Neurotrophic Factors

Sandra E. Loughlin, James H. Fallon

• Publisher: Academic Press
• Year: 2012
• Print ISBN: 9780124558304
• eBook ISBN: 9780080571324
• Topic: Biological Sciences
• Subtopic: Cell Biology
• Index: Biological Sciences

This volume clearly synthesizes current information on defined neurotrophic factors, emphasizing their localization and molecular/cellular function in the central nervous system. Brain development and aging, neurodegenerative disorders, plasticity, and memory all are closely examined within the context of this rapidly expanding field. Researchers in neurobiology, cell biology, and molecular biology will find Neurotrophic Factors an invaluable reference for their research libraries. - Offers the most up-do-date synthesis of concepts on neurotrophic factors in the nervous system - Integrates molecular, cellular, and neuroanatomical concepts of neurotrophic factor function - Includes special chapters on primary, secondary, and tertiary messenger systems - Examines brain development, differentiation, neurodegenerative disorders, and adult plasticity

1

Functional Implications of the Anatomical Localization of Neurotrophic Factors

James H. Fallon; Sandra E. Loughlin

I INTRODUCTION

This volume is devoted to the analysis and review of a class of growth factors that acts on neural tissue, namely, neurotrophic factors. The history of growth factor and neurotrophic factor research can be presented differently, depending on the definitions used and the scientific discipline of the writer. As neuroanatomists, we trace the first conceptualization of neuronal trophic factors to the visionary neuroanatomist, Ramón y Cajal (1882, 1891; De Felipe and Jones, 1991). This concept, together with studies by Hamburger (1934) on neuronal development, had its foundation in a developmental Zeitgeist of 19th century European embryologists (see Chapter 2). Growth factor research per se is believed to have had its experimental genesis in 1916 when Robertson coined the term “tethelin” for the growth-stimulating activity of pituitary extracts in vitro (reviewed by Burgess, 1989). A decade later, insulin was recognized for its broad growth-promoting effects (Banting and Best, 1922). Growth factors were shown to be present in the brain over 50 years ago, when it was demonstrated that brain homogenates contained factors that stimulated fibroblasts to divide in vitro (Trowell et al., 1939; Hoffman, 1940). This fibroblast growth factor activity later was purified partially and was shown to have effects on many other tissues (Gospodarowicz, 1974). During the 1950s, the landmark studies by Levi-Montalcini and Hamburger (1953) established a conceptual and experimental blueprint for subsequent studies in the field of growth factors in the nervous system.

Despite a wealth of in vitro and in vivo molecular, biochemical, physiological, and pharmacological data generated on growth factors over the past 50 years, relatively little anatomical information on the localization of growth factors has been available until the past decade. This has been especially true for neurotrophic factors in the central nervous system. For example, epidermal growth factor was isolated 30 years ago by Cohen (1962) but the anatomical localization of epidermal growth factor-like immunoreactivity in the brain was not known until the 1980s (Fallon et al., 1984). This lag in morphological information is, in part, due to the low levels of neurotrophic factors present in the brain. However, new sensitive immunocytochemical, in situ hybridization, and receptor autoradiographic techniques have afforded the neuroanatomist powerful tools for locating neurotrophic factor systems in the brain. With these techniques, an abundance of neuroanatomical information has been gathered at the light microscopic level in the past few years that has confirmed predictions by Ramón y Cajal on the presence and importance of trophic factors in the brain.

In this introductory chapter, we will present some neuroanatomical perspectives on the roles of neurotrophic factors in the brain. Because of the sheer volume of the newly available anatomical information on the distribution of neurotrophic factors in the nervous system, it is impractical to present atlas mappings of all known neurotrophic factors. This chapter will stress some key morphological issues concerning neurotrophic factors in the central nervous system and how knowledge of the distribution of these growth factor systems is critical to our understanding of how these substances may be involved in developing, adult, aging, and damaged nervous systems.

II NEUROTROPHIC FACTORS INCLUDED IN THIS VOLUME

Growth factors include substances that stimulate cells to divide (hyperplasia) or increase in size (hypertrophy). Many growth factors are now known to exist (Table 1). Trophic factors include those substances that have effects on cell differentiation, survival, phenotypic expression, and plasticity, as well as on cell hypertrophy, for example, neurite extension (also considered a “trophic” action). Neurotrophic factors, a subset of growth factors acting on neural tissue, have been defined in a myriad of ways ranging from very restrictive to very general. Restrictive definitions are based on the nerve growth factor model, which recognizes only the specific aspects of developmental events, such as cell survival and neurite extension, that are supported by proteins and peptides. This restrictive definition of a neurotrophic substance parallels the restrictive definition of and requirements for a neurotransmitter, which were based on experimental paradigms developed for acetylcholine. Coincidentally, nerve growth factor and acetylcholine not only have forged our fundamental definitions of a neural growth factor and a neurotransmitter, respectively, but also are associated closely in brain function. As more putative “neurotransmitters” and “neurotrophic factors” have been discovered and analyzed, it has become clear that broader definitions of each group are necessary to capture the range of subtle and profound actions of these neuromessengers.

