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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The Role of Calcium Flux in the Regulation of Filopodia Dynamics

Ademuyiwa, Omolade Mary 12 August 2019 (has links)
No description available.
2

Spatio-temporal properties of membrane-localized actin nucleating complexes

Kondo, Hanae January 2019 (has links)
The actin cytoskeleton plays a vital role in various biological processes such as cell migration, morphogenesis, and intracellular trafficking. The polymerization of actin filaments at membranes provides the force for generating dynamic actin structures such as protrusions and invaginations that drive these processes. In filopodia, which are finger-like protrusions comprised of bundled actin filaments, actin regulatory proteins are believed to assemble a distal 'tip complex' which stimulates actin nucleation at the membrane. However how these regulators collectively behave in a macromolecular complex still remains poorly understood. To understand the macromolecular nature of these complexes, I investigated the dynamic properties and spatial organization of actin regulatory factors, using an in vitro reconstitution assay for filopodia-like structures (FLS) utilizing artificial lipid bilayers and Xenopus laevis egg extracts. FRAP analysis of seven actin regulatory factors (Toca-1, N-WASP, GTPase-binding domain, Ena, VASP, Diaph3, Fascin) revealed that the FLS tip complex has both dynamic and stable properties, with different proteins displaying distinct dynamics. Further analyses on the membrane-binding protein Toca-1 showed that its dynamic turnover is controlled by interactions with actin and exchange of molecules with solution. Single-molecule localization microscopy resolved the nanoscale organization of Toca-1, showing its arrangement into flat plaque-like and narrowly elevated tubular substructures. Plaque-like structures showed similarities to phase-transition patterns, while tubule-like structures closely resembled those previously found to decorate membrane tubules in vitro, which are thought to be involved in endocytic membrane remodeling. Endocytic accessory proteins such as SNX9 and Dynamin2 were also found to localize to FLS tips. This work provides new insights into the dynamics and organization of protein ensembles at actin nucleation sites, and proposes a novel link between endocytosis and filopodia formation, which is relevant to understanding how cells decide when and where to assemble actin at the membrane.
3

Modelling and Simulation of Filopodial Protrusion

Ezeanochie, Tochukwu Chinedu January 2015 (has links)
The effect of substrate surface topology on the interaction of living cells with inanimate substrates is a well-established phenomenon. When cells are placed on biomaterials, they outgrow protrusions called filopodia that sense surface features in their immediate surroundings and initiate the formation of stable cell adhesion complexes closer to the cell body. Adhesion proteins permit filopodia to constantly explore the surrounding microenvironment. A better understanding of the relationship of filopodia with surface features is highly relevant for exploiting custom-made surfaces to guide cell activity. In this work, mathematical modeling and simulation were used to describe different phenomena related to the interaction of a filopodium with its microenvironment, with the aim of reproducing experimentally observed phenomena associated to filopodia growth and interactions with substrates. The Kelvin Voigt model was used for the viscoelastic response of filopodia. Result predict filopodia protrusion under test conditions and helps improving our understanding on the effect of substrate topology on the biomechanical response of filopodial extensions.
4

Regulation of filopodia dynamics is critical for proper synapse formation

Gauthier-Campbell, Catherine 05 1900 (has links)
Despite the importance of proper synaptogenesis in the CNS, the molecular mechanisms that regulate the formation and development of synapses remain poorly understood. Indeed, the mechanisms through which initial synaptic contacts are established and modified during synaptogenesis have not been fully determined and a precise understanding of these mechanisms may shed light on synaptic development, plasticity and many CNS developmental diseases. The development and formation of spiny synapses has been thought to occur via filopodia shortening followed by the recruitment of proper postsynaptic proteins, however the precise function of filopodia remains controversial. Thus the goal of this study was to investigate the dynamics of dendritic filopodia and determine their role in the development of synaptic contacts. We initially define and characterize short lipidated motifs that are sufficient to induce process outgrowth. Indeed, the palmitoylated protein motifs of GAP-43 and paralemmin are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and dendritic branches in neurons. We showed that the morphological changes induced by these FIMs (filopodia inducing motifs) require on-going protein palmitoylation and are modulated by a specific GTPase, Cdc42, that regulates actin dynamics. We also show that their function is palmitoylation dependent and is dynamically regulated by reversible protein palmitoylation. Significantly, our work suggests a general role for those palmitoylated motifs in the development of structures important for synapse formation and maturation. We combined several approaches to monitor the formation and development of filopodia. We show that filopodia continuously explore the environment and probe for appropriate contacts with presynaptic partners. We find that shortly after establishing a contact with axons, filopodia induce the recruitment of presynaptic elements. Remarkably, we find that expression of acylated motifs or the constitutively active form of cdc-42 enhances filopodia number and motility, but reduces the recruitment of synaptophysin positive presynaptic elements and the probability of forming stable axo-dendritic contacts. We provide evidence for the rapid transformation of filopodia to spines within hours of imaging live neurons and reveal potential molecules that accelerate this process.
5

