DOCSLIB.ORG

How Does an Axon Grow?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
How Does an Axon Grow? Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW How does an axon grow? Jeffrey L. Goldberg1 Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305, USA How do axons grow during development, and why do cisions to advance, retract, pause, or turn (Fig. 1). All of they fail to regrow when injured? In the complicated these are potential regulatory sites that could control a mesh of our nervous system, the axon is the information neuron’s ability to elongate or regenerate its axon. superhighway, carrying all of the data we use to sense our environment and carry out behaviors. To wire up our Production of the building blocks, nervous system properly, neurons must elongate their both membrane and cytoplasmic axons during development to reach their targets. This is no simple task, however. The complex morphology of Rapid axon growth requires rapid manufacture and sup- axons and dendrites puts neurons among the most intri- ply of cytoplasm and membrane. Where are the lipid and cate and beautiful cells in the body. Knowledge of how protein building blocks made? It was known from classic neurons extend axons and dendrites, elongate at a par- experiments that axons cut off from the cell bodies of ticular rate, and stop growing at the proper time is criti- adult sensory neurons continue to elongate in culture cal to understanding the development of our nervous (Shaw and Bray 1977), but evidence for local production system, yet the regulation of these processes is poorly of membrane and cytoplasmic elements went lacking for understood. Considerable attention in recent years has decades. Secreted proteins, both transmembrane and ex- focused on understanding how growth cones are guided tracellular, as well as glycolipids are likely synthesized and steered through complicated pathways (for review, at the cell body, where the rough endoplasmic reticulum see Schmidt and Hall 1998; Mueller 1999), and even how (ER) and golgi complex are located, and shipped in neurons initiate new processes (for review, see Da Silva vesicles down the axon for membrane insertion. What and Dotti 2002), but what mechanisms are involved in about other lipids? Blocking lipid synthesis interferes elongation itself? Are environmental signals needed to with axon growth (Posse de Chaves et al. 1995a,b), al- drive axon growth and, if so, what are the intracellular though it is not clear how much this represents depen- molecular mechanisms by which they induce elonga- dence on supply from the cell body or from the axon. tion? What controls the rate of axon growth? How do Smooth ER is located throughout the axon, however, and CNS neurons know whether to extend axons or den- experiments using radioactive lipid precursors added to drites? Is the signaling of axon versus dendrite growth axons but not to the cell bodies of neurons either in attributable to different extracellular signals, different compartmented cultures (Fig. 3, below) or in vivo show neuronal states, or both? All of these questions bear criti- that at least some lipid synthesis can occur in axons cally on our understanding of axon growth and here I (Gould et al. 1987a,b; Vance et al. 1991, 1994; Posse de review recent answers and approaches to the above ques- Chaves et al. 1995b). Similarly, experiments in sympa- tions, and highlight their relevance during development, thetic neurons demonstrate that the cell body is respon- injury, and disease. sible for cholesterol synthesis, but if synthesis is insuf- ficient or is blocked pharmacologically, both the cell body and axons can take up cholesterol from high-den- How does an axon grow? sity and low-density lipoproteins, locally gathering Axons are generally on the scale of 1 µm thick and some needed material from an external source (Vance et al. are more than 1 m long, making neurons the largest cells 1994; Posse de Chaves et al. 1997, 2000). From these in the body by both volume and surface area. Sustaining various experiments it appears that the major burden of such massive growth, however, requires the interplay of producing plasma membrane must fall to the cell body, many factors—producing membrane and cytoplasmic el- but it may be that longer axons in vivo rely more heavily ements in the proper proportions; shipping these build- on local, axonal production of these building blocks. ing blocks to the right compartment and inserting them Until recently, cytoplasmic proteins for axons were into the growing axon; and coordinating the timing of all similarly thought to be entirely cell body-derived, but of these with the growth cone’s moment-by-moment de- the possibility of local, intra-axonal production has re- ceived new support. Ribosomes and mRNAs have been localized to mammalian axons, suggesting at least a pos- 1E-MAIL [email protected]; FAX (650) 725-3958. