Neural Regeneration

Kwok Fai So, Xiao-Ming Xu

• Publisher: Academic Press
• Year: 2015
• Print ISBN: 9780128017326
• eBook ISBN: 9780128018347
• Topic: Biological Sciences
• Subtopic: Neuroscience
• Index: Biological Sciences

Neural Regeneration provides an overview of cutting-edge knowledge on a broad spectrum of neural regeneration, including: - Neural regeneration in lower vertebrates - Neural regeneration in the peripheral nervous system - Neural regeneration in the central nervous system - Transplantation-mediated neural regeneration - Clinical and translational research on neural regeneration The contributors to this book are experts in their fields and work at distinguished institutions in the United States, Canada, Australia, and China. Nervous system injuries, including peripheral nerve injuries, brain and spinal cord injuries, and stroke affect millions of people worldwide every year. As a result of this high incidence of neurological injuries, neural regeneration and repair is becoming a rapidly growing field dedicated to the new discoveries to promote structural and functional recoveries based on neural regeneration. The ultimate goal is to translate the most optimal regenerative strategies to treatments of human nervous system injuries. This valuable reference book is useful for students, postdoctors, and basic and clinical scientists who are interested in neural regeneration research. - Provides an overview of cutting-edge knowledge on a broad spectrum of neural regeneration - Highly translational and clinically-relevance - International authors who are leaders in their respective fields - Vivid art work making the chapters easily understood

Section IV

Neural Regeneration in the CNS

Outline

Chapter 9. Myelin-Associated Inhibitors in Axonal Growth after Central Nervous System Injury

Chapter 10. The Nogo Receptor Pathway in Central Nervous System Axon Regeneration and Therapeutic Opportunities

Chapter 11. Astrogliosis and Axonal Regeneration

Chapter 12. The Intrinsic Determinants of Axon Regeneration in the Central Nervous System

Chapter 13. Optic Nerve Regeneration in Lower Vertebrates and Mammals: Bridging the Gap

Chapter 14. Self-Assembling Peptides Mediate Neural Regeneration

Chapter 15. Wnt Signaling in Spinal Cord Injury

Chapter 16. Inflammation and Secondary Damage after Spinal Cord Injury

Chapter 17. Neuroprotection of Retinal Ganglion Cells in Glaucoma by Blocking LINGO-1 Function or Using a Nogo-66 Receptor Antagonist

Chapter 18. Axonal Regeneration in the Sensory Dorsal Column Pathway

Chapter 9

Myelin-Associated Inhibitors in Axonal Growth after Central Nervous System Injury

Cédric C. Geoffroy, and Binhai Zheng Department of Neurosciences, University of California San Diego, La Jolla, California, USA

Abstract

A major hypothesis for the limited axon regeneration in the injured central nervous system (CNS) is the presence of axon growth inhibitors associated with CNS myelin. Extensive biochemical and cell culture studies have yielded a wealth of information on the molecular identity and signaling network of myelin-associated axon growth inhibitors and their neuronal receptors. Significant effort has been made to delineate their roles in injury-induced axonal growth in vivo, including the regeneration of injured axons and the compensatory sprouting of uninjured axons. There is strong evidence that myelin inhibitors modulate axon sprouting, a form of CNS’s innate repair process, albeit in unexpectedly complex ways. Meanwhile, axon regeneration remains limited by targeting myelin inhibitors alone and their function in regeneration may depend on other factors such as an elevated level of neuron-intrinsic growth capacity. In addition to the prototypical myelin inhibitors Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein, several axon guidance molecules have been proposed to serve similar functions. Understanding the in vivo role of myelin inhibitors in axon sprouting and regeneration along with their interplay with other axon growth regulators remains an important challenge for CNS injury and repair research.

Keywords

Axon growth; Axon regeneration; Axon sprouting; CNS injury; CNS repair; Corticospinal tract (CST); Myelin inhibitors; Nogo

1. Introduction

Injury to the central nervous system (CNS), such as the spinal cord, often leads to debilitating and irreversible functional impairments in humans. This is mainly the result of very limited axon regeneration in the mammalian CNS after traumatic lesions. Primary injury refers to the physical damage including even complete severing of specific axons that occurs at the time of injury. This is followed by a more complex cascade of secondary injury response, which can lead to local neuronal death, demyelination, and initiation of an immune response. It is now generally accepted that an axon’s ability to grow after injury is regulated by both extrinsic and intrinsic mechanisms. In particular, extrinsic factors in the CNS environment may inhibit axon growth (we use the term “growth” here to be more inclusive in the phenomena being discussed than what the more specific term, “regeneration,” would have implied; see below). After CNS injury, the glial environment and the injury-induced changes to this environment, such as myelin breakdown (this chapter) and the formation of a glial scar (see Chapter 11), present major sources of axon growth inhibition. While extrinsic growth inhibition represented a major area of investigation for CNS repair research, recent studies highlighted the increasing importance of neuron-intrinsic mechanisms (see Chapters 12 and 14).

