Publications by authors named "Dennis Mathew"

23 Publications

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New study on prevalence of anosmia in COVID-19 implicates the D614G virus mutation as a major contributing factor to chemosensory dysfunction.

Eur Arch Otorhinolaryngol 2021 Mar 31. Epub 2021 Mar 31.

L. Rydygier Collegium Medicum, Nicolaus Copernicus University, 85-094, Bydgoszcz, Poland.

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http://dx.doi.org/10.1007/s00405-021-06759-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011370PMC
March 2021

Loss of Smell in COVID-19 Patients: Lessons and Opportunities.

Authors:
Dennis Mathew

Front Hum Neurosci 2020 26;14:598465. Epub 2020 Nov 26.

Department of Biology, University of Nevada, Reno, NV, United States.

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http://dx.doi.org/10.3389/fnhum.2020.598465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732576PMC
November 2020

A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS.

Genes (Basel) 2020 04 20;11(4). Epub 2020 Apr 20.

Department of Biology, University of Nevada, Reno, NV 89557, USA.

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes and (involved in GABA signaling), and (involved in intracellular Ca ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.
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http://dx.doi.org/10.3390/genes11040448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230244PMC
April 2020

Mechanism underlying starvation-dependent modulation of olfactory behavior in Drosophila larva.

Sci Rep 2020 02 20;10(1):3119. Epub 2020 Feb 20.

Department of Biology, University of Nevada, Reno, NV, 89557, USA.

Starvation enhances olfactory sensitivity that encourage animals to search for food. The molecular mechanisms that enable sensory neurons to remain flexible and adapt to a particular internal state remain poorly understood. Here, we study the roles of GABA and insulin signaling in starvation-dependent modulation of olfactory sensory neuron (OSN) function in the Drosophila larva. We show that GABA-receptor and insulin-receptor play important roles during OSN modulation. Using an OSN-specific gene expression analysis, we explore downstream targets of insulin signaling in OSNs. Our results suggest that insulin and GABA signaling pathways interact within OSNs and modulate OSN function by impacting olfactory information processing. We further show that manipulating these signaling pathways specifically in the OSNs impact larval feeding behavior and its body weight. These results challenge the prevailing model of OSN modulation and highlight opportunities to better understand OSN modulation mechanisms and their relationship to animal physiology.
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http://dx.doi.org/10.1038/s41598-020-60098-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033209PMC
February 2020

Odors: from chemical structures to gaseous plumes.

Neurosci Biobehav Rev 2020 04 10;111:19-29. Epub 2020 Jan 10.

Biology and Neuroscience, University of Nevada, Reno, United States. Electronic address:

We are immersed within an odorous sea of chemical currents that we parse into individual odors with complex structures. Odors have been posited as determined by the structural relation between the molecules that compose the chemical compounds and their interactions with the receptor site. But, naturally occurring smells are parsed from gaseous odor plumes. To give a comprehensive account of the nature of odors the chemosciences must account for these large distributed entities as well. We offer a focused review of what is known about the perception of odor plumes for olfactory navigation and tracking, which we then connect to what is known about the role odorants play as properties of the plume in determining odor identity with respect to odor quality. We end by motivating our central claim that more research needs to be conducted on the role that odorants play within the odor plume in determining odor identity.
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http://dx.doi.org/10.1016/j.neubiorev.2020.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031008PMC
April 2020

Effect of gut microbes on olfactory behavior of larva.

Bios 2019 Dec;90(4):227-238

Department of Biology, University of Nevada, Reno, NV 89557.