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ sible role for axonal translation (Tennyson 1970; Bassell gad.1062303. et al. 1998; Koenig et al. 2000), as had been found previ- GENES & DEVELOPMENT 17:941–958 © 2003 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/03 $5.00; www.genesdev.org 941 Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Goldberg Figure 1. Axon growth, like an automobile, requires (A) the supply of building blocks (gasoline); as well as (B) cycling filaments in the growth cone (the running motor); (C) connections between growth cone filaments and the growth substrate (the clutch); and (D) a way to translate external, directional cues into pathfinding decisions (the steering wheel). Steps forward in our understanding of these processes and their regulation are the subjects of this review. ously for dendrites (for review, see Job and Eberwine axonal protein synthesis the growth cone otherwise 2001). Furthermore, severed axons locally synthesize adapts and stops responding (Ming et al. 2002). such axonal structural building blocks as neurofila- In studies of Xenopus neurons in culture, which ex- ments, tubulin, and actin (Eng et al. 1999; Zheng et al. hibit a presynaptic potentiation in response to the 2001). Intriguingly, axonal localization may be specific soluble trophic factor brain-derived neurotrophic factor for axon growth-related processes—only ␤-actin mRNA (BDNF), blocking protein synthesis for 45min before is enriched in neurites and growth cones, corresponding BDNF application had no effect, but a 2-h blockade com- to ␤-actin protein’s localization to distal growth cones pletely eliminated the presynaptic response to BDNF. and filipodia of actively growing neurites in vitro (Bassell This led the authors to hypothesize that protein synthe- et al. 1998) and in vivo (Weinberger et al. 1996). In con- sis in the axon terminals may not be specifically induced trast ␥-actin protein is localized throughout the cell body by BDNF, but rather that constitutive ongoing protein and neurites of embryonic cortical neurons, and ␥-actin synthesis is required for the response to BDNF (Zhang mRNA is not enriched in growing axons. and Poo 2002). The axonal localization of specific mRNAs raises the The specific induction of protein synthesis in axons question, is there any physiologic contribution made by was demonstrated beautifully using chick spinal cord these mRNAs? Recent experiments suggest that they are axons, which normally up-regulate axonal expression of not there by accident. In adult dorsal root ganglion the EphA2 guidance receptor after crossing the midline (DRG) neurons in vitro, blocking axonal protein synthe- (Brittis et al. 2002). An RNA reporter construct consist- sis causes growth cones to retract, but only when the ing of green fluorescent protein (GFP) RNA followed by axons are cut off from the cell body. These experiments the 3Ј untranslated region (UTR) of EphA2 RNA was suggest that axonal translation is sufficient to maintain transfected into these neurons using electroporation. the growth cone, at least over short periods of time, but Brittis and colleagues (2002) found that GFP expression that axonal translation is not necessary if cell body-me- was specifically up-regulated in the distal axons and diated protein synthesis is available (Zheng et al. 2001). growth cones of these spinal neurons only after the Embryonic Xenopus retinal axons cut off from their cell axons crossed the midline, suggesting that a local protein bodies can elongate and turn in vivo (Harris et al. 1987) synthesis mechanism was being activated in response to and in vitro in response to guidance cues (Campbell and extracellular cues and was mediated by the EphA2 Holt 2001). After adding protein synthesis inhibitors, 3ЈUTR sequence (Brittis et al. 2002). These experiments they fail to respond to steering cues from soluble guid- provided evidence that localized protein synthesis is ance molecules netrin-1 or Sema3a (Campbell and Holt critical to rejuvenating and changing the growth cone’s 2001). All of these data are consistent with the hypoth- responsiveness to various environmental signals. esis that axonal protein synthesis is constantly required Although in the presence of the connected cell body to resensitize the growth cone to guidance cues; without axonal protein synthesis may not be necessary for 942 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Mechanisms of axon growth growth, these experiments point to a physiologic role for (Craig et al. 1995). On the other hand, in vivo metabolic local protein synthesis. Could local protein synthesis labeling studies suggest that certain proteins and lipids also have a role in axon elongation or regeneration? The are inserted all along the axon (Griffin et al. 1981; Toews response to axonal injury may include an initial period et al. 1988; Harel and Futerman 1996), and physically wherein axonal synthesis may be crucial to maintaining stretching the axon leads to remarkably rapid axon elon- the growth cone to allow the cell body time to jumpstart gation and new membrane insertion along its length into regeneration mode.
