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Frazzled and netrin: a story of neuronal confusion and competition in the drosophila giant fiber system
Title
Frazzled and netrin: a story of neuronal confusion and competition in the drosophila giant fiber system.
Creator
Orr, Brian, Murphey, Rodney K., Graduate College
Date Issued
2011-04-08
PURL
http://purl.flvc.org/fcla/dt/3164669
Subject Headings
Neural circuitry, Drosophila, Synapses
Format
Document (PDF)
The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration
Title
The PHR proteins: intracellular signaling hubs in neuronal development and axon degeneration.
Creator
Grill, Brock, Murphey, Rodney K., Borgen, Melissa A.
Abstract/Description
During development, a coordinated and integrated series of events must be accomplished in order to generate functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1) function in each of these events in development. Here, we review PHR function across species, as well as the myriad of signaling pathways PHR proteins regulate. These...
Show moreDuring development, a coordinated and integrated series of events must be accomplished in order to generate functional neural circuits. Axons must navigate toward target cells, build synaptic connections, and terminate outgrowth. The PHR proteins (consisting of mammalian Phr1/MYCBP2, Drosophila Highwire and C. elegans RPM-1) function in each of these events in development. Here, we review PHR function across species, as well as the myriad of signaling pathways PHR proteins regulate. These findings collectively suggest that the PHR proteins are intracellular signaling hubs, a concept we explore in depth. Consistent with prominent developmental functions, genetic links have begun to emerge between PHR signaling networks and neurodevelopmental disorders, such as autism, schizophrenia and intellectual disability. Finally, we discuss the recent and important finding that PHR proteins regulate axon degeneration, which has further heightened interest in this fascinating group of molecules.
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Date Issued
2016-12-23
PURL
http://purl.flvc.org/fau/fd/FAUIR000039
Format
Citation
Netrin-Frazzled signaling instructs synaptogenesis and plasticity at an identified central synapse in Drosophila
Title
Netrin-Frazzled signaling instructs synaptogenesis and plasticity at an identified central synapse in Drosophila.
Creator
Orr, Brian, Murphey, Rodney K., Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
The classic guidance molecules, Netrin and its receptor Frazzled (Fra), dictate the strength of synaptic connections in the giant fiber system (GFS) of Drosophila melanogaster by regulating gap junction localization in the pre-synaptic terminal. In Netrin mutant animals the synaptic coupling between a giant interneuron and the jump motor neuron was weakened. Dye-coupling between these two neurons was severely compromised or absent. These mutants exhibited anatomically and physiologically...
Show moreThe classic guidance molecules, Netrin and its receptor Frazzled (Fra), dictate the strength of synaptic connections in the giant fiber system (GFS) of Drosophila melanogaster by regulating gap junction localization in the pre-synaptic terminal. In Netrin mutant animals the synaptic coupling between a giant interneuron and the jump motor neuron was weakened. Dye-coupling between these two neurons was severely compromised or absent. These mutants exhibited anatomically and physiologically defective synapses between the giant fiber (GF) and tergotrochanteral motor neuron (TTMn). In cases where Netrin mutants displayed apparently normal synaptic anatomy, half of the specimens exhibited physiologically defective synapses. Dye-coupling between the giant fiber and the motor neuron was reduced or eliminated, suggesting that gap junctions were disrupted in the Netrin mutants. When we examined the gap junctions with antibodies to Shaking-B Innexin (ShakB), they were significantly decreased or absent in the pre-synaptic terminal of the mutant GF. This data is the first to show that Netrin and Frazzled regulate placement of gap junctions pre-synaptically at a central synapse. In the Drosophila Giant Fiber System, we demonstrate a mechanism that ensures the monoinnervation of two homologous motor neurons by two homologous interneurons. In a scenario where both interneurons could synapse with both motor neuron targets, each interneuron exclusively synapsed with only one target and the circuit functions at normal physiological levels. This innervation pattern depended on the ratio of netrin-to-frazzled expression. When Netrin was over expressed in the system, shifting the ratio in favor of Netrin, both interneurons synapsed with both target motor neurons and physiological function was reduced. This resulted in the polyinnervationof a single target. In contrast, when Frazzled was over expressed in the system, one interneuron innervated both targets and excluded the remaining interneuron from making any synaptic contact. This resulted in a single interneuron mono-innervating both motor neurons and physiological function was mutant. The orphaned interneuron made no synaptic contact with either motor neuron target. Physiological function was only normal when the Netrin-Frazzled ratio was at endogenous levels and each GF monoinnervated one motor neuron. When we examined the gap junctions at this synapse in experimental animals, there was a significant reduction of gap junction hemichannels in the presynaptic terminal of axons that deviated from normal innervation patterns. While the synapse dyecoupled, the reduction in gap junction hemichannels reduced function in the circuit.
