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RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice
Title
RanBP9 Plays a Critical Role in Neonatal Brain Development in Mice.
Creator
Palavicini, Juan Pablo, Lloyd, Brandon N., Hayes, Crystal D., Bianchi, Elisabetta, Kang, David E., Dawson-Scully, Ken, Lakshmana, Madepalli K., Okazawa, Hitoshi
Abstract/Description
RanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized...
Show moreRanBP9 is known to act as a scaffolding protein bringing together a variety of cell surface receptors and intracellular targets thereby regulating functions as diverse as neurite and axonal outgrowth, cell morphology, cell proliferation, myelination, gonad development, myofibrillogenesis and migration of neuronal precursors. Though RanBP9 is ubiquitously expressed in all tissues, brain is one of the organs with the highest expression levels of RanBP9. In the neurons, RanBP9 is localized mostly in the cytoplasm but also in the neurites and dendritic processes. We recently demonstrated that RanBP9 plays pathogenic role in Alzheimer’s disease. To understand the role of RanBP9 in the brain, here we generated RanBP9 null mice by genetrap based strategy. Most of Ran-/- mice die neonatally due to defects in the brain growth and development. The major defects include smaller cortical plate (CP), robustly enlarged lateral ventricles (LV) and reduced volume of hippocampus (HI). The lethal phenotype is due to a suckling defect as evidenced by lack of milk in the stomachs even several hours after parturition. The complex somatosensory system which is required for a behavior such as suckling appears to be compromised in Ran-/- mice due to under developed CP. Most importantly, RanBP9 phenotype is similar to ERK1/2 double knockout and the neural cell adhesion receptor, L1CAM knockout mice. Both ERK1 and L1CAM interact with RanBP9. Thus, RanBP9 appears to control brain growth and development through signaling mechanisms involving ERK1 and L1CAM receptor.
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Date Issued
2013-06-26
PURL
http://purl.flvc.org/fau/fd/FAUIR000081
Format
Citation
Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization
Title
Glial Hsp70 Protects K+ Homeostasis in the Drosophila Brain during Repetitive Anoxic Depolarization.
Creator
Armstrong, Gary A. B., Xiao, Chengfeng, Krill, Jennifer L., Seroude, Laurent, Dawson-Scully, Ken, Robertson, R. Meldrum, Roman, Gregg
Abstract/Description
Neural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat...
Show moreNeural tissue is particularly vulnerable to metabolic stress and loss of ion homeostasis. Repetitive stress generally leads to more permanent dysfunction but the mechanisms underlying this progression are poorly understood. We investigated the effects of energetic compromise in Drosophila by targeting the Na+/K+-ATPase. Acute ouabain treatment of intact flies resulted in subsequent repetitive comas that led to death and were associated with transient loss of K+ homeostasis in the brain. Heat shock pre-conditioned flies were resistant to ouabain treatment. To control the timing of repeated loss of ion homeostasis we subjected flies to repetitive anoxia while recording extracellular [K+] in the brain. We show that targeted expression of the chaperone protein Hsp70 in glial cells delays a permanent loss of ion homeostasis associated with repetitive anoxic stress and suggest that this is a useful model for investigating molecular mechanisms of neuroprotection.
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Date Issued
2011-12-12
PURL
http://purl.flvc.org/fau/fd/FAUIR000078
Format
Citation
Pushing the limit: Examining factors that affect anoxia tolerance in a single genotype of adult D. melanogaster
Title
Pushing the limit: Examining factors that affect anoxia tolerance in a single genotype of adult D. melanogaster.
Creator
Benasayag Meszaros, Raquel, Risley, Monica G., Hernandez, Priscilla, Fendrich, Margo, Dawson-Scully, Ken
Abstract/Description
Drosophila melanogaster is a promiscuous species that inhabits a large range of harsh environments including flooded habitats and varying temperature changes. To survive these environments, fruit flies have adapted mechanisms of tolerance that allow them to thrive. During exposure to anoxic stress, fruit flies and other poikilotherms enter into a reversible, protective coma. This coma can be manipulated based on controlled environmental conditions inside the laboratory. Here we utilize a...
Show moreDrosophila melanogaster is a promiscuous species that inhabits a large range of harsh environments including flooded habitats and varying temperature changes. To survive these environments, fruit flies have adapted mechanisms of tolerance that allow them to thrive. During exposure to anoxic stress, fruit flies and other poikilotherms enter into a reversible, protective coma. This coma can be manipulated based on controlled environmental conditions inside the laboratory. Here we utilize a common laboratory raised strain of D. melanogaster to characterize adaptation abilities to better understand coma recovery and survival limitations. Our goal is to mimic the fly’s natural environments (wet anoxia) and relate findings to a typical gas induced environment (dry anoxia) that is commonly used in a laboratory. Despite the abundance of research regarding acute and chronic anoxic exposure and cold stress, the literature is lacking evidence linking anoxic stress with variable environmental conditions such as animal age and stress duration. We present novel ways to assess coma recovery and survival using readily available laboratory tools. Our findings suggest that younger age, exposure to colder temperatures and wet environments increase resistance to anoxic stress.
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Date Issued
2015-08-17
PURL
http://purl.flvc.org/fau/fd/FAUIR000065
Format
Citation
Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent
Title
Pseudopterosin A: Protection of Synaptic Function and Potential as a Neuromodulatory Agent.