Load more

Recommended publications
  • Oligodendrocytes in Development, Myelin Generation and Beyond
    cells Review Oligodendrocytes in Development, Myelin Generation and Beyond Sarah Kuhn y, Laura Gritti y, Daniel Crooks and Yvonne Dombrowski * Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University Belfast, Belfast BT9 7BL, UK; [email protected] (S.K.); [email protected] (L.G.); [email protected] (D.C.) * Correspondence: [email protected]; Tel.: +0044-28-9097-6127 These authors contributed equally. y Received: 15 October 2019; Accepted: 7 November 2019; Published: 12 November 2019 Abstract: Oligodendrocytes are the myelinating cells of the central nervous system (CNS) that are generated from oligodendrocyte progenitor cells (OPC). OPC are distributed throughout the CNS and represent a pool of migratory and proliferative adult progenitor cells that can differentiate into oligodendrocytes. The central function of oligodendrocytes is to generate myelin, which is an extended membrane from the cell that wraps tightly around axons. Due to this energy consuming process and the associated high metabolic turnover oligodendrocytes are vulnerable to cytotoxic and excitotoxic factors. Oligodendrocyte pathology is therefore evident in a range of disorders including multiple sclerosis, schizophrenia and Alzheimer’s disease. Deceased oligodendrocytes can be replenished from the adult OPC pool and lost myelin can be regenerated during remyelination, which can prevent axonal degeneration and can restore function. Cell population studies have recently identified novel immunomodulatory functions of oligodendrocytes, the implications of which, e.g., for diseases with primary oligodendrocyte pathology, are not yet clear. Here, we review the journey of oligodendrocytes from the embryonic stage to their role in homeostasis and their fate in disease. We will also discuss the most common models used to study oligodendrocytes and describe newly discovered functions of oligodendrocytes.
    [Show full text]
  • Chapter 8 Nervous System
    Chapter 8 Nervous System I. Functions A. Sensory Input – stimuli interpreted as touch, taste, temperature, smell, sound, blood pressure, and body position. B. Integration – CNS processes sensory input and initiates responses categorizing into immediate response, memory, or ignore C. Homeostasis – maintains through sensory input and integration by stimulating or inhibiting other systems D. Mental Activity – consciousness, memory, thinking E. Control of Muscles & Glands – controls skeletal muscle and helps control/regulate smooth muscle, cardiac muscle, and glands II. Divisions of the Nervous system – 2 anatomical/main divisions A. CNS (Central Nervous System) – consists of the brain and spinal cord B. PNS (Peripheral Nervous System) – consists of ganglia and nerves outside the brain and spinal cord – has 2 subdivisions 1. Sensory Division (Afferent) – conducts action potentials from PNS toward the CNS (by way of the sensory neurons) for evaluation 2. Motor Division (Efferent) – conducts action potentials from CNS toward the PNS (by way of the motor neurons) creating a response from an effector organ – has 2 subdivisions a. Somatic Motor System – controls skeletal muscle only b. Autonomic System – controls/effects smooth muscle, cardiac muscle, and glands – 2 branches • Sympathetic – accelerator “fight or flight” • Parasympathetic – brake “resting and digesting” * 4 Types of Effector Organs: skeletal muscle, smooth muscle, cardiac muscle, and glands. III. Cells of the Nervous System A. Neurons – receive stimuli and transmit action potentials
    [Show full text]
  • Neuron Morphology Influences Axon Initial Segment Plasticity1,2,3
    New Research Neuronal Excitability Neuron Morphology Influences Axon Initial Segment Plasticity1,2,3 Allan T. Gulledge1 and Jaime J. Bravo2 DOI:http://dx.doi.org/10.1523/ENEURO.0085-15.2016 1Department of Physiology and Neurobiology, Geisel School of Medicine at Dartmouth, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, and 2Thayer School of Engineering at Dartmouth, Hanover, New Hampshire 03755 Visual Abstract In most vertebrate neurons, action potentials are initiated in the axon initial segment (AIS), a specialized region of the axon containing a high density of voltage-gated sodium and potassium channels. It has recently been proposed that neurons use plasticity of AIS length and/or location to regulate their intrinsic excitability. Here we quantify the impact of neuron morphology on AIS plasticity using computational models of simplified and realistic somatodendritic morphologies. In small neurons (e.g., den- tate granule neurons), excitability was highest when the AIS was of intermediate length and located adjacent to the soma. Conversely, neu- rons having larger dendritic trees (e.g., pyramidal neurons) were most excitable when the AIS was longer and/or located away from the soma. For any given somatodendritic morphology, increasing dendritic mem- brane capacitance and/or conductance favored a longer and more distally located AIS. Overall, changes to AIS length, with corresponding changes in total sodium conductance, were far more effective in regulating neuron excitability than were changes in AIS location, while dendritic capacitance had a larger impact on AIS performance than did dendritic conductance. The somatodendritic influence on AIS performance reflects modest soma- to-AIS voltage attenuation combined with neuron size-dependent changes in AIS input resistance, effective membrane time constant, and isolation from somatodendritic capacitance.
