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Summary: Scientists have discovered a key role for the “Frazzled” protein in building and maintaining rapid neural connections that allow fruit flies to react within milliseconds. When Frazzled is missing, neurons lose vital junctions, slowing communication and weakening muscle responses.
Reintroducing part of the protein restored proper wiring and signal speed, demonstrating that control of Frazzled’s gene activity is essential for healthy neural communication. The findings reveal how one molecule can shape both the structure and function of neuronal networks, offering insights relevant to brain development and repair across species.
Key facts
Control of neural wiring: Frazzled protein regulates how neurons form fast, reliable electrical connections. Signal Speed: Loss of Frazzled disrupts junctions, slowing communication between the brain and muscles. Conserved mechanism: Similar proteins may play the same role in mammals, linking the findings to broader brain function and repair.
Source: FAU
Neuroscientists at Florida Atlantic University have discovered a surprising role for a protein called “Frazzled” (known as DCC in mammals) in the nervous system of fruit flies, showing how it helps neurons connect and communicate at lightning speed.
The discovery sheds light on the fundamental mechanisms that ensure neurons form reliable connections, or synapses, a process essential for all nervous systems, from insects to humans.
In the study, the researchers focused on the Drosophila giant fiber (GF) system, a neural circuit that controls this fruit fly’s rapid escape reflex. With this work, the team has not only revealed a key molecular player in fruit fly neural circuits, but has also demonstrated the power of combining genetics, imaging, physiology and computational models to discover how brains stay connected and what happens when they don’t.
The results, published in the journal eNeuro, reveal that when Frazzled is missing or mutated, the system fails: neurons fail to form proper electrical connections, the fly’s neuronal responses slow down, and communication between GF neurons and the muscles they control weakens.
These defects are related to the loss of gap junctions, small channels that allow neurons to transmit signals directly and quickly. In particular, the team found that the loss of a protein called shake-B(neural+16), which forms these junctions in presynaptic terminals, is the cause of much of the misfiring.
To understand the precise role of Frazzled, the researchers used a genetic tool known as the UAS-GAL4 system to reintroduce different pieces of the Frazzled protein into mutant flies. Surprisingly, only the intracellular portion of Frazzled (the part inside the neuron that can influence gene expression) was enough to restore both the structure of synapses and the speed of neuronal communication.
When this portion was disrupted, for example by deleting a key domain called P3 or mutating a crucial site within it, the rescue failed, indicating that control of Frazzled’s genetic activity is essential for building gap junctions.
Beyond the laboratory experiments, the team also created a computational model of the GF system, simulating how the number of gap junctions affects the neurons’ ability to fire reliably. The model confirmed that even small changes in gap junction density can dramatically alter the speed and precision of neural signals.
“Combining experimental and computational work allowed us to see not only that Frazzled matters, but exactly how it shapes the connections that allow neurons to communicate with each other,” said Rodney Murphey, Ph.D., senior author and professor of biological sciences in FAU’s Charles E. Schmidt College of Sciences.
“Our next steps are to explore whether similar mechanisms control neural circuits in other species, including mammals, and to see how this could influence learning, memory or even repair after injury.”
Interestingly, while Frazzled has long been studied as a guidance molecule (helping neurons grow along the right paths), the study revealed that its intracellular domain also directly regulates synapse formation.
Flies lacking Frazzled often showed neurons growing in random directions and failing to reach their targets. Restoration of intracellular dominance corrected many of these targeting errors, demonstrating a dual role for Frazzled in both wiring neurons and fine-tuning their communication.
This work also establishes parallels with other organisms. Similar proteins in worms and vertebrates have been shown to influence chemical synapses, suggesting that Frazzled and its relatives may play a broadly conserved role in shaping neural networks.
By showing how a single protein controls the physical and functional aspects of electrical synapses, this study opens a window into the fundamental rules that govern the assembly of the nervous system.
“Understanding how neurons form reliable connections is a central question in neuroscience,” Murphey said.
“Frazzled gives us a clear idea of one piece of that puzzle. Our findings could inform future studies on neural development, neurodegenerative diseases, and strategies to repair damaged circuits.”
Co-authors of the study are first author Juan López, Ph.D., a postdoctoral researcher in the Charles E. Schmidt College of Sciences; Jana Boerner, Ph.D., managing director of the Advanced Cell Imaging Core at the FAU Stiles-Nicholson Brain Institute; Kelli Robbins, research staff in the FAU Department of Biological Sciences; and Rodrigo Peña, Ph.D., assistant professor of biological sciences in the Charles E. Schmidt College of Sciences.
Key questions answered:
A: It helps neurons form electrical connections (gap junctions) that allow for fast and accurate communication.
A: Neural signals slow down, connections weaken, and neurons may misfire or fail to reach their targets.
A: It reveals a molecular mechanism that ensures a rapid flow of information in the nervous system, which will inform future studies on brain development and recovery.
About this research news in genetics and neuroscience
Author: Gisèle Galoustian
Source: FAU
Contact: Gisele Galoustian – FAU
Image: Image is credited to Neuroscience News.
Original Research: Closed access.
“Frazzled/DCC regulates gap junction formation at a Drosophila giant synapse” by Rodney Murphey, et al. eNeuro
Abstract
Frazzled/DCC regulates gap junction formation at a Drosophila giant synapse
Frazzled/DCC loss-of-function (LOF) mutants disrupt synaptogenesis in the Drosophila giant fiber (GF) system.
We observed weaker physiology in male and female LOF specimens, characterized by longer latencies and reduced response frequencies between GFs and motor neurons.
These physiological phenotypes are related to a loss of gap junctions in GFs, specifically the loss of the jerk B (neural + 16) isoform of innexin in the presynaptic terminal. We present evidence for the role of Frazzled in regulating gap junctions by utilizing the UAS-GAL4 system in Drosophila to rescue mutant phenotypes.
Expression of several UAS-Frazzled constructs in a Frazzled LOF background was used to analyze the role of different parts of the Frazzled receptor in electrical synapse assembly. Expression of the intracellular domain of Frazzled in Frazzled LOF mutants rescued axon pathfinding and synaptogenesis.
This is supported by the complementary result that Frazzled fails to rescue synaptic function when the transcriptional activation domain is disrupted, as demonstrated by deletion of the highly conserved intracellular P3 domain or by a construct with a point mutation in the highly conserved P3 domain known to be required for transcriptional activation.
A computational model clarifies the role of gap junctions and the function of the GF system.
The present work shows how several domains of a guide molecule regulate synaptogenesis by regulating synaptic components.
