Neuromuscular Junctions in Drosophila
Neuromuscular Junctions in Drosophila

Author:

Publisher: Academic Press

Published: 1999-04-29

Total Pages: 317

ISBN-13: 0080857779

DOWNLOAD EBOOK

Neuromuscular Junctions in Drosophila gathers the main contributions that research using the fruit fly Drosophila melanogaster has made in the area of synapse development, synapse physiology, and excitability of muscles and nerve cells. The chapters in this book represent a synthesis of major advances in our understanding of neuronal development and synaptic physiology, which have been obtained using the above approach.This book is directed to the general neuroscience audience: researchers, instructors, graduate students, and advanced undergraduates who are interested in the mechanisms of synapse development and physiology. However, the book will also be a valuable resource for those that use the fruit fly as a model system in their laboratories. Key Features* Synthesizes the genetic approaches used to study synaptic development and function at the neuromuscular junction, using flies as a model system* Covers major recent advances in muscle development, pathfinding, synapse maturation and plasticity, exo- and endocytosis, and ion channel function* Written in clear language that is easily understandable to readers not already familiar with fruit fly research* Includes numerous diagrams and extensive reference lists

Molecular Mechanisms that Regulate Synaptic Efficacy at the Drosophila Neuromuscular Junction
Molecular Mechanisms that Regulate Synaptic Efficacy at the Drosophila Neuromuscular Junction

Author: Stephanie D. Albin

Publisher:

Published: 2006

Total Pages: 298

ISBN-13:

DOWNLOAD EBOOK

The molecular mechanisms underlying the retrograde control of presynaptic neurotransmitter release at the NMJ are not well understood. Here we describe the identification of the first known inhibitor of synaptic homeostasis. Identification of the pathways through which this inhibitor act may eventually lead to a greater understanding of the mechanisms that regulate homeostasis.

Genetic Studies of Synaptic Development and Neurodegeneration in Drosophila
Genetic Studies of Synaptic Development and Neurodegeneration in Drosophila

Author:

Publisher:

Published: 2014

Total Pages: 146

ISBN-13:

DOWNLOAD EBOOK

Synaptic development and neural maintenance are essential for proper neural function. In my dissertation, I investigated the molecular and genetic mechanisms of synaptic development and neural maintenance using Drosophila as an experimental model. In part one of my thesis work, I focused on the regulation of synaptic development. To identify novel regulators of synaptic development, we used the Drosophila larval NMJ as a model system and conducted a forward genetic screen for variants affecting NMJ morphology in a collection of isogenic lines isolated from natural populations of Drosophila melanogaster from Africa. I successfully identified the lipocalin family member, Neural Lazarillo (NLaz) as a negative regulator of NMJ development. I extended this discovery by examining the effect of other family members on NMJ development. Analysis of Glial Lazarillo (GLaz) and its human ortholog, Apolipoprotein D (ApoD), uncovered a novel mechanism regulating NMJ development, in which glial expression of GLaz (or ApoD) negatively controls NMJ development by down-regulating a retrograde insulin signaling mechanism that promotes NMJ growth. This finding has identified a novel role for lipocalin and insulin signaling in the regulation of NMJ development, furthering our understanding of the complex mechanisms that mediate synaptic development and whose impairment in humans could lead to neurological disease. The goal of the second part of my work was to identify novel mechanisms for age-dependent neural maintenance. In a forward genetic screen for neurodegeneration mutants in Drosophila, we have identified a mutation of defense repressor 1 (dnr1) that encodes an inhibitor of the immune deficiency (Imd) pathway. Further experiments revealed that loss of dnr1 causes shortened lifespan and age-dependent neurodegeneration associated with activation of the Imd pathway and elevated expression of antimicrobial peptides (AMP). Furthermore, we demonstrated that over-activation of innate immune response in the brain by bacterial infection in the brain or neural overexpression of AMP genes, is responsible for neurodegeneration. Following this work, we have found that mutations of trabid, encoding another negative regulator of Imd pathway also causes neurodegeneration owing to over-activation of the innate immune response. These results may have important implications for the role of neuroinflammation in human neurodegenerative diseases.

