Molecular Mechanisms Of Axon Growth And Regeneration
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Molecular Mechanisms Of Axon Growth And Regeneration
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Author : Dana Watt
language : en
Publisher:
Release Date : 2015
Molecular Mechanisms Of Axon Growth And Regeneration written by Dana Watt and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2015 with Electronic dissertations categories.
Neurons are cells with unique and extremely polarized morphologies. The axon allows communication between the cell soma and the distantly located synaptic terminal and can extend up to one meter in humans. This exceptional cellular structure therefore has specialized biological processes dedicated to its growth, maintenance and regeneration. The structure that carries out axon elongation during development and regeneration is the growth cone, which features a cytoskeletal structure that is both highly dynamic yet consistent in overall organization. The growth cone coordinates a leading edge of dynamic actin with the microtubules of the growing axon, enabling directed outgrowth while maintaining the structural integrity of the axon. In the axon, microtubules are oriented uniformly with their plus-ends facing away from the cell body, providing directionality for cargo transport streams. Axonal transport is critical during growth and after the axon has reached its target to ensure proper distribution of organelles and other necessary components of the axonal biology machinery. Axon transport is especially important because the axon is capable of independently carrying out tasks ranging from protein synthesis to synaptic transmission. Therefore a thorough understanding of microtubule biology and axon transport is critical for understanding how axons grow during development and regeneration. I first investigated the role of a neuron-specific molecular motor adaptor, JIP3, in axon elongation. JIP3 had been previously demonstrated to bind both the anterograde motor kinesin-1 and the retrograde motor complex dynein/dynactin, generating cargo-specific directional transport in the axon. Furthermore, our lab had also demonstrated that JIP3 was capable of binding directly and activating dimeric kinesin heavy chain (KHC) for motility. While the function of dimeric KHC is still debated, tetrameric kinesin-1 is known as the primary anterograde motor in axons. I therefore investigated the role of JIP3 in regulating tetrameric kinesin-1 motility, and the functional significance of this interaction in axons. I used a total internal reflection fluorescence (TIRF)-based single molecule imaging assay to demonstrate that JIP3 binds to the kinesin-1 tetramer in at least a 2:1 ratio. I also used this TIRF assay to show that JIP3 binding to the cargo-adapting kinesin light chain (KLC) activated tetrameric kinesin-1 for microtubule binding, while JIP3 binding to KHC activated tetrameric kinesin-1 motility along microtubules. Furthermore, while the JIP3/KLC interaction is dispensable for axon growth and regeneration in neurons in vitro, the JIP3/KHC interaction is necessary for both these activities. This work demonstrated that a single molecule can activate tetrameric kinesin-1 for microtubule binding and motility. Furthermore, this work demonstrated that regulation of molecular motor activity supports axon growth and regeneration. I next investigated the small GTPase Ran and its role in axon elongation. Ran is best known for its canonical function as a nuclear transport protein, but it can also stabilize microtubules during mitotic spindle formation and is located in the axon. While Ran has a proposed role in regulating a retrograde injury signaling complex in adult axons, it is unknown whether Ran also regulates cytoskeletal dynamics in developing axons. I used Ran knockdown to demonstrate that Ran promotes axon elongation on growth-promoting substrates, and restricts axon elongation on growth-inhibiting substrates. This effect is at least partially mediated by microtubule dynamics, as microtubule imaging using a cell-permeable pan-tubulin marker showed decreased microtubule dynamics in Ran knockdown cells on growth-promoting substrates. Furthermore, I demonstrated that a Ran activating protein, RanBP10, is enriched in growth cones and promotes axon elongation, and that both of these phenomena are Ran-dependent. This work raises the exciting possibility that Ran controls microtubule dynamics in the growth cone, distinct from its canonical role in nucleocytoplasmic trafficking.