The symbiotic relationship between an animal and its gut microbiota is known to influence host neural function and behavior. The mechanisms by which gut microbiota influence brain function are not well understood. This study measures the impact of gut microbiota on olfactory behavior of larvae and explores possible mechanisms by which gut microbiota communicate with neural circuits. The microbiota load in larvae was altered by treating them with antibiotics or probiotics. Control larvae and larvae with altered microbiota loads were subjected to olfactory assays to analyze the chemotaxis response of larvae to odorants. Larvae treated with antibiotics had reduced microbiota load and exhibited reduced chemotaxis response toward odorants compared to control animals. This behavioral phenotype was partially rescued in larvae treated with probiotics that resulted in partial recovery of microbiota loads. Expression levels of several olfactory genes in larvae subjected to different treatments were analyzed. The results suggest that the expression of certain components of the GABA signaling pathway is sensitive to microbiota load. The study concludes that the microbiota influences homeostatic mechanisms in the host that control GABA production and GABA-receptor expression, which are known to impact host olfactory behavior. These results have implications for understanding the bidirectional communication between a host organism and its microbiota as well as for understanding the modulation of olfactory neuron function.
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http://dx.doi.org/10.1893/0005-3155-90.4.227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153377PMC
December 2019

Behavior Responses to Chemical and Optogenetic Stimuli in Larvae.

Front Behav Neurosci 2018 21;12:324. Epub 2018 Dec 21.

Department of Biology, University of Nevada, Reno, NV, United States.

An animal's ability to navigate an olfactory environment is critically dependent on the activities of its first-order olfactory receptor neurons (ORNs). While considerable research has focused on ORN responses to odorants, the mechanisms by which olfactory information is encoded in the activities of ORNs and translated into navigational behavior remain poorly understood. We sought to determine the contributions of most larval ORNs to navigational behavior. Using odorants to activate ORNs and a larval tracking assay to measure the corresponding behavioral response, we observed that larval ORN activators cluster into four groups based on the behavior responses elicited from larvae. This is significant because it provides new insights into the functional relationship between ORN activity and behavioral response. Subsequent optogenetic analyses of a subset of ORNs revealed previously undescribed properties of larval ORNs. Furthermore, our results indicated that different temporal patterns of ORN activation elicit different behavioral outputs: some ORNs respond to stimulus increments while others respond to stimulus decrements. These results suggest that the ability of ORNs to encode temporal patterns of stimulation increases the coding capacity of the olfactory circuit. Moreover, the ability of ORNs to sense stimulus increments and decrements facilitates instantaneous evaluations of concentration changes in the environment. Together, these ORN properties enable larvae to efficiently navigate a complex olfactory environment. Ultimately, knowledge of how ORN activity patterns and their weighted contributions influence odor coding may eventually reveal how peripheral information is organized and transmitted to subsequent layers of a neural circuit.
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http://dx.doi.org/10.3389/fnbeh.2018.00324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308144PMC
December 2018

Strength in diversity: functional diversity among olfactory neurons of the same type.

J Bioenerg Biomembr 2019 02 2;51(1):65-75. Epub 2019 Jan 2.

Department of Biology, University of Nevada, 1664 N. Virginia St., MS: 0314, Reno, NV, 89557, USA.

Most animals depend upon olfaction to find food, mates, and to avoid predators. An animal's olfactory circuit helps it sense its olfactory environment and generate critical behavioral responses. The general architecture of the olfactory circuit, which is conserved across species, is made up of a few different neuronal types including first-order receptor neurons, second- and third-order neurons, and local interneurons. Each neuronal type differs in their morphology, physiology, and neurochemistry. However, several recent studies have suggested that there is intrinsic diversity even among neurons of the same type and that this diversity is important for neural function. In this review, we first examine instances of intrinsic diversity observed among individual types of olfactory neurons. Next, we review potential genetic and experience-based plasticity mechanisms that underlie this diversity. Finally, we consider the implications of intrinsic neuronal diversity for circuit function. Overall, we hope to highlight the importance of intrinsic diversity as a previously underestimated property of circuit function.
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http://dx.doi.org/10.1007/s10863-018-9779-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382560PMC
February 2019

Dual release of growth factor from nanocomposite fibrous scaffold promotes vascularisation and bone regeneration in rat critical sized calvarial defect.

Acta Biomater 2018 09 29;78:36-47. Epub 2018 Jul 29.

Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Japan. Electronic address:

A promising strategy for augmenting bone formation involves the local delivery of multiple osteoinductive and vasculogenic growth factors. However, success depends on sustained growth factor release and its appropriate combination to induce stem cells and osteogenic cells at the bony site. Herein, we have developed a nanocomposite fibrous scaffold loaded with fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) and its ability to promote vascularisation and bone regeneration in critical sized calvarial defect was compared to the scaffold with VEGF + BMP2 and FGF2 + BMP2. Simple loading of growth factors on the scaffold could provide a differential release pattern, both in vitro and in vivo (VEGF release for 1 week where as BMP2 and FGF2 release for 3 weeks). Among all the groups, dual growth factor loaded scaffold (VEGF + BMP2 & FGF2 + BMP2) enhanced vascularisation and new bone formation, but there was no difference between FGF2 and VEGF loaded scaffolds although its release pattern was different. FGF2 mainly promoted stem cell migration, whereas VEGF augmented new blood vessel formation at the defect site. This study suggests that biomimetic nanocomposite scaffold is a promising growth factor delivery vehicle to improve bone regeneration in critical sized bone defects.

Statement Of Significance: Many studies have shown the effect of growth factors like VEGF-BMP2 or FGF2-BMP2 in enhancing bone formation in critical sized defects, but there are no reports that demonstrate the direct comparison of VEGF-BMP2 and FGF2-BMP2. In this study, we have developed a nanocomposite fibrous scaffold that could differentially release growth factors like VEGF, BMP2 and FGF2 (VEGF release for 1 week where as BMP2 and FGF2 release for 3 weeks), which in turn promoted neovascularisation and new bone formation in critical sized defects. There was no difference in vascularisation and bone formation induced by VEGF + BMP2 or FGF2 + BMP2. The growth factor was loaded in a simple manner, which would ensure ease of use for the end-user, especially for the surgeons treating a patient in an operating room.
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http://dx.doi.org/10.1016/j.actbio.2018.07.050DOI Listing
September 2018

Tracking Drosophila Larval Behavior in Response to Optogenetic Stimulation of Olfactory Neurons.

J Vis Exp 2018 03 21(133). Epub 2018 Mar 21.

Department of Biology, MS-0314, University of Nevada; Integrated Neuroscience Graduate Program, University of Nevada;

The ability of insects to navigate toward odor sources is based on the activities of their first-order olfactory receptor neurons (ORNs). While a considerable amount of information has been generated regarding ORN responses to odorants, the role of specific ORNs in driving behavioral responses remains poorly understood. Complications in behavior analyses arise due to different volatilities of odorants that activate individual ORNs, multiple ORNs activated by single odorants, and the difficulty in replicating naturally observed temporal variations in olfactory stimuli using conventional odor-delivery methods in the laboratory. Here, we describe a protocol that analyzes Drosophila larval behavior in response to simultaneous optogenetic stimulation of its ORNs. The optogenetic technology used here allows for specificity of ORN activation and precise control of temporal patterns of ORN activation. Corresponding larval movement is tracked, digitally recorded, and analyzed using custom written software. By replacing odor stimuli with light stimuli, this method allows for a more precise control of individual ORN activation in order to study its impact on larval behavior. Our method could be further extended to study the impact of second-order projection neurons (PNs) as well as local neurons (LNs) on larval behavior. This method will thus enable a comprehensive dissection of olfactory circuit function and complement studies on how olfactory neuron activities translate in to behavior responses.
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http://dx.doi.org/10.3791/57353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933234PMC
March 2018

Differential Contributions of Olfactory Receptor Neurons in a Drosophila Olfactory Circuit.

eNeuro 2016 Jul-Aug;3(4). Epub 2016 Jul 28.

Department of Biology, University of Nevada , Reno, Nevada 89557.