Regulation of filopodia dynamics is critical for proper synapse formation

Gauthier-Campbell, Catherine 05 1900 (has links)
Despite the importance of proper synaptogenesis in the CNS, the molecular mechanisms that regulate the formation and development of synapses remain poorly understood. Indeed, the mechanisms through which initial synaptic contacts are established and modified during synaptogenesis have not been fully determined and a precise understanding of these mechanisms may shed light on synaptic development, plasticity and many CNS developmental diseases. The development and formation of spiny synapses has been thought to occur via filopodia shortening followed by the recruitment of proper postsynaptic proteins, however the precise function of filopodia remains controversial. Thus the goal of this study was to investigate the dynamics of dendritic filopodia and determine their role in the development of synaptic contacts. We initially define and characterize short lipidated motifs that are sufficient to induce process outgrowth. Indeed, the palmitoylated protein motifs of GAP-43 and paralemmin are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and dendritic branches in neurons. We showed that the morphological changes induced by these FIMs (filopodia inducing motifs) require on-going protein palmitoylation and are modulated by a specific GTPase, Cdc42, that regulates actin dynamics. We also show that their function is palmitoylation dependent and is dynamically regulated by reversible protein palmitoylation. Significantly, our work suggests a general role for those palmitoylated motifs in the development of structures important for synapse formation and maturation. We combined several approaches to monitor the formation and development of filopodia. We show that filopodia continuously explore the environment and probe for appropriate contacts with presynaptic partners. We find that shortly after establishing a contact with axons, filopodia induce the recruitment of presynaptic elements. Remarkably, we find that expression of acylated motifs or the constitutively active form of cdc-42 enhances filopodia number and motility, but reduces the recruitment of synaptophysin positive presynaptic elements and the probability of forming stable axo-dendritic contacts. We provide evidence for the rapid transformation of filopodia to spines within hours of imaging live neurons and reveal potential molecules that accelerate this process.
6

Regulation of filopodia dynamics is critical for proper synapse formation

Gauthier-Campbell, Catherine 05 1900 (has links)
Despite the importance of proper synaptogenesis in the CNS, the molecular mechanisms that regulate the formation and development of synapses remain poorly understood. Indeed, the mechanisms through which initial synaptic contacts are established and modified during synaptogenesis have not been fully determined and a precise understanding of these mechanisms may shed light on synaptic development, plasticity and many CNS developmental diseases. The development and formation of spiny synapses has been thought to occur via filopodia shortening followed by the recruitment of proper postsynaptic proteins, however the precise function of filopodia remains controversial. Thus the goal of this study was to investigate the dynamics of dendritic filopodia and determine their role in the development of synaptic contacts. We initially define and characterize short lipidated motifs that are sufficient to induce process outgrowth. Indeed, the palmitoylated protein motifs of GAP-43 and paralemmin are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and dendritic branches in neurons. We showed that the morphological changes induced by these FIMs (filopodia inducing motifs) require on-going protein palmitoylation and are modulated by a specific GTPase, Cdc42, that regulates actin dynamics. We also show that their function is palmitoylation dependent and is dynamically regulated by reversible protein palmitoylation. Significantly, our work suggests a general role for those palmitoylated motifs in the development of structures important for synapse formation and maturation. We combined several approaches to monitor the formation and development of filopodia. We show that filopodia continuously explore the environment and probe for appropriate contacts with presynaptic partners. We find that shortly after establishing a contact with axons, filopodia induce the recruitment of presynaptic elements. Remarkably, we find that expression of acylated motifs or the constitutively active form of cdc-42 enhances filopodia number and motility, but reduces the recruitment of synaptophysin positive presynaptic elements and the probability of forming stable axo-dendritic contacts. We provide evidence for the rapid transformation of filopodia to spines within hours of imaging live neurons and reveal potential molecules that accelerate this process. / Medicine, Faculty of / Graduate
7