Table 1

Examples of growth factors

Family	Specific examples
Neurotrophin	Nerve growth factor (NGF)
	Brain-derived neurotrophic factor (BDNF)
	Neurotrophin 3 (NT-3)
EGF	Epidermal growth factor (EGF)
	Transforming growth factor alpha (TGFα)
	Vaccinia virus growth factor
	Amphiregulin (AR)
	Schwannoma-derived growth factor (SDGF)
FGF	Acidic fibroblast growth factor (aFGF)
	Basic fibroblast growth factor (bFGF)
	INT-2, FGF-5, FGF-6, KGF, HST/KGF
Insulin-like	Insulin
	Insulin-like growth factors (somatomedins)
	Relaxin
Others	Growth hormone (GH)
	Platelet-derived growth factor (PDGF)
	Mast cell growth factor (MGS)
	Colony stimulating factors Ciliary neurotrophic factor (CNTF)
	Ciliary neurotrophic factor (CNTF)
	Glial maturation factor
	Protease nexin I, II
	Sweat gland factor
	Cholinergic neuronal differentiation factor (CDF)
	Muscle-derived growth factors (MDGF)
	Striatal-derived neuronotrophic factor
	Transforming growth factor beta (TGFβ)/inhibin/activin family
	Membrane-associated neurotransmitter stimulating factor (MANS)
	Thrombin
	Entactin
	Erythropoietin
	Neurite inducing factor
	Stem cell factor (SCF)
	Interleukin 1,3.6
	Glial-derived nexin
	Heparin-binding NF
Extracellular matrix/adhesion factors	Laminin
	Fibronectin
	Purpurin
	Apolipoproteins
	Gangliosides
Transmitters	Neurotransmitters
	Neuropeptides
Nonpeptide hormones	Steroid
	T3/T4
	Ion fluxes
	Neuronal activity

A focused definition that integrates both traditional and modern components of neurotrophic activity is presented by Hefti and co-workers in this volume (Chapter 2). This definition states that “neurotrophic factors are endogenous, soluble proteins regulating survival, growth, morphological plasticity, or synthesis of proteins for differential functions of neurons.” This volume includes chapters on soluble proteins that fulfill these formal criteria, as well as on other protein and nonprotein factors that could be considered neurotrophic factors based on their trophic and trophic-related functions.

The neurotrophic factors (as just defined) discussed in this volume include nerve growth factor (NGF; Chapters 5, 6, and 7), brain-derived neurotrophic factor (BDN; Chapter 8), ciliary neurotrophic factor (CNF; Chapter 15), fibroblast growth factors (FGF; Chapters 9 and 10), insulin and insulin-like growth factors (IGF; Chapters 13 and 14), epidermal growth factor (EGF; Chapter 11), transforming growth factors α and β (TGF; Chapter 12), and skeletal muscle-derived neurotrophic factors (Chapter 16). The effects of a number of growth factors, especially platelet-derived growth factor, on glial cells are also described (Chapter 17). In addition to the roles of these factors, the roles of adhesion factors (Chapter 18), neurotransmitters, and neuropeptides (Chapter 20) as neurotrophic factors are included by virtue of their important neurotrophic activity. These chapters focus on our present knowledge of the neurotrophic factors (first messengers), their receptor systems, and associated transducing mechanisms (second messengers). Many neurotrophic factors effect phenotypic responses in cells through rapid ligand-induced primary response genes (third messengers). These cellular mechanisms are discussed in Chapter 4. Synergistic interactions between neurotrophic factors and intrinsic cellular systems, especially with respect to cell death and survival, are examined in Chapter 3. The role of neurotrophic factors and other cellular mediators as phenotype-specifying factors is developed in Chapter 19. These factors include neurotransmitters, neuropeptides, steroids, and membrane-bound substances, as well as neuronal activity. Thus, links are formed between neurotrophic activity and related cellular mechanisms.

III REVIEW OF CELLULAR EVENTS OF NEUROTROPHIC FACTOR SYSTEMS

Each of the chapters in this volume details specific molecular and cellular aspects of neurotrophic factors. In this section, a brief overview of these ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright page
• Contributors
• Preface
• 1: Functional Implications of the Anatomical Localization of Neurotrophic Factors
• 2: Neurotrophic Factors: What Are They and What Are They Doing?
• 3: Synergy, Retrograde Transport, and Cell Death
• 4: Primary Response Gene Expression in the Nervous System
• 5: Nerve Growth Factor and Related Substances: Structure and Mechanism of Action
• 6: Regulation of Nerve Growth Factor Expression
• 7: Nerve Growth Factor: Actions in the Peripheral and Central Nervous Systems
• 8: Brain-Derived Neurotrophic Factor: An NGF-Related Neurotrophin
• 9: Biochemistry and Molecular Biology of Fibroblast Growth Factors
• 10: Fibroblast Growth Factors: Their Roles in the Central and Peripheral Nervous System
• 11: Epidermal Growth Factor: Structure, Expression, and Functions in the Central Nervous System
• 12: Transforming Growth Factors Alpha and Beta
• 13: Insulin-Like Growth Factors in the Brain
• 14: Neurobiology of Insulin and Insulin-Like Growth Factors
• 15: Ciliary Neuronotrophic Factor
• 16: Skeletal Muscle-Derived Neurotrophic Factors and Motoneuron Development
• 17: Growth Factors for Myelinating Glial Cells in the Central and Peripheral Nervous Systems
• 18: Adhesion Factors
• 19: Instructive Neuronal Differentiation Factors
• 20: Neurotransmitters as Neurotrophic Factors
• Index