The ability of an animal to detect, discriminate, and respond to odors depends on the functions of its olfactory receptor neurons (ORNs). The extent to which each ORN, upon activation, contributes to chemotaxis is not well understood. We hypothesized that strong activation of each ORN elicits a different behavioral response in the Drosophila melanogaster larva by differentially affecting the composition of its navigational behavior. To test this hypothesis, we exposed Drosophila larvae to specific odorants to analyze the effect of individual ORN activity on chemotaxis. We used two different behavioral paradigms to analyze the chemotaxis response of larvae to odorants. When tested with five different odorants that elicit strong physiological responses from single ORNs, larval behavioral responses toward each odorant differed in the strength of attraction as well as in the composition of discrete navigational elements, such as runs and turns. Further, behavioral responses to odorants did not correlate with either the strength of odor gradients tested or the sensitivity of each ORN to its cognate odorant. Finally, we provide evidence that wild-type larvae with all ORNs intact exhibit higher behavioral variance than mutant larvae that have only a single pair of functional ORNs. We conclude that individual ORNs contribute differently to the olfactory circuit that instructs chemotactic responses. Our results, along with recent studies from other groups, suggest that ORNs are functionally nonequivalent units. These results have implications for understanding peripheral odor coding.
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http://dx.doi.org/10.1523/ENEURO.0045-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987412PMC
October 2017

Biomimetic composite scaffolds containing bioceramics and collagen/gelatin for bone tissue engineering - A mini review.

Int J Biol Macromol 2016 Dec 15;93(Pt B):1390-1401. Epub 2016 Jun 15.

Amrita Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences & Research Center, Amrita Vishwa Vidyapeetham University, Kochi, 682041 Kerala, India. Electronic address:

Bone is a natural composite material consisting of an organic phase (collagen) and a mineral phase (calcium phosphate, especially hydroxyapatite). The strength of bone is attributed to the apatite, while the collagen fibrils are responsible for the toughness and visco-elasticity. The challenge in bone tissue engineering is to develop such biomimetic composite scaffolds, having a balance between biological and biomechanical properties. This review summarizes the current state of the field by outlining composite scaffolds made of gelatin/collagen in combination with bioactive ceramics for bone tissue engineering application.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.06.043DOI Listing
December 2016

Decreased Staphylococcus aureus and increased osteoblast density on nanostructured electrophoretic-deposited hydroxyapatite on titanium without the use of pharmaceuticals.

Int J Nanomedicine 2014 8;9:1775-81. Epub 2014 Apr 8.

Department of Chemical Engineering and Program in Bioengineering, Northeastern University, Boston, MA, USA ; Center of Excellence for Advanced Materials Research, University of King Abdulaziz, Jeddah, Saudi Arabia.

Background: Plasma-spray deposition of hydroxyapatite on titanium (Ti) has proven to be a suboptimal solution to improve orthopedic-implant success rates, as demonstrated by the increasing number of orthopedic revision surgeries due to infection, implant loosening, and a myriad of other reasons. This could be in part due to the high heat involved during plasma-spray deposition, which significantly increases hydroxyapatite crystal growth into the nonbiologically inspired micron regime. There has been a push to create nanotopographies on implant surfaces to mimic the physiological nanostructure of native bone and, thus, improve osteoblast (bone-forming cell) functions and inhibit bacteria functions. Among the several techniques that have been adopted to develop nanocoatings, electrophoretic deposition (EPD) is an attractive, versatile, and effective material-processing technique.

Objective: The in vitro study reported here aimed to determine for the first time bacteria responses to hydroxyapatite coated on Ti via EPD.

Results: There were six and three times more osteoblasts on the electrophoretic-deposited hydroxyapatite on Ti compared with Ti (control) and plasma-spray-deposited hydroxyapatite on Ti after 5 days of culture, respectively. Impressively, there were 2.9 and 31.7 times less Staphylococcus aureus on electrophoretic-deposited hydroxyapatite on Ti compared with Ti (control) and plasma-spray-deposited hydroxyapatite on Ti after 18 hours of culture, respectively.

Conclusion: Compared with uncoated Ti and plasma-sprayed hydroxyapatite coated on Ti, the results provided significant promise for the use of EPD to improve bone-cell density and be used as an antibacterial coating without resorting to the use of antibiotics.
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http://dx.doi.org/10.2147/IJN.S55733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986289PMC
August 2014

Functional diversity among sensory receptors in a Drosophila olfactory circuit.

