Researchers at Florida Atlantic University have made a significant discovery regarding the role of a protein named “Frazzled” in the nervous system of fruit flies. This study highlights how Frazzled, also known as DCC in mammals, is crucial for maintaining fast and precise neuronal connections.
The team examined the Giant Fiber (GF) System in Drosophila, which is responsible for the fruit fly”s rapid escape reflex. Their findings, published in the journal eNeuro, reveal that the absence or mutation of Frazzled impairs the formation of electrical connections between neurons, resulting in slower responses and weakened movements.
Frazzled is linked to the establishment of reliable synapses, which are essential for effective communication within nervous systems across species. The researchers found that when Frazzled is missing, the fly”s neurons struggle to create proper electrical connections and exhibit slower neural responses, ultimately affecting muscle control.
The study identified a notable loss of gap junctions—tiny channels crucial for direct neuronal signaling. Specifically, the absence of a protein called shaking-B(neural+16), which is vital for forming these junctions in presynaptic terminals, was found to contribute significantly to neuronal misfiring.
To better understand the specific function of Frazzled, the scientists employed the UAS-GAL4 genetic tool to reintroduce various segments of the Frazzled protein into mutant flies. Remarkably, the intracellular portion of Frazzled was sufficient to restore both the structure of synapses and the speed of neuronal communication. Disruptions to this portion, such as the deletion of a critical domain or mutations within it, hindered the rescue efforts, underscoring the importance of Frazzled in regulating gene activity necessary for forming gap junctions.
In addition to experimental methods, the researchers developed a computational model of the GF System to simulate how variations in gap junction density impact neuronal firing reliability. This model confirmed that even minor fluctuations in gap junction quantity could significantly affect the speed and precision of neural signals.
Rodney Murphey, Ph.D., the senior author of the study and a professor of biological sciences at FAU, stated, “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.” The next steps for the research team involve investigating whether similar mechanisms govern neural circuits in other organisms, including mammals, and how these processes may affect learning, memory, or recovery from injuries.
Interestingly, while Frazzled has been previously recognized as a guidance molecule that aids neurons in navigating toward their targets, this study highlights its additional role in directly regulating synapse formation. Flies deficient in Frazzled displayed erratically growing neurons that failed to reach their intended destinations. By restoring the intracellular domain of Frazzled, many of these guidance errors were corrected, illustrating its dual functionality in both wiring neurons and refining their communication.
This research draws intriguing parallels to other species, as similar proteins in organisms such as worms and vertebrates have been shown to influence chemical synapses. This suggests that Frazzled and its counterparts may play a broadly conserved role in shaping neural networks across different life forms.
The findings from this study contribute to a deeper understanding of the fundamental principles governing nervous system development. Murphey noted, “Understanding how neurons form reliable connections is a central question in neuroscience. Frazzled gives us a clear handle on one piece of that puzzle.” This research could pave the way for future investigations into neural development, neurodegenerative disorders, and potential strategies for repairing damaged neural circuits.
The study”s co-authors include first author Juan Lopez, Ph.D., a postdoctoral researcher in the Charles E. Schmidt College of Science; Jana Boerner, Ph.D., managing director of the Advanced Cell Imaging Core at the FAU Stiles-Nicholson Brain Institute; Kelli Robbins, a research staff member in FAU”s Department of Biological Sciences; and Rodrigo Pena, Ph.D., an assistant professor of biological sciences in the same college.
About Florida Atlantic University: Florida Atlantic University educates over 32,000 undergraduate and graduate students across six campuses along the southeastern coast of Florida. The institution is recognized for its high research output and commitment to social mobility, being one of only 21 U.S. universities to achieve dual designations from the Carnegie Classification. With a ranking among the Top 100 Public Universities by U.S. News & World Report, FAU is also acknowledged as a leading engine for upward mobility.
