To address the third factor (genetics), researchers at Sanford-Burnham recently turned to fruit flies.
Fly and human genes are so closely related that the sequences of newly discovered human genes, including many that contribute to disease, can often be matched up with fly counterparts.
Since fruit flies are relatively easy to work with (they’re small, breed quickly, and don’t require a lot of maintenance), they often give scientists clues to the functions of human genes and helps them develop drugs that target them.
As Dr. Rolf Bodmer, director of Sanford-Burnham’s Development and Aging Program, explains in the Journal of Cell Biology, “We use fruit flies to learn about the fundamental genetic mechanisms that are important for the development and function of the heart.”
Dr. Bodmer himself discovered early in his career that flies lacking Tinman, a protein that regulates the expression of other genes, fail to develop heart tissue during embryonic development. If Tinman is removed later during fly development, the flies’ hearts don’t function properly.
Now researchers in Dr. Bodmer’s lab, led by postdoctoral researcher Dr. Li Qian, uncovered a genetic network that controls heart development and function in fruit flies and mice, with additional clues that it might also play a role in human heart health.
In a study published June 20 in the Journal of Cell Biology, the researchers first found a genetic link between Tinman and a protein called Cdc42 in fruit flies. Cdc42 is well known to regulate actin filaments, which act like scaffolding to help cells maintain their shape. Without fully functioning Tinman and Cdc42, the flies’ hearts didn’t beat as regularly and heart muscle fibers weren’t arranged in a parallel, organized fashion like they are in normal flies.
But Dr. Bodmer, Dr. Qian, and colleagues didn’t stop with fruit flies—they also wanted to see if Tinman and Cdc42 affect heart development and function in mice. Indeed, they found that mice with reduced Tinman and Cdc42 levels experienced poor heart contraction and rhythm. But, in a final layer of complexity, the team also discovered how Tinman works—it inhibits microRNAs, small strands of genetic material that can influence protein production. More specifically, Tinman impairs one microRNA called miR1, which in turn decreases levels of Cdc42 and another gene. In other words, miR1 serves as the middleman in the interaction between Tinman and Cdc42, and the other genes they regulate.
Finally, to determine how their lab findings might translate into human disease, Dr. Qian and colleagues screened more than 600 heart disease patients to find mutations in the gene that codes for Cdc42. They found one patient with a Cdc42 mutation that was not found in healthy control patients, suggesting that malfunctions in this pathway might impact human health.
“Our next goal is to look for more genes that interact with Tinman or with other factors that we know are important for the heart,” says Dr. Bodmer.