Proc Natl Acad Sci U S A 2013 Jun 20;110(23):E2134-43. Epub 2013 May 20.

Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA.

The ability of an animal to detect, discriminate, and respond to odors depends on the function of its olfactory receptor neurons (ORNs), which in turn depends ultimately on odorant receptors. To understand the diverse mechanisms used by an animal in olfactory coding and computation, it is essential to understand the functional diversity of its odor receptors. The larval olfactory system of Drosophila melanogaster contains 21 ORNs and a comparable number of odorant receptors whose properties have been examined in only a limited way. We systematically screened them with a panel of ∼500 odorants, yielding >10,000 receptor-odorant combinations. We identify for each of 19 receptors an odorant that excites it strongly. The responses elicited by each of these odorants are analyzed in detail. The odorants elicited little cross-activation of other receptors at the test concentration; thus, low concentrations of many of these odorants in nature may be signaled by a single ORN. The receptors differed dramatically in sensitivity to their cognate odorants. The responses showed diverse temporal dynamics, with some odorants eliciting supersustained responses. An intriguing question in the field concerns the roles of different ORNs and receptors in driving behavior. We found that the cognate odorants elicited behavioral responses that varied across a broad range. Some odorants elicited strong physiological responses but weak behavioral responses or weak physiological responses but strong behavioral responses.
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http://dx.doi.org/10.1073/pnas.1306976110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677458PMC
June 2013

Controlling airborne cues to study small animal navigation.

Nat Methods 2012 Jan 15;9(3):290-6. Epub 2012 Jan 15.

Department of Physics and Center for Brain Science, Harvard University, Cambridge, Massachusetts, USA.

Small animals such as nematodes and insects analyze airborne chemical cues to infer the direction of favorable and noxious locations. In these animals, the study of navigational behavior evoked by airborne cues has been limited by the difficulty of precisely controlling stimuli. We present a system that can be used to deliver gaseous stimuli in defined spatial and temporal patterns to freely moving small animals. We used this apparatus, in combination with machine-vision algorithms, to assess and quantify navigational decision making of Drosophila melanogaster larvae in response to ethyl acetate (a volatile attractant) and carbon dioxide (a gaseous repellant).
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http://dx.doi.org/10.1038/nmeth.1853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513333PMC
January 2012

Similar odorants elicit different behavioral and physiological responses, some supersustained.

J Neurosci 2011 May;31(21):7891-9

Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520, USA.

An intriguing question in the field of olfaction is how animals distinguish among structurally similar odorants. We systematically analyzed olfactory responses elicited by a panel of 25 pyrazines. We found that structurally similar pyrazines elicit a wide range of behavioral responses from Drosophila larvae. Each pyrazine was tested against all functional receptors of the larval Odor receptor (Or) repertoire, yielding 525 odorant-receptor combinations. Different pyrazines vary markedly in the responses they elicit from the Or repertoire, with most strong responses deriving from two receptors, Or33b and Or59a. Surprisingly, 2-ethylpyrazine and 2-methylpyrazine, which elicit strikingly similar physiological responses across the receptor repertoire, elicit dramatically different behavioral responses. A small fraction of odorant-receptor combinations elicit remarkably long responses. These responses, which we term "supersustained" responses, are receptor specific and odorant specific, and can last for minutes. Such supersustained responses may prevent olfactory neurons from reporting contemporaneous information about the local odor environment. Odors that elicit such responses could provide a novel means of controlling insect pests and vectors of human disease by impairing the location of human hosts, food sources, and mates.
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http://dx.doi.org/10.1523/JNEUROSCI.6254-10.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116233PMC
May 2011

Translation of sensory input into behavioral output via an olfactory system.

Neuron 2008 Jul;59(1):110-24

Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, USA.