    [Show full text]
  • Regulation of Myelin Structure and Conduction Velocity by Perinodal Astrocytes
    Correction NEUROSCIENCE Correction for “Regulation of myelin structure and conduc- tion velocity by perinodal astrocytes,” by Dipankar J. Dutta, Dong Ho Woo, Philip R. Lee, Sinisa Pajevic, Olena Bukalo, William C. Huffman, Hiroaki Wake, Peter J. Basser, Shahriar SheikhBahaei, Vanja Lazarevic, Jeffrey C. Smith, and R. Douglas Fields, which was first published October 29, 2018; 10.1073/ pnas.1811013115 (Proc. Natl. Acad. Sci. U.S.A. 115,11832–11837). The authors note that the following statement should be added to the Acknowledgments: “We acknowledge Dr. Hae Ung Lee for preliminary experiments that informed the ultimate experimental approach.” Published under the PNAS license. Published online June 10, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1908361116 12574 | PNAS | June 18, 2019 | vol. 116 | no. 25 www.pnas.org Downloaded by guest on October 2, 2021 Regulation of myelin structure and conduction velocity by perinodal astrocytes Dipankar J. Duttaa,b, Dong Ho Wooa, Philip R. Leea, Sinisa Pajevicc, Olena Bukaloa, William C. Huffmana, Hiroaki Wakea, Peter J. Basserd, Shahriar SheikhBahaeie, Vanja Lazarevicf, Jeffrey C. Smithe, and R. Douglas Fieldsa,1 aSection on Nervous System Development and Plasticity, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; bThe Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817; cMathematical and Statistical Computing Laboratory, Office of Intramural Research, Center for Information
    [Show full text]
  • NEURAL CONNECTIONS: Some You Use, Some You Lose
    NEURAL CONNECTIONS: Some You Use, Some You Lose by JOHN T. BRUER SOURCE: Phi Delta Kappan 81 no4 264-77 D 1999 . The magazine publisher is the copyright holder of this article and it is reproduced with permission. Further reproduction of this article in violation of the copyright is prohibited JOHN T. BRUER is president of the James S. McDonnell Foundation, St. Louis. This article is adapted from his new book, The Myth of the First Three Years (Free Press, 1999), and is reprinted by arrangement with The Free Press, a division of Simon Schuster Inc. ©1999, John T. Bruer . OVER 20 YEARS AGO, neuroscientists discovered that humans and other animals experience a rapid increase in brain connectivity -- an exuberant burst of synapse formation -- early in development. They have studied this process most carefully in the brain's outer layer, or cortex, which is essentially our gray matter. In these studies, neuroscientists have documented that over our life spans the number of synapses per unit area or unit volume of cortical tissue changes, as does the number of synapses per neuron. Neuroscientists refer to the number of synapses per unit of cortical tissue as the brain's synaptic density. Over our lifetimes, our brain's synaptic density changes in an interesting, patterned way. This pattern of synaptic change and what it might mean is the first neurobiological strand of the Myth of the First Three Years. (The second strand of the Myth deals with the notion of critical periods, and the third takes up the matter of enriched, or complex, environments.) Popular discussions of the new brain science trade heavily on what happens to synapses during infancy and childhood.
