Florida Atlantic University neuroscientists have identified a new function for the protein Frazzled in fruit flies, showing how it is essential for the formation and maintenance of neural connections. The study, published in eNeuro, focused on the Giant Fiber System in Drosophila melanogaster, which controls the insect’s rapid escape reflex.
The researchers found that when Frazzled is missing or mutated, neurons fail to establish proper electrical connections. This results in slower neural responses and weaker communication between neurons and muscles. The team linked these defects to a loss of gap junctions—channels that allow direct and fast signal transmission between neurons. Specifically, they observed that the absence of shaking-B(neural+16), a protein forming these junctions at presynaptic terminals, contributed significantly to faulty signaling.
To investigate further, scientists used genetic tools to reintroduce various segments of the Frazzled protein into mutant flies. They discovered that only the intracellular portion of Frazzled was necessary to restore both synapse structure and neuronal communication speed. If this segment was disrupted—either by deleting a key domain called P3 or mutating an important site—the rescue failed. This indicated that Frazzled’s role in gene regulation within neurons is crucial for constructing gap junctions.
In addition to laboratory experiments, the team developed a computational model simulating how changes in gap junction density impact neural firing reliability. Their simulations confirmed that even minor reductions in gap junction numbers could significantly affect both speed and precision of neural signals.
“The combination of experimental and computational work allowed us to see not just that Frazzled matters, but exactly how it shapes the connections that let neurons talk to each other,” said Rodney Murphey, Ph.D., senior author and professor of biological sciences at FAU Charles E. Schmidt College of Science. “Our next steps are to explore whether similar mechanisms control neural circuits in other species, including mammals, and to see how this might influence learning, memory or even repair after injury.”
The study also highlighted that while Frazzled has been known as a guidance molecule directing neuron growth paths, its intracellular domain directly regulates synapse formation as well. Flies lacking this protein often had neurons growing incorrectly; restoring the intracellular domain corrected many such errors.
This research draws comparisons with findings from worms and vertebrates where related proteins influence chemical synapses. It suggests that proteins like Frazzled may play a broadly conserved role across species in organizing neural networks.
“Understanding how neurons form reliable connections is a central question in neuroscience,” Murphey said. “Frazzled gives us a clear handle on one piece of that puzzle. Our findings could inform future studies of neural development, neurodegenerative diseases and strategies to repair damaged circuits.”
The research team included Juan Lopez, Ph.D., postdoctoral researcher; Jana Boerner, Ph.D., managing director at FAU Stiles-Nicholson Brain Institute; Kelli Robbins from FAU’s Department of Biological Sciences; and Rodrigo Pena, Ph.D., assistant professor at FAU Charles E. Schmidt College of Science.