We investigate the logic by which sensory input is translated into behavioral output. First we provide a functional analysis of the entire odor receptor repertoire of an olfactory system. We construct tuning curves for the 21 functional odor receptors of the Drosophila larva and show that they sharpen at lower odor doses. We construct a 21-dimensional odor space from the responses of the receptors and find that the distance between two odors correlates with the extent to which one odor masks the other. Mutational analysis shows that different receptors mediate the responses to different concentrations of an odorant. The summed response of the entire receptor repertoire correlates with the strength of the behavioral response. The activity of a small number of receptors is a surprisingly powerful predictor of behavior. Odors that inhibit more receptors are more likely to be repellents. Odor space is largely conserved between two dissimilar olfactory systems.
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http://dx.doi.org/10.1016/j.neuron.2008.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2496968PMC
July 2008

Nuclear trafficking of Drosophila Frizzled-2 during synapse development requires the PDZ protein dGRIP.

Proc Natl Acad Sci U S A 2006 May 8;103(20):7841-6. Epub 2006 May 8.

Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.

The Wingless pathway plays an essential role during synapse development. Recent studies at Drosophila glutamatergic synapses suggest that Wingless is secreted by motor neuron terminals and binds to postsynaptic Drosophila Frizzled-2 (DFz2) receptors. DFz2 is, in turn, endocytosed and transported to the muscle perinuclear area, where it is cleaved, and the C-terminal fragment is imported into the nucleus, presumably to regulate transcription during synapse growth. Alterations in this pathway interfere with the formation of new synaptic boutons and lead to aberrant synaptic structures. Here, we show that the 7 PDZ protein dGRIP is necessary for the trafficking of DFz2 to the nucleus. dGRIP is localized to Golgi and trafficking vesicles, and dgrip mutants mimic the synaptic phenotypes observed in wg and dfz2 mutants. DFz2 and dGRIP colocalize in trafficking vesicles, and a severe decrease in dGRIP levels prevents the transport of endocytosed DFz2 receptors to the nucleus. Moreover, coimmunoprecipitation experiments in transfected cells and yeast two-hybrid assays suggest that the C terminus of DFz2 interacts directly with the PDZ domains 4 and 5. These results provide a mechanism by which DFz2 is transported from the postsynaptic membrane to the postsynaptic nucleus during synapse formation and implicate dGRIP as an essential molecule in the transport of this signal.
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http://dx.doi.org/10.1073/pnas.0600387103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472532PMC
May 2006

Wingless signaling at synapses is through cleavage and nuclear import of receptor DFrizzled2.

Science 2005 Nov;310(5752):1344-7

Department of Neurobiology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Wingless secretion provides pivotal signals during development by activating transcription of target genes. At Drosophila synapses, Wingless is secreted from presynaptic terminals and is required for synaptic growth and differentiation. Wingless binds the seven-pass transmembrane DFrizzled2 receptor, but the ensuing events at synapses are not known. We show that DFrizzled2 is endocytosed from the postsynaptic membrane and transported to the nucleus. The C terminus of DFrizzled2 is cleaved and translocated into the nucleus; the N-terminal region remains just outside the nucleus. Translocation of DFrizzled2-C into the nucleus, but not its cleavage and transport, depends on Wingless signaling. We conclude that, at synapses, Wingless signal transduction occurs through the nuclear localization of DFrizzled2-C for potential transcriptional regulation of synapse development.
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http://dx.doi.org/10.1126/science.1117051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535279PMC
November 2005

FASt remodeling of synapses in Drosophila.

Curr Opin Neurobiol 2003 Oct;13(5):527-34

Department of Neurobiology, University of Massachusetts Medical School, Aaron Lazare Medical Research Building, 364 Plantation Street, Worcester, MA 01605-2324, USA.

