrate proteins, some known to be involved in cancers, carry a structural feature similar to the Tramtrack protein," Lai says. "We are now searching for other biological systems where genes for Tramtrack-like proteins prevent cell development."

This research was supported in Lai's lab by the National Science Foundation and by Lai's March of Dimes Basil O'Connor Starter Scholar Research Award. This research in Carthew's lab was supported by the National Institutes of Health, the March of Dimes Birth Defects Foundation, and the Pew Foundation.

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