    [Show full text]
  • Nomina Histologica Veterinaria, First Edition
    NOMINA HISTOLOGICA VETERINARIA Submitted by the International Committee on Veterinary Histological Nomenclature (ICVHN) to the World Association of Veterinary Anatomists Published on the website of the World Association of Veterinary Anatomists www.wava-amav.org 2017 CONTENTS Introduction i Principles of term construction in N.H.V. iii Cytologia – Cytology 1 Textus epithelialis – Epithelial tissue 10 Textus connectivus – Connective tissue 13 Sanguis et Lympha – Blood and Lymph 17 Textus muscularis – Muscle tissue 19 Textus nervosus – Nerve tissue 20 Splanchnologia – Viscera 23 Systema digestorium – Digestive system 24 Systema respiratorium – Respiratory system 32 Systema urinarium – Urinary system 35 Organa genitalia masculina – Male genital system 38 Organa genitalia feminina – Female genital system 42 Systema endocrinum – Endocrine system 45 Systema cardiovasculare et lymphaticum [Angiologia] – Cardiovascular and lymphatic system 47 Systema nervosum – Nervous system 52 Receptores sensorii et Organa sensuum – Sensory receptors and Sense organs 58 Integumentum – Integument 64 INTRODUCTION The preparations leading to the publication of the present first edition of the Nomina Histologica Veterinaria has a long history spanning more than 50 years. Under the auspices of the World Association of Veterinary Anatomists (W.A.V.A.), the International Committee on Veterinary Anatomical Nomenclature (I.C.V.A.N.) appointed in Giessen, 1965, a Subcommittee on Histology and Embryology which started a working relation with the Subcommittee on Histology of the former International Anatomical Nomenclature Committee. In Mexico City, 1971, this Subcommittee presented a document entitled Nomina Histologica Veterinaria: A Working Draft as a basis for the continued work of the newly-appointed Subcommittee on Histological Nomenclature. This resulted in the editing of the Nomina Histologica Veterinaria: A Working Draft II (Toulouse, 1974), followed by preparations for publication of a Nomina Histologica Veterinaria.
    [Show full text]
  • New Approaches to Analyse Axon- Oligodendrocyte Communication In
    Neuroforum 2017; 23(4): A175–A181 Tim Czopka* and Franziska Auer New Approaches to Analyse Axon- Oligodendrocyte Communication in vivo https://doi.org/10.1515/nf-2017-A010 the temporal timing, with which signals are exchanged between neurons. Abstract: A major challenge for understanding our nerv- The regions in which axons exchange information ous system is to elucidate how its constituting cells coordi- between different brain areas are called the ‘white mat- nate each other to form and maintain a functional organ. ter’ (the grey matter being the areas where neuronal cell The interaction between neurons and oligodendrocytes bodies reside). White matter appears white due to the represents a unique cellular entity. Oligodendrocytes mye- presence of myelin, a fatty coating that surrounds most ax- linate axons by tightly ensheathing them. Myelination reg- ons. Myelin is an evolutionary acquisition of vertebrates, ulates speed of signal transduction, thus communication which electrically insulates axons and enables rapid between neurons, and supports long-term axonal health. and energy efficient signal transmission. It is likely that Despite their importance, we still have large gaps in our these properties have in fact enabled the evolution of our understanding of the mechanisms underlying myelinated complex nervous system with its high cell number. In the axon formation, remodelling and repair. Zebrafish repre- central nervous system (CNS), myelin is produced by spe- sent an increasingly popular model organism, particular- cialised glial cells, the Oligodendrocytes. Genetic defects ly due to their suitability for live cell imaging and genetic that perturb formation or maintenance of myelin (e.g. in manipulation. Here, we provide an overview about this Leukodystrophies) lead to severe motoric and cognitive research area, describe how zebrafish have helped under- symptoms.