Creator
Caplan, Stacee Lee, Zheng, Bo, Dawson-Scully, Ken, White, Catherine, West, Lyndon
Date Issued
2016-03-10
PURL
http://purl.flvc.org/fau/fd/FAUIR000130
Format
Citation
cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae
Title
cGMP-Dependent Protein Kinase Inhibition Extends the Upper Temperature Limit of Stimulus-Evoked Calcium Responses in Motoneuronal Boutons of Drosophila melanogaster Larvae.
Creator
Krill, Jennifer L., Dawson-Scully, Ken, McCabe, Brian D.
Abstract/Description
While the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals....
Show moreWhile the mammalian brain functions within a very narrow range of oxygen concentrations and temperatures, the fruit fly, Drosophila melanogaster, has employed strategies to deal with a much wider range of acute environmental stressors. The foraging (for) gene encodes the cGMP-dependent protein kinase (PKG), has been shown to regulate thermotolerance in many stress-adapted species, including Drosophila, and could be a potential therapeutic target in the treatment of hyperthermia in mammals. Whereas previous thermotolerance studies have looked at the effects of PKG variation on Drosophila behavior or excitatory postsynaptic potentials at the neuromuscular junction (NMJ), little is known about PKG effects on presynaptic mechanisms. In this study, we characterize presynaptic calcium ([Ca^2+]i) dynamics at the Drosophila larval NMJ to determine the effects of high temperature stress on synaptic transmission. We investigated the neuroprotective role of PKG modulation both genetically using RNA interference (RNAi), and pharmacologically, to determine if and how PKG affects presynaptic [Ca^2+]i dynamics during hyperthermia. We found that PKG activity modulates presynaptic neuronal Ca^2+ responses during acute hyperthermia, where PKG activation makes neurons more sensitive to temperatureinduced failure of Ca^2+ flux and PKG inhibition confers thermotolerance and maintains normal Ca^2+ dynamics under the same conditions. Targeted motoneuronal knockdown of PKG using RNAi demonstrated that decreased PKG expression was sufficient to confer thermoprotection. These results demonstrate that the PKG pathway regulates presynaptic motoneuronal Ca^2+ signaling to influence thermotolerance of presynaptic function during acute hyperthermia.
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Date Issued
2016-10-06
PURL
http://purl.flvc.org/fau/fd/FAUIR000079
Format
Citation
Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage
Title
Combination of Sulindac and Dichloroacetate Kills Cancer Cells via Oxidative Damage.
Creator
Ayyanathan, Kasirajan, Kesaraju, Shailaja, Dawson-Scully, Ken, Weissbach, Herbert, Bauer, Joseph Alan
Date Issued
2012-07-17
PURL
http://purl.flvc.org/fau/fd/FAUIR000091
Format
Citation
Postprandial sleep mechanics in Drosophila
Title
Postprandial sleep mechanics in Drosophila.
Creator
Murphy, Keith R, Deshpande, Sonali A, Yurgel, Maria E, Quinn, James P, Weissbach, Jennifer L, Keene, Alex C, Dawson-Scully, Ken, Huber, Robert, Tomchik, Seth M, Ja, William W
Date Issued
2016-11-22
PURL
http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.7554_eLife.19334_1644866459
Format
Document (PDF)
RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease
Title
RanBP9 overexpression accelerates loss of dendritic spines in a mouse model of Alzheimer's disease.
Creator
Wang, Ruizhi, Palavicini, Juan Pablo, Wang, Hongjie, Maiti, Panchanan, Bianchi, Elisabetta, Xu, Shaohua, Lloyd, B.N., Dawson-Scully, Ken, Kang, David E., Lakshmana, Madepalli K.
Date Issued
2014-09
PURL
http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1016_j.nbd.2014.05.029_1644863302
Format
Document (PDF)
A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction
Title
A cGMP-dependent protein kinase (PKG) controls synaptic transmission tolerance to acute oxidative stress at the Drosophila larval neuromuscular junction.
Creator
Caplan, Stacee Lee, Milton, Sarah L., Dawson-Scully, Ken
Date Issued
2013-02-01
PURL
http://purl.flvc.org/fau/flvc_fau_islandoraimporter_10.1152_jn.00784.2011_1644861569
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)
egl‑4 modulates electroconvulsive seizure duration in C. elegans
Title
egl‑4 modulates electroconvulsive seizure duration in C. elegans.
Creator
Monica G. Risley, Stephanie P. Kelly, Justin Minnerly, Kailiang Jia, Ken Dawson‑Scully
Abstract/Description
Increased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that...
Show moreIncreased neuronal excitability causes seizures with debilitating symptoms. Effective and noninvasive treatments are limited for easing symptoms, partially due to the complexity of the disorder and lack of knowledge of specific molecular faults. An unexplored, novel target for seizure therapeutics is the cGMP/protein kinase G (PKG) pathway, which targets downstream K+ channels, a mechanism similar to Retigabine, a recently FDA-approved antiepileptic drug. Our results demonstrate that increased PKG activity decreased seizure duration in C. elegans utilizing a recently developed electroconvulsive seizure assay. While the fly is a well-established seizure model, C. elegans are an ideal yet unexploited model which easily uptakes drugs and can be utilized for high-throughput screens. In this study, we show that treating the worms with either a potassium channel opener, Retigabine or published pharmaceuticals that increase PKG activity, significantly reduces seizure recovery times. Our results suggest that PKG signaling modulates downstream K+ channel conductance to control seizure recovery time in C. elegans. Hence, we provide powerful evidence, suggesting that pharmacological manipulation of the PKG signaling cascade may control seizure duration across phyla.
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Date Issued
2018
PURL
http://purl.flvc.org/fau/fd/FAUIR000532
Format
Document (PDF)