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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
Analysis of Expression and Subcellular Localization of OGT-1 in C. elegans
Title
Analysis of Expression and Subcellular Localization of OGT-1 in C. elegans.
Creator
Tavora, Rubens, Grill, Brock, Florida Atlantic University, Harriet L. Wilkes Honors College
Abstract/Description
EEL-1, the HUWE1 ortholog in C. elegans, is a large E3 ubiquitin ligase that is involved in the regulation of neuronal function and development. Huwe1 has been shown to be associated with intellectual disability. Through the use of electrophysiology and cell specific rescue it has been shown that EEL-1 is involved in GABAergic synaptic transmission. The mechanism of action of EEL-1 within GABA neurons remains largely unknown. Affinity purification proteomics have identified OGT-1, an ortholog...
Show moreEEL-1, the HUWE1 ortholog in C. elegans, is a large E3 ubiquitin ligase that is involved in the regulation of neuronal function and development. Huwe1 has been shown to be associated with intellectual disability. Through the use of electrophysiology and cell specific rescue it has been shown that EEL-1 is involved in GABAergic synaptic transmission. The mechanism of action of EEL-1 within GABA neurons remains largely unknown. Affinity purification proteomics have identified OGT-1, an ortholog of mammalian O-linked N-acetylglucosamine (O-GlcNAc) transferase (Ogt), as an EEL-1 binding protein. By analyzing the expression pattern of OGT-1 in transgenic animals, we show that OGT-1 is expressed both GABAergic motor neurons and cholinergic motor neurons. Analysis of the subcellular distribution within GABAergic motor neurons shows that OGT-1 is enriched in presynaptic terminals. These findings support the hypothesis that EEL-1 and OGT-1 form a complex within GABA motor neurons to regulate synaptic transmission.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FAUHT00048
Format
Document (PDF)
The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development
Title
The HECT Family Ubiquitin Ligase EEL-1 Regulates Neuronal Function and Development.
Creator
Opperman, Karla J., Mulcahy, Ben, Giles, Andrew C., Risley, Monica G., Birnbaum, Rayna L., Tulgren, Erik D., Dawson-Scully, Ken, Zhen, Mei, Grill, Brock
Date Issued
2017-04
PURL
http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1016_j.celrep.2017.04.003_1644939781
Format
Document (PDF)
Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs
Title
Modulating Behavior in C. elegans Using Electroshock and Antiepileptic Drugs.
Creator
Monica G. Risley, Stephanie P. Kelly, Kailiang Jia, Brock Grill, Ken Dawson- Scully
Abstract/Description
The microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to...
Show moreThe microscopic nematode Caenorhabditis elegans has emerged as a valuable model for understanding the molecular and cellular basis of neurological disorders. The worm offers important physiological similarities to mammalian models such as conserved neuron morphology, ion channels, and neurotransmitters. While a wide-array of behavioral assays are available in C. elegans, an assay for electroshock/electroconvulsion remains absent. Here, we have developed a quantitative behavioral method to assess the locomotor response following electric shock in C. elegans. Electric shock impairs normal locomotion, and induces paralysis and muscle twitching; after a brief recovery period, shocked animals resume normal locomotion. We tested electric shock responses in loss-of-function mutants for unc-25, which encodes the GABA biosynthetic enzyme GAD, and unc-49, which encodes the GABAA receptor. unc-25 and unc-49 mutants have decreased inhibitory GABAergic transmission to muscles, and take significantly more time to recover normal locomotion following electric shock compared to wild-type. Importantly, increased sensitivity of unc-25 and unc-49 mutants to electric shock is rescued by treatment with antiepileptic drugs, such as retigabine. Additionally, we show that pentylenetetrazol (PTZ), a GABAA receptor antagonist and proconvulsant in mammalian and C. elegans seizure models, increases susceptibility of worms to electric shock.
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Date Issued
2016
PURL
http://purl.flvc.org/fau/fd/FAUIR000530
Format
Document (PDF)