Molecular Mechanisms Of Axon Guidance In The Developing Spinal Cord
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Author : Liseth M. Parra
language : en
Publisher:
Release Date : 2009
Molecular Mechanisms Of Axon Guidance In The Developing Spinal Cord written by Liseth M. Parra and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009 with categories.
The formation of intricate neural circuits requires that nascent axons navigate the complex environment of the developing embryo and precisely determine the trajectories that would lead them to their final synaptic targets. Although many guidance cues and their receptors have been identified, the intracellular signaling cascades that control and direct axonal growth remained to be fully understood. Developing axons constantly reassess the immediate environment to distinguish between a myriad of guidance molecules that are simultaneously present along their trajectory. Exactly how the axon interpret these signals at a specific time and space are limited, thus understanding how guidance cues work in concert during axonal pathfinding is a major goal in developmental neurobiology and in the regeneration of axonal connections after injury and disease. In this dissertation we studied the pathfinding of spinal cord commissural axons to understand the molecular mechanisms underlying changes in axonal responses from attraction to repulsion during floor plate crossing at the spinal cord ventral midline. Here, we found that chemorepellent signals emanating from floor plate cells of the Slit and class 3 Semaphorin family of proteins synergize in vitro to repel precrossing commissural axons possibly through Neuropilin2 pathways. In addition, we propose that Sonic Hedgehog (Shh) plays a pivotal role in mediating commissural axon repulsive guidance during floor plate crossing. We provide evidence that Shh is a regulator of class 3 Semaphorin signals in precrossing axons and specifically show that knockdown of Shh pathway components, Patched1 (PTC1) and Smoothened (Smo) disrupted proper guidance of commissural axons during floor plate crossing. We also show that both Smo and PTC1 are expressed around the developmental stages we studied and are key determinants of this regulation. The third major finding of this dissertation is that the activation of Semaphorin3 signals by Shh might be induced through the alteration of cAMP/PKA levels via Smo dependent activation of inhibitory G alpha proteins. Together the data presented in this dissertation propose new exciting models in which axon guidance regulatory pathways can induce profound changes in axonal navigational responses by successfully integrating and interpreting signaling inputs from external and internal axon guidance systems.
Axon Growth And Regeneration
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Author : Andrew J. Murray
language : en
Publisher:
Release Date : 2014
Axon Growth And Regeneration written by Andrew J. Murray and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2014 with Axons categories.
Axon Growth And Regeneration Part 2
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Author :
language : en
Publisher: Academic Press
Release Date : 2012-12-31
Axon Growth And Regeneration Part 2 written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-31 with Medical categories.
Leading authors review state-of-the-art in their field of investigation and provide their views and perspectives for future research. Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered. All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist Leading authors review state-of-the-art in their field of investigation and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist
Axon Growth And Regeneration Part 1
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Author :
language : en
Publisher: Academic Press
Release Date : 2012-12-31
Axon Growth And Regeneration Part 1 written by and has been published by Academic Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2012-12-31 with Science categories.
Published since 1959, International Review of Neurobiology is a well-known series appealing to neuroscientists, clinicians, psychologists, physiologists, and pharmacologists. Led by an internationally renowned editorial board, this important serial publishes both eclectic volumes made up of timely reviews and thematic volumes that focus on recent progress in a specific area of neurobiology research. This volume reviews existing theories and current research surrounding Axon Growth and Regeneration. Leading authors review state-of-the-art in their field of investigation and provide their views and perspectives for future research Chapters are extensively referenced to provide readers with a comprehensive list of resources on the topics covered All chapters include comprehensive background information and are written in a clear form that is also accessible to the non-specialist
Molecular Mechanisms In Brain Regeneration
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Author : Bipin Abhipradnya
language : en
Publisher:
Release Date : 2023-10-30
Molecular Mechanisms In Brain Regeneration written by Bipin Abhipradnya and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2023-10-30 with categories.