Cell adhesion molecules of the immunoglobulin superfamily (IgCAMS) play pivotal roles during synapse development and remodeling, being required in both activity-dependent and activity independent aspects of these processes. Recent advances using the fruit fly neuromuscular junction, as well as the mollusk Aplysia californica, have provided evidence for at least three mechanisms by which levels of IgCAMs are regulated during synapse remodeling--activity-dependent regulation of IgCAM clustering by PSD-95-type molecules, IgCAM internalization by MAP kinase pathway activation, and postsynaptic IgCAM exocytosis. These studies offer convincing evidence that synaptic cell adhesion brings about both negative and positive forces that stabilize synapses, while maintaining their ability to change in an activity-dependent manner.
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http://dx.doi.org/10.1016/j.conb.2003.09.008DOI Listing
October 2003

Drosophila amphiphysin functions during synaptic Fasciclin II membrane cycling.

J Neurosci 2003 Nov;23(33):10710-6

Molecular and Cellular Biology Program, University of Massachusetts, Amherst, Massachusetts 01003, USA.

Recent studies have revealed that endocytosis and exocytosis of postsynaptic receptors play a major role in the regulation of synaptic function, particularly during long-term potentiation and long-term depression. Interestingly, many of the proteins implicated in exocytosis and endocytosis of synaptic vesicles are also involved in postsynaptic protein cycling. In vertebrates, Amphiphysin is postulated to function during endocytosis in nerve terminals; however, several recent reports using a Drosophila amphiphysin (damph) null mutant have failed to substantiate such a role at fly synapses. In addition, Damph is surprisingly enriched at the postsynapse. Here we used the glutamatergic larval neuromuscular junction to study the synaptic role of Damph. By selectively labeling internal and external pools of the cell adhesion molecule Fasciclin II (FasII), and by using a novel in vivo surface FasII immunocapture protocol, we show that the level of external FasII is decreased in damph mutants although the total level of FasII remains constant. In vivo FasII internalization assays indicate that the reincorporation of FasII molecules into the cell surface is severely inhibited in damph mutants. Moreover, we show that blocking soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) function in postsynaptic muscle cells interferes with FasII exocytosis. These experiments suggest that in Drosophila, Damph functions during SNARE-dependent postsynaptic FasII membrane cycling. This study challenges the notion that synaptic Amphiphysin is involved exclusively in endocytosis and suggests a novel role for this protein in postsynaptic exocytosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6740931PMC
November 2003

Wnts and TGF beta in synaptogenesis: old friends signalling at new places.

Nat Rev Neurosci 2003 Feb;4(2):113-20

Department of Biology and Molecular and Cellular Biology Graduate Program, University of Massachusetts at Amherst, Amherst, Massachusetts 01003, USA.

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http://dx.doi.org/10.1038/nrn1036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3503525PMC
February 2003

Recruitment of scribble to the synaptic scaffolding complex requires GUK-holder, a novel DLG binding protein.

Curr Biol 2002 Apr;12(7):531-9

Department of Biology and Molecular and Cellular Biology Program, University of Massachusetts, Amherst, MA 01003, USA.

Background: Membrane-associated guanylate kinases (MAGUKs), such as Discs-Large (DLG), play critical roles in synapse maturation by regulating the assembly of synaptic multiprotein complexes. Previous studies have revealed a genetic interaction between DLG and another PDZ scaffolding protein, SCRIBBLE (SCRIB), during the establishment of cell polarity in developing epithelia. A possible interaction between DLG and SCRIB at synaptic junctions has not yet been addressed. Likewise, the biochemical nature of this interaction remains elusive, raising questions regarding the mechanisms by which the actions of both proteins are coordinated.

Results: Here we report the isolation of a new DLG-interacting protein, GUK-holder, that interacts with the GUK domain of DLG and which is dynamically expressed during synaptic bouton budding. We also show that at Drosophila synapses DLG colocalizes with SCRIB and that this colocalization is likely to be mediated by direct interactions between GUKH and the PDZ2 domain of SCRIB. We show that DLG, GUKH, and SCRIB form a tripartite complex at synapses, in which DLG and GUKH are required for the proper synaptic localization of SCRIB.

Conclusions: Our results provide a mechanism by which developmentally important PDZ-mediated complexes are associated at the synapse.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4661175PMC
http://dx.doi.org/10.1016/s0960-9822(02)00758-3DOI Listing
April 2002