Genetic Flaw Starts Neurofibromatosis’ Biochemical Domino Effect

By Jade Boyd

Michael Stern’s latest research into the formation of neurofibromatosis tumors reads something like a federal racketeering indictment, except that Stern is tracing proteins instead of laundered money, and he’s looking not at offshore accounts but at biochemical paths of cause and effect.

Neurofibromatosis is characterized by the formation of tumors of peripheral nerve cells. Scientists know the disease is caused by defects in a gene called Nf1, but they have yet to find out precisely how the defective genes cause tumors to form.

In seeking biochemical pathways responsible for neurofibromatosis tumors in humans, Stern’s research group compiled evidence from dozens of painstaking experiments on mutant fruit flies, each with a specific genetic flaw that testified to the power of the one or more proteins involved. The researchers used fruit flies for several reasons: The insect’s genome has been sequenced, it takes only two weeks to grow a new generation of fruit flies, and scientists know which fruit fly genes are analogous to the human genes associated with neurofibromatosis.

“Our results suggest that having a defect in Nf1 begins a kind of biochemical domino effect that eventually leads to tumor growth,” said Stern, professor of biochemistry and cell biology.
In their experiments, the researchers created more than two dozen mutant strains of fruit flies, including varieties that were either missing the genes to make one of the four proteins or were encoded to over express, or make extra amounts of, one of the four. Some mutants were designed to carry more than one defective trait.

Nerves from each mutant strain were examined. By comparing the mutant strains — each with a specific defect or set of defects — the researchers built a case that the absence of neurofibromin allows several proteins to work in concert to inhibit a regulatory group of proteins that are key players in regulating genes responsible for programmed cell death and DNA repair — two common culprits in cancer.

Stern says the project required an enormous amount of work in the lab and wouldn’t have been possible without the dedication and motivation of research technician William Lavery. A paper on the research appeared in the Journal of Neuroscience, and Stern and Lavery’s co-authors include research technician Michelle Wells, postdoctoral research assistant Veronica Hall, graduate student James Yager and undergraduate Alex Rottgers. The research is supported by the Department of Defense Neurofibromatosis Research Program.