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Date Issued
2013
PURL
http://purl.flvc.org/fau/fd/FA0004041
Subject Headings
Cellular control mechanisms, Cellular signal transduction, Drosophila melanogaster -- Cytogenetics, Genetic transcription, Transcription factors
Format
Document (PDF)
Frazzled’s Role in Synapse Formation at a Drosophila Giant Synapse
Title
Frazzled’s Role in Synapse Formation at a Drosophila Giant Synapse.
Creator
Lopez, Juan, Murphey, Rodney K., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
In Drosophila melanogaster, the GFS is synaptically coupled to the Tergotrochanteral motoneurons; these neurons form a signaling pathway from the brain to the jump muscles (Thomas and Wyman, 1983). Part of this signaling is done through gap junctions, and placement of these gap junctions was partially shown to be regulated by the binding of Netrin, a class of guidance molecule (Orr et al., 2014). In the present study we investigate the role of Netrin's receptor Frazzled in the placement of...
Show moreIn Drosophila melanogaster, the GFS is synaptically coupled to the Tergotrochanteral motoneurons; these neurons form a signaling pathway from the brain to the jump muscles (Thomas and Wyman, 1983). Part of this signaling is done through gap junctions, and placement of these gap junctions was partially shown to be regulated by the binding of Netrin, a class of guidance molecule (Orr et al., 2014). In the present study we investigate the role of Netrin's receptor Frazzled in the placement of gap junctions in Drosophila at: 1) Presynaptic neurons (Giant Fibers [GF]), 2) Postsynaptic neurons (Tergotrochanteral motoneurons [TTMn]), and 3) Presynaptic + Postsynaptic neurons simultaneously. Effects of Frazzled were tested using Frazzled RNAi and a combination of electrophysiological recordings and imaging of the GF-TTMn synapse. The results from this study show that presynaptic and postsynaptic knockdown of Frazzled delayed muscular responses and altered the anatomy of both the GF's and TTMn's.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FA00013085
Subject Headings
Drosophila melanogaster--Nervous system., Gap Junctions., Synapses., Netrin Receptors.
Format
Document (PDF)
Synaptic Rearrangements and the Role of Netrin-Frazzled Signaling in Shaping the Drosophila Giant Fiber Circuit
Title
Synaptic Rearrangements and the Role of Netrin-Frazzled Signaling in Shaping the Drosophila Giant Fiber Circuit.
Creator
Lloyd, Brandon N., Murphey, Rodney K., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
In the developing CNS, presynaptic neurons often have exuberant overgrowth and form excess (and overlapping) postsynaptic connections. Importantly, these excess connections are refined during circuit maturation so that only the appropriate connections remain. This synaptic rearrangement phenomenon has been studied extensively in vertebrates but many of those models involve complex neuronal circuits with multiple presynaptic inputs and postsynaptic outputs. Using a simple escape circuit in...