Effects of advection on non-equilibrium systems

Barrett-Freeman, Conrad January 2012 (has links)
We study a number of non-equilibrium models of interest to both active matter and biological physicists. Using microscopic agent-based simulation as well as numerical integration of stochastic PDEs, we uncover the non-trivial behaviour exhibited when active transport, or an advection field, is added to out of equilibrium systems. When gravity is included in the celebrated Fisher-Kolmogoro Petrovsky Piscouno (F-KPP) equation, to model sedimentation of active bacteria in a container, we observe a discontinuous phase transition between a `sedimentation' and a `growth' phase, which should in principle be observable in real systems. With the addition of multiplicative noise, the resulting model contains, as its limits, both the bacterial sedimentation previously described and the fluctuating hydrodynamic description of Directed Percolation (DP), an important and well-studied non-equilibrium system whose physics incorporate many universal features which are typical of systems with absorbing states. We map out the phase diagram describing all the systems in between these two limiting cases, finding that adding an advection term, however small, immediately lifts the resulting system out of the DP universality class. Furthermore, we find two distinct low-density phases separated by a dynamical phase transition reminiscent of a spinodal transition. Finally, we attempt to improve the current diffusion-limited model for the growth of filopodia, which are intriguing networks of actin fibres used by moving cells to sense their environment. By the addition of directed transport of actin monomers to the fibre tip complex by myosin molecular motors, we show that, under appropriate conditions, the resulting dynamics may be more efficient that transport by diffusion alone, which would result in filopodial lengths better corresponding to experimental observation.
8

ROLES OF NEUROTRANSMITTERS IN THE REGULATION OF NEURONAL ELECTRICAL PROPERTIES AND GROWTH CONE MOTILITY

Zhong, Lei 24 July 2013 (has links)
In addition to acting in synaptic transmission, neurotransmitters have been shown to play roles in the development of nervous system. Developing neurons extend neurites to connect to their target cells, and growth cones at the tip of growing neurites are critical for pathfinding. Although evidence for the regulation of axonal growth and growth cone guidance by neurotransmitters and neuromodulators is emerging, less is known about the mechanisms by which neurotransmitters affect developing neurons. Here, I focus on three neurotransmitters/ neuromodulators and describe their actions (a) at the level of growth cone, especially on filopodia, which serve as sensors that allow growth cones to probe the environment they are traversing, and (b) on how neurotransmitters modulate neuronal electrical properties, which, in itself, have been shown to affect neurite extension. The goals of this dissertation are to investigate 1) the cholinergic modulation of neuronal activity and its effects on growth cone motility; 2) the excitatory modulation of neuronal excitability by nitric oxide (NO); and 3) the inhibitory modulation of neuronal activity by dopamine (DA). The work uses a well-established model system to investigate growth cone motility and neuronal activity: identified neurons from the pond snail Helisoma trivolvis studied in cell culture or in the intact ganglion in situ. The study of B5 neurons demonstrates that acetylcholine (ACh) induces filopodial elongation, which is mediated by opening of nicotinic ACh receptors, membrane depolarization, and elevation of intracellular Ca level in growth cones. This dissertation also shows that NO inhibits two types of Ca-activated K channels to depolarize the membrane potential of B19 neurons. Additionally, the study reveals that DA serves as an inhibitory neurotransmitter to hyperpolarize and silence the electrical activity of firing B5 neurons via a D2-like receptor/PLC/K channel pathway. Taken together, this dissertation elucidates novel cellular mechanisms through which neurotransmitters can regulate growth cone motility and neuronal electrical properties, further supporting evidence for potential roles of neurotransmitters in axon pathfinding and synaptic transmission in vivo.
9