Regulation of Synaptic Structure and Function at the Drosophila Neuromuscular Junction
Regulation of Synaptic Structure and Function at the Drosophila Neuromuscular Junction

Author: Aline Dorret Blunk

Publisher:

Published: 2013

Total Pages: 177

ISBN-13:

DOWNLOAD EBOOK

Neuronal communication requires a spatially organized synaptic apparatus to coordinate neurotransmitter release from synaptic vesicles and activation of postsynaptic receptors. Structural remodeling of synaptic connections can strengthen neuronal communication and synaptic efficacy during development and behavioral plasticity. Here, I describe experimental approaches that have revealed how the actin cytoskeleton participates in transynaptic signaling to control synapse assembly. I also describe my studies on how regulation of endocytic trafficking controls synaptic growth during neuronal development. To identify regulators of synapse assembly, I carried out a large-scale EMS mutagenesis screen of the second chromosome. From this screen I identified a mutation in actin 57B that disrupts synaptic morphology and presynaptic active zone organization. Actin 57B is one of six actin genes in Drosophila and is expressed in body wall muscle during larval development. The isolated allele harbors a point mutation disrupting a highly conserved amino acid present throughout the actin family. Homozygous mutant larvae show impaired alignment and spacing of presynaptic active zones. Additionally, disruption of the organization of the postsynaptic density is observed, with mislocalization of the Spectrin cytoskeleton and the PSD-homolog Disc-Large. Phallodin staining reveals a severe disruption of postsynaptic actin surrounding presynaptic boutons, with the formation of aberrant large actin swirls. Based on these results, we hypothesize that the loss of a synaptic interaction mediated by actin 57B leads to disruption of postsynaptic cytoskeletal organization and dysregulation of signals required to organize presynaptic active zones. Additionally, I present data that provide new insights into the mechanisms controlling synaptic growth signaling during transit through the endocytic pathway. Nervous Wreck (Nwk) is a presynaptic F-BAR/SH3 protein that regulates synaptic growth signaling in Drosophila. Here, I show that Nwk acts through a physical interaction with Sorting Nexin 16 (SNX16). SNX16 promotes synaptic growth signaling by activated BMP receptors, and live imaging in neurons reveals that SNX16-positive early endosomes undergo transient interactions with Nwkcontaining recycling endosomes. We identify an alternative signal termination pathway in the absence of Snx16 that is controlled by ESCRT-mediated internalization of receptors into the endosomal lumen. Our results define a presynaptic trafficking pathway mediated by SNX116, NWK and the ESCRT complex that functions to control synaptic growth signaling at the interface between endosomal compartments. Together, these experiments have expanded our understanding of the molecular mechanisms that control synaptic growth and assembly, highlighting the role of the postsynaptic actin cytoskeleton and the presynaptic endosomal trafficking pathway as key regulators.

Genetic and Evolutionary Analysis of the Drosophila Larval Neuromuscular Junction
Genetic and Evolutionary Analysis of the Drosophila Larval Neuromuscular Junction

Author:

Publisher:

Published: 2012

Total Pages: 292

ISBN-13:

DOWNLOAD EBOOK

Although evolution of brains and behaviors is of fundamental biological importance, we lack comprehensive understanding of the general principles governing these processes or the specific mechanisms and molecules through which the evolutionary changes are effected. Because synapses are the basic structural and functional units of nervous systems, one way to address these problems is to dissect the genetic and molecular pathways responsible for morphological evolution of a defined synapse. I have undertaken such an analysis by examining morphology of the larval neuromuscular junction (NMJ) in wild caught D. melanogaster as well as in over 20 other species of Drosophila. Whereas variation in NMJ morphology within a species is limited, I discovered a surprisingly extensive variation among different species. Compared with evolution of other morphological traits, NMJ morphology appears to be evolving very rapidly. Moreover, my data indicate that natural selection rather than genetic drift is primarily responsible for evolution of NMJ morphology. To dissect underlying molecular mechanisms that may govern NMJ growth and evolutionary divergence, I focused on a naturally occurring variant in D. melanogaster that causes NMJ overgrowth. I discovered that the variant mapped to Mob2, a gene encoding a kinase adapter protein originally described in yeast as a member of the Mitotic Exit Network (MEN). I have subsequently examined mutations in the Drosophila orthologs of all the core components of the yeast MEN and found that all of them function as part of a common pathway that acts presynaptically to negatively regulate NMJ growth. As in the regulation of yeast cytokinesis, these components of the MEN appear to act ultimately by regulating actin dynamics during the process of bouton growth and division. These studies have thus led to the discovery of an entirely new role for the MEN--regulation of synaptic growth--that is separate from its function in cell division. This work has identified a rich source of material for discovery of novel genes and mechanisms that regulate synaptic growth and development, and has also provided new insights into the mechanisms that underlie morphological evolution of nervous systems.