    [Show full text]
  • 11 Introduction to the Nervous System and Nervous Tissue
    11 Introduction to the Nervous System and Nervous Tissue ou can’t turn on the television or radio, much less go online, without seeing some- 11.1 Overview of the Nervous thing to remind you of the nervous system. From advertisements for medications System 381 Yto treat depression and other psychiatric conditions to stories about celebrities and 11.2 Nervous Tissue 384 their battles with illegal drugs, information about the nervous system is everywhere in 11.3 Electrophysiology our popular culture. And there is good reason for this—the nervous system controls our of Neurons 393 perception and experience of the world. In addition, it directs voluntary movement, and 11.4 Neuronal Synapses 406 is the seat of our consciousness, personality, and learning and memory. Along with the 11.5 Neurotransmitters 413 endocrine system, the nervous system regulates many aspects of homeostasis, including 11.6 Functional Groups respiratory rate, blood pressure, body temperature, the sleep/wake cycle, and blood pH. of Neurons 417 In this chapter we introduce the multitasking nervous system and its basic functions and divisions. We then examine the structure and physiology of the main tissue of the nervous system: nervous tissue. As you read, notice that many of the same principles you discovered in the muscle tissue chapter (see Chapter 10) apply here as well. MODULE 11.1 Overview of the Nervous System Learning Outcomes 1. Describe the major functions of the nervous system. 2. Describe the structures and basic functions of each organ of the central and peripheral nervous systems. 3. Explain the major differences between the two functional divisions of the peripheral nervous system.
    [Show full text]
  • Nervous System -I
    Body Tissues Epithelial Connective Tissues Muscle Nervous Nervous system Controlling & Coordinating System Conducts nerve impulses between body structures and controls body functions Functions • Sensory Internal External • Integration> Analysis> storage>interpret>decide • Motor> Response • Regulates all activity (Voluntary & Involuntary) • Adjust according to changing external and internal environment Nervous System Subdivisions: CNS (Central Nervous System) PNS( Peripheral Nervous System) ANS (Autonomic Nervous system) Nervous tissue - Cell Types Functionally • Neuron (Nerve Cell) -Conduction Variable Shape , Size, Function • Neuroglia - Supportive -- Macroglia -- Microglia • Ependymal Cells • Schwann Cells - In PNS Neuron ( Nerve Cell) Components 1.Cell Body 2.Cell Processes (Neurites) Cell Body - Size vary from 5 µm - 120 µm (Perikaryon) – Plasma membrane Nucleus Cytoplasm Axon Hillock Neuronal Skeleton Cell Processes 1.Dendrites : Short , irregular thickness. Freely Branching, Afferent processes , Contain Nissl Granules 2. Axon – Long , Single, Efferent process of Uniform Diameter, Devoid of Nissl Granules, Ensheathed by Schwann cells, Gives collateral branches Terminal branches called telodendria (axon terminals) Terminate – within CNS - Always with another neuron Outside CNS – Either may end in relation to the effector organ or Synapse with neurons of Peripheral ganglia Types Of Neuron 1.Acc. To no of Processes Bipolar Multipolar Pseudounipolar 2. Acc. To Function Sensory Motor 3. Acc. To Axon Length Golgi type-1(long) Golgi type-II Synapse site of junction of neuron Types Axo- Dendritic Axo – Somatic Axo- Axonal Neuroglia • Astrocytes : Fibrous Protoplasmic Metabolism of neurotransmitters K+ Balance Contribute in brain development Blood brain barrier Link between neurons and blood vessels • Oligodendrocytes: Form a supporting network around neurons Produce myelin sheath around several neurons Neuroglia- contd. • Microglia: Phagocytic cells; Migrate to area of injured nervous tissue.
    [Show full text]
  • On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function
    The Journal of Neuroscience, October 18, 2017 • 37(42):10023–10034 • 10023 Viewpoints On Myelinated Axon Plasticity and Neuronal Circuit Formation and Function X Rafael G. Almeida1,2,3 and David A. Lyons1,2,3 1Centre for Discovery Brain Sciences, 2MS Society Centre for Translational Research, and 3Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, EH16 4SB Edinburgh, United Kingdom Studiesofactivity-drivennervoussystemplasticityhaveprimarilyfocusedonthegraymatter.However,MRI-basedimagingstudieshave shown that white matter, primarily composed of myelinated axons, can also be dynamically regulated by activity of the healthy brain. Myelination in the CNS is an ongoing process that starts around birth and continues throughout life. Myelin in the CNS is generated by oligodendrocytes and recent evidence has shown that many aspects of oligodendrocyte development and myelination can be modulated by extrinsic signals including neuronal activity. Because modulation of myelin can, in turn, affect several aspects of conduction, the concept has emerged that activity-regulated myelination represents an important form of nervous system plasticity. Here we review our increasing understanding of how neuronal activity regulates oligodendrocytes and myelinated axons in vivo, with a focus on the timing of relevant processes. We highlight the observations that neuronal activity can rapidly tune axonal diameter, promote re-entry of oligodendrocyte progenitor cells into the cell cycle, or drive their direct differentiation into oligodendrocytes. We suggest that activity- regulated myelin formation and remodeling that significantly change axonal conduction properties are most likely to occur over time- scales of days to weeks. Finally, we propose that precise fine-tuning of conduction along already-myelinated axons may also be mediated by alterations to the axon itself.