Axon Regeneration
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Author : Ava J. Udvadia
language : en
Publisher: Humana
Release Date : 2024-03-22
Axon Regeneration written by Ava J. Udvadia and has been published by Humana this book supported file pdf, txt, epub, kindle and other format this book has been release on 2024-03-22 with Medical categories.
This volume covers a wide range of approaches utilized to decipher cellular and molecular mechanisms that contribute to successful nerve regeneration leading to functional recovery. Chapters detail a variety of models utilizing both in vivo and in vitro approaches, physical injury models, methods for the isolation/analysis of various macromolecules, live and fixed imaging of regenerating axons, and for quantifying behavioral endpoints enable measurements of regenerative success. Written in the format of the highly successful Methods in Molecular Biology series, each chapter includes an introduction to the topic, lists necessary materials and methods, includes tips on troubleshooting and known pitfalls, and step-by-step, readily reproducible protocols. Authoritative and cutting-edge, Axon Regeneration: Methods and Protocols aims to be comprehensive guide for researchers.
Cell Biology Of The Axon
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Author : Edward Koenig
language : en
Publisher: Springer Science & Business Media
Release Date : 2009-09-01
Cell Biology Of The Axon written by Edward Koenig and has been published by Springer Science & Business Media this book supported file pdf, txt, epub, kindle and other format this book has been release on 2009-09-01 with Science categories.
Recent years have witnessed striking advances in research on axons at a cellular level that substantially impact our current understanding of axonal biology. Newer findings and their ramifications are critically reviewed in the 16 chapters of this volume by authors highly qualified by virtue of their scientific contributions to research areas they know and write about. Five basic areas (I to V) germane to axonal biology are highlighted, beginning with (I) signaling interactions mediating myelination, and differentiation of axonal membrane domains; (IIa) issues surrounding organization and transport dynamics of neurofilaments in axons, (IIb) mechanisms regulating microtubule organization and dynamics, misregulation of which causes axonal degeneration, and (IIc) the roles actin binding proteins play in regulating organization and functions of the actin filament system in mature and growing axons; (IIIa) myosin motor proteins and cargoes intrinsic to the axon compartment, (IIIb) mitochondrial transport motors, and imperatives governing transport dynamics and directional delivery, (IIIc) mechanisms mediating retrograde signaling associated with NGF’s role in trophic-dependent neuronal survival, and (IIId) potential for impaired subcellular targeting of a -synuclein as a mechanism for accumulation of Lewy body inclusions in synucleinopathies; (IVa) occurrence and organization of discrete ribosome-containing domains in axons, (IVb) endogenous mRNAs, classes of proteins translated locally, and RNP trafficking in axons, (IVc) importance of locally synthesized nuclear encoded mitochondrial proteins for maintenance, function and survival of axons, (IVd) occurrence of RNA trafficking from glial cells to axons, and significance glial RNA transcripts may play in expression in axons and axon terminals, (IVe) RNA trafficking and localization of RNA transcripts in axonal growth cones, and signaling pathways that modulate local protein synthesis for directional elongation, and (IVf) genetic and molecular defects underlying spinal muscular atrophy, and roles that SMN gene product plays as a molecular chaperone in mRNA transport and translation; (Va) injury-induced local synthesis of a protein forming a retrograde signaling complex in axons to stimulate regeneration, and (Vb) endogenous and exogenous factors that condition axonal regenerative capacity in PNS and CNS, including injury-induced activation of specific genes governing regeneration. Emergent complexities revealed in this volume compel a major revision in the traditional conceptual model of the axon’s intrinsic makeup and capacities.
Exploring Mechanisms Underlying Axon Regeneration Using Drosophila Sensory Neurons
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Author : Kavitha Rao
language : en
Publisher:
Release Date : 2016
Exploring Mechanisms Underlying Axon Regeneration Using Drosophila Sensory Neurons written by Kavitha Rao and has been published by this book supported file pdf, txt, epub, kindle and other format this book has been release on 2016 with categories.