Show moreIn the developing CNS, presynaptic neurons often have exuberant overgrowth and form excess (and overlapping) postsynaptic connections. Importantly, these excess connections are refined during circuit maturation so that only the appropriate connections remain. This synaptic rearrangement phenomenon has been studied extensively in vertebrates but many of those models involve complex neuronal circuits with multiple presynaptic inputs and postsynaptic outputs. Using a simple escape circuit in Drosophila melanogaster (the giant fiber circuit), we developed tools that enabled us to study the molecular development of this circuit; which consists of a bilaterally symmetrical pair of presynaptic interneurons and postsynaptic motorneurons. In the adult circuit, each presynaptic interneuron (giant fiber) forms a single connection with the ipsilateral, postsynaptic motorneuron (TTMn). Using new tools that we developed we labeled both giant fibers throughout their development and saw that these neurons overgrew their targets and formed overlapping connections. As the circuit matured, giant fibers pruned their terminals and refined their connectivity such that only a single postsynaptic connection remained with the ipsilateral target. Furthermore, if we ablated one of the two giant fibers during development in wildtype animals, the remaining giant fiber often retained excess connections with the contralateral target that persisted into adulthood. After demonstrating that the giant fiber circuit was suitable to study synaptic rearrangement, we investigated two proteins that might mediate this process. First, we were able to prevent giant fibers from refining their connectivity by knocking out highwire, a ubiquitin ligase that prevented pruning. Second, we investigated whether overexpressing Netrin (or Frazzled), part of a canonical axon guidance system, would affect the refinement of giant fiber connectivity. We found that overexpressing Netrin (or Frazzled) pre- & postsynaptically resulted in some giant fibers forming or retaining excess connections, while exclusively presynaptic (or postsynaptic) expression of either protein had no effect. We further showed that by simultaneously reducing (Slit-Robo) midline repulsion and elevating Netrin (or Frazzled) pre- & postsynaptically, we significantly enhanced the proportion of giant fibers that formed excess connections. Our findings suggest that Netrin-Frazzled and Slit-Robo signaling play a significant role in refining synaptic circuits and shaping giant fiber circuit connectivity.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FA00004758, http://purl.flvc.org/fau/fd/FA00004758
Subject Headings
Drosophila melanogaster--Cytogenetics., Genetic transcription., Transcription factors., Cellular signal transduction., Cellular control mechanisms., Cell receptors.
Format
Document (PDF)
Highwire coordinates synapse formation and maturation by regulating both a map kinase cascade and the ability of the axon to respond to external cues in the giant fiber system of Drosophila Melanogaster
Title
Highwire coordinates synapse formation and maturation by regulating both a map kinase cascade and the ability of the axon to respond to external cues in the giant fiber system of Drosophila Melanogaster.
Creator
Borgen, Melissa A., Murphey, Rodney K., Florida Atlantic University, Charles E. Schmidt College of Science, Department of Biological Sciences
Abstract/Description
The ubiquitin ligase Highwire is responsible for cell-autonomously promoting synapse formation in the Drosophila Giant Fiber system. highwire mutants show defects in synaptic function and extra branching at the axon terminal, corresponding to transient branching that occur in the course of giant synapse formation during metamorphosis. The MAP kinase pathway, including Wallenda and JNK/Basket, plus the transcription factor Jun, act to suppress synaptic function and axon pruning in a dosage...
Show moreThe ubiquitin ligase Highwire is responsible for cell-autonomously promoting synapse formation in the Drosophila Giant Fiber system. highwire mutants show defects in synaptic function and extra branching at the axon terminal, corresponding to transient branching that occur in the course of giant synapse formation during metamorphosis. The MAP kinase pathway, including Wallenda and JNK/Basket, plus the transcription factor Jun, act to suppress synaptic function and axon pruning in a dosage sensitive manner, suggesting different molecular mechanisms downstream of the MAP kinase pathway govern function and pruning. A novel role for Highwire is revealed, regulating the giant fiber axon’s ability to respond to external cues regulated by Fos. When expression of the transcription factor Fos is disrupted in the post-synaptic TTMn or surrounding midline glia of highwire mutants, the giant fiber axons show a marked increase in axon overgrowth and midline crossing. However, synaptic function is rescued by the cell nonautonomous manipulation of Fos, indicating distinct mechanisms downstream of Highwire regulating synaptic function and axon morphology.
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Date Issued
2014
PURL
http://purl.flvc.org/fau/fd/FA00004081, http://purl.flvc.org/fau/fd/FA00004081
Subject Headings
Cell differentiation, Cellular control mechanisms, Cellular signal transduction, Drosophila melanogaster -- Cytogenetics, Gene expression, Genetic transcription
Format
Document (PDF)