    [Show full text]
  • Microglial Process Convergence on Axonal Segments in Health and Disease
    Benusa et al. Neuroimmunol Neuroinflammation 2020;7:23-39 Neuroimmunology DOI: 10.20517/2347-8659.2019.28 and Neuroinflammation Review Open Access Microglial process convergence on axonal segments in health and disease Savannah D. Benusa, Audrey D. Lafrenaye Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA. Correspondence to: Dr. Audrey D. Lafrenaye, Department of Anatomy and Neurobiology, Virginia Commonwealth University Medical Center, P.O. Box 980709, Richmond, VA 23298, USA. E-mail: [email protected] How to cite this article: Benusa SD, Lafrenaye AD. Microglial process convergence on axonal segments in health and disease. Neuroimmunol Neuroinflammation 2020;7:23-39. http://dx.doi.org/10.20517/2347-8659.2019.28 Received: 31 Dec 2019 First Decision: 6 Feb 2020 Revised: 19 Feb 2020 Accepted: 27 Feb 2020 Published: 21 Mar 2020 Science Editor: Jeffrey Bajramovic Copy Editor: Jing-Wen Zhang Production Editor: Tian Zhang Abstract Microglia dynamically interact with neurons influencing the development, structure, and function of neuronal networks. Recent studies suggest microglia may also influence neuronal activity by physically interacting with axonal domains responsible for action potential initiation and propagation. However, the nature of these microglial process interactions is not well understood. Microglial-axonal contacts are present early in development and persist through adulthood, implicating microglial interactions in the regulation of axonal integrity in both the developing and mature central nervous system. Moreover, changes in microglial-axonal contact have been described in disease states such as multiple sclerosis (MS) and traumatic brain injury (TBI). Depending on the disease state, there are increased associations with specific axonal segments.
    [Show full text]
  • Radial Glial Cell–Neuron Interaction Directs Axon Formation at the Opposite Side of the Neuron from the Contact Site
    The Journal of Neuroscience, October 28, 2015 • 35(43):14517–14532 • 14517 Development/Plasticity/Repair Radial Glial Cell–Neuron Interaction Directs Axon Formation at the Opposite Side of the Neuron from the Contact Site Chundi Xu, Yasuhiro Funahashi, Takashi Watanabe, Tetsuya Takano, Shinichi Nakamuta, Takashi Namba, and Kozo Kaibuchi Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Showa, Nagoya 466-8550, Japan How extracellular cues direct axon–dendrite polarization in mouse developing neurons is not fully understood. Here, we report that the radial glial cell (RGC)–cortical neuron interaction directs axon formation at the opposite side of the neuron from the contact site. N-cadherin accumulates at the contact site between the RGC and cortical neuron. Inhibition of the N-cadherin-mediated adhesion decreases this oriented axon formation in vitro, and disrupts the axon–dendrite polarization in vivo. Furthermore, the RGC–neuron interaction induces the polarized distribution of active RhoA at the contacting neurite and active Rac1 at the opposite neurite. Inhibition of Rho–Rho-kinase signaling in a neuron impairs the oriented axon formation in vitro, and prevents axon–dendrite polarization in vivo. Collectively, these results suggest that the N-cadherin-mediated radial glia–neuron interaction determines the contacting neurite as the leading process for radial glia-guided neuronal migration and directs axon formation to the opposite side acting through the Rho family GTPases. Key words: axon formation; axon–dendrite
    [Show full text]