Axons and dendrites form two morphologically and functionally distinct compartments of a polarized neuron, and thus require different sets of proteins and organelles. Microtubules are at the crux of neuronal polarity, as they facilitate directional trafficking within the neuron. Moreover, microtubule orientation within each compartment is considered to be one of the key determinants of axonal and dendritic identity. Neurons are vulnerable to various types of injury and it is critical for these cells to repair, as most neurons cannot be replaced. The overarching theme of the upcoming sections is neuronal responses to injury and the underlying molecular mechanisms. Loss of an axon is a major challenge to a neuron. Neurons in both vertebrates and invertebrates respond to axon loss by converting a dendrite to an axon. In Chapter 2, we show that the nociceptive Class IV sensory neurons in Drosophila, also respond to complete axon loss or proximal axotomy by converting a dendrite to a new axon. However, distal axotomy frequently led to formation of two axons, one from the axon stump and another by converting a dendrite. Using microtubule polarity changes as a read-out, we describe a novel feedback mechanism between the two regenerating axons, such that when growth from the stump is blocked, the decision to convert a dendrite becomes accelerated. Previous studies have discovered that axon regeneration in Drosophila sensory neurons requires spastin, a microtubule-severing enzyme. However, it is not known how loss of spastin leads to this defect. In Chapter 3, we present evidence that loss of atlastin, a protein that interacts with spastin, also results in defective axon regeneration. Interestingly, impaired axon regeneration was observed only when reduced levels of spastin or atlastin were combined with the presence of a dominant-negative microtubule regulator. Further, impaired axon regeneration due to loss of spastin or atlastin was associated with defects in localization of the endoplasmic reticulum (ER) at regenerating axon tips. Thus, we propose a model where, spastin and atlastin are involved in ER-microtubule co-ordination during axon regeneration. In comparison to axon regeneration, very little is known about dendrite regeneration. Previous studies in the dendrites of Drosophila peripheral neurons have revealed that dendrite regeneration does not require the dual leucine-zipper kinase (DLK) signaling pathway, which is critical during axon regeneration. In order to extend these studies to vertebrates, somatosensory neurons in zebrafish can be used as a model. However, the input-receiving sensory branches of these neurons have been considered as axons, and not dendrites. In Chapter 4, microtubule polarity of the sensory endings in zebrafish Rohon-Beard neurons is investigated by live imaging techniques, in an effort to resolve their identity. Also, tools to test the requirement of the DLK pathway in the regeneration of zebrafish sensory endings are also described.
Wiring The Nervous System Mechanisms Of Axonal And Dendritic Remodelling In Health And Disease
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Author : Tracy S. Tran
language : en
Publisher: CRC Press
Release Date : 2024-01-31
Wiring The Nervous System Mechanisms Of Axonal And Dendritic Remodelling In Health And Disease written by Tracy S. Tran and has been published by CRC Press this book supported file pdf, txt, epub, kindle and other format this book has been release on 2024-01-31 with Science categories.
This book examines recent key findings on the mechanisms of axonal and dendritic remodeling in different model organisms. Each chapter is contributed by a panel of experts in their respective subfields of neurosciences, to provide and discuss the latest discoveries ranging from neuronal morphogenesis during development, experience-dependent structural plasticity, to neuronal degeneration, regeneration, and pathologies in neurological disorders. The process of neuronal remodeling, specifically their axons and dendrites, is essential for the proper wiring of the nervous system during early development and continues during postnatal ages to shape the pattern of synaptic connections throughout the life of the organism, including humans. Over recent years, substantial progress has been made in our understanding of the cellular and molecular mechanisms that control neuronal remodeling. In addition, there is accumulating evidence demonstrating how the nervous system could remodel in response to injury and in pathological conditions. Topics discussed in the book include: Axonal degeneration during development and in pathological or disease conditions Neuronal morphogenesis (axons and dendrites) Experience-dependent structural plasticity to synaptogenesis Dendrite degeneration and regeneration