In contrast to the CNS, axons from the peripheral nervous system (PNS) can regenerate after injury and may even reach appropriate synaptic targets. A main difference between the two environments (CNS vs PNS) resides in the origin of the myelin and its composition. CNS myelin is made by oligodendrocytes, while PNS myelin is made by Schwann cells. Since the 1980s, CNS myelin has been a main suspect responsible for the limited axon growth after CNS injury and continues to be an important area of research for CNS repair today.

In the following, we will start with a brief history of myelin inhibition research. We will then discuss the molecular structure, localization, in vitro properties, and physiological roles of individual myelin-associated inhibitors (MAIs) and their receptors. This is followed by a discussion on the functional roles of MAIs in injury-induced axon growth (regeneration and sprouting) and how manipulating MAIs might contribute to repair and recovery after CNS injury and possibly in other neurological conditions.

2. Brief History of Myelin Inhibition Research

A century ago, Santiago Ramón y Cajal already hypothesized that the CNS environment presents an “unfavorable chemical milieu” for regeneration [1]. Tello, Cajal’s disciple, conducted peripheral nerve transplant experiments and observed what he believed to be central axon regeneration into the peripheral nerve graft. They interpreted these data as CNS axons being capable of regeneration, if provided with a favorable environment. After a long, dormant period in CNS regeneration research, similar findings were much more convincingly shown with modern axon tracing techniques in the early 1980s by Aguayo and colleagues. A transplanted peripheral nerve graft would support the growth of central axons as much as several centimeters, an impressive distance [2,3]. Together these studies indicated that the environment in which axons grow is an important consideration for the success of axon regeneration.

Berry first proposed that the breakdown products of myelin after CNS injury could impede axon regeneration [4]. In the mid/late 1980s, Schwab and colleagues started a series of studies to formally test this hypothesis. They first demonstrated that CNS, but not PNS, myelin inhibits axon outgrowth in vitro [5] and that the CNS white matter, more than the gray matter, is responsible for this inhibitory effect due to the production of specific proteins by mature oligodendrocytes [6,7]. To understand the molecular players involved in this phenomenon, a monoclonal antibody named IN-1 was raised against a biochemically purified inhibitory fraction of CNS myelin. The IN-1 antibody could neutralize, at least to some extent, myelin’s inhibitory activity in vitro [8] and promoted corticospinal tract (CST) axon regeneration when applied in vivo [9]. This work had a major, lasting influence in the field and indicated the appealing possibility that targeting one (or a few) myelin-associated growth inhibitor(s) might eventually provide a viable therapeutic approach for treating spinal cord injury.

Further characterization of the putative antigen for the IN-1 antibody led to the discovery of Nogo, a member of the Reticulon family of proteins [10–12]. Because of the promising results from the earlier work with the IN-1 antibody, significant effort has been made to investigate the molecular mechanisms of myelin-associated growth inhibition. First, a number of additional myelin-associated inhibitors have been identified. So far, almost 10 different proteins have been found to have inhibitory activity on neurite growth in vitro. Myelin-associated glycoprotein (MAG) was in fact the first MAI identified [13,14]. Oligodendrocyte myelin glycoprotein (OMgp; also known as OMG) was discovered as an MAI later by He and colleagues [15,16]. Although sharing no structural homology, these three molecules (Nogo, MAG, and OMgp) are often referred to as the prototypical MAIs because they share common receptors such as Nogo receptor (NgR1) and (later) paired immunoglobulin-like receptor B (PirB) [17,18]. Other molecules, mainly members of the guidance cues involved in axon pathfinding during development, have been found in CNS myelin or otherwise expressed by oligodendrocytes, including Semaphorin-4D [19], Semaphorin-5A [20], Netrin [21], and Ephrin-B3 [22].

3. Multiple Myelin-Associated Inhibitors

3.1. Nogo

3.1.1. Molecular Structure/Isoforms

There are three isoforms of Nogo (Nogo-A, Nogo-B, and Nogo-C) that are generated by alternative splicing and alternative promoter usage of the Reticulon 4 gene (RTN4, or Nogo Figure 1(A)). Nogo-A is the most studied isoform because it is the most highly expressed in the CNS among the three isoforms [23] and has multiple inhibitory domains (see below). Nogo-A is a transmembrane protein of 1192 amino acids. The three isoforms all share the same C-terminus of 188 amino acids, the Reticulon homology domain (RTN domain) [10,11]. This domain includes two transmembrane structures and an intervening extracellular 66 amino acid loop named Nog...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Preface
• Section I. Introduction
• Section II. Neural Regeneration in Lower Vertebrates
• Section III. Neural Regeneration in the Peripheral Nervous System
• Section IV. Neural Regeneration in the CNS
• Section V. Transplantation-Mediated Neural Regeneration
• Section VI. Clinical and Translational Research on Neural Regeneration
• Index