Roles of Neurotransmitters in the Regulation of Neuronal Electrical Properties and Growth Cone Motility

Zhong, Lei 24 July 2013 (has links)
In addition to acting in synaptic transmission, neurotransmitters have been shown to play roles in the development of nervous system. Developing neurons extend neurites to connect to their target cells, and growth cones at the tip of growing neurites are critical for pathfinding. Although evidence for the regulation of axonal growth and growth cone guidance by neurotransmitters and neuromodulators is emerging, less is known about the mechanisms by which neurotransmitters affect developing neurons. Here, I focus on three neurotransmitters/ neuromodulators and describe their actions (a) at the level of growth cone, especially on filopodia, which serve as sensors that allow growth cones to probe the environment they are traversing, and (b) on how neurotransmitters modulate neuronal electrical properties, which, in itself, have been shown to affect neurite extension. The goals of this dissertation are to investigate 1) the cholinergic modulation of neuronal activity and its effects on growth cone motility; 2) the excitatory modulation of neuronal excitability by nitric oxide (NO); and 3) the inhibitory modulation of neuronal activity by dopamine (DA). The work uses a well-established model system to investigate growth cone motility and neuronal activity: identified neurons from the pond snail Helisoma trivolvis studied in cell culture or in the intact ganglion in situ. The study of B5 neurons demonstrates that acetylcholine (ACh) induces filopodial elongation, which is mediated by opening of nicotinic ACh receptors, membrane depolarization, and elevation of intracellular Ca level in growth cones. This dissertation also shows that NO inhibits two types of Ca-activated K channels to depolarize the membrane potential of B19 neurons. Additionally, the study reveals that DA serves as an inhibitory neurotransmitter to hyperpolarize and silence the electrical activity of firing B5 neurons via a D2-like receptor/PLC/K channel pathway. Taken together, this dissertation elucidates novel cellular mechanisms through which neurotransmitters can regulate growth cone motility and neuronal electrical properties, further supporting evidence for potential roles of neurotransmitters in axon pathfinding and synaptic transmission in vivo.
10

Roles Of Gaseous Neuromodulators NO And CO In Determining Neuronal Electrical Activity And Growth Cone Motility

Estes, Stephen 17 December 2015 (has links)
Throughout neuronal development, bouts of spontaneous electrical activity are critical for the proper wiring of neuronal connections. Alterations in firing activity can affect growth cones, which tip developing and regenerating neurites and are responsible for the integration of extracellular guidance cues into pathfinding behaviors. While growing evidence implicates gaseous signaling molecules, nitric oxide (NO) and carbon monoxide (CO), as modulators of neuronal firing activity, less is understood about how they affect growth cone motility. Therefore, in this dissertation, I focus on how NO and CO affect electrical activity of developing and regenerating neurons and how these effects translate into changes at the growth cone level. The specific goals of this dissertation were to investigate 1) the neuron-type-specific effects of NO on growth cone motility; 2) the role of CO in the regulation of neuronal firing activity and excitability; and 3) the role CO plays in the regulation of growth cone motility. Using the well-established developmental model, Helisoma trivolvis, neurons were isolated in single-cell culture allowing for the maximal control over environmental conditions for the direct characterization of NO and CO. In the study of NO, differences in B5 and B19 growth cone responses to NO were due to neuron-type-specific differences in action potential duration. Moreover, the non-responsive B19 growth cones could be made responsive to NO treatment upon the pharmacological broadening of its action potentials. While NO has been found to increase firing activity, the study of CO revealed that CO had the opposite effect on electrical activity, silencing spontaneous firing activity and decreasing neuronal excitability. The study of CO on growth cone motility showed that CO increased growth cone filopodial length through a soluble guanylyl cyclase/protein kinase G/ryanodine receptor mediated pathway without inducing robust increases in growth cone calcium concentration. Taken together, this dissertation reveals new insight into how NO and CO regulate electrical activity and growth cone motility, providing evidence for these gases as important signaling messengers during for the development and regeneration of nervous system.

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