Neurotrophic Factors

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ThiS is a FM Blank Page
Gary R. Lewin • Bruce D. Carter
Editors

Neurotrophic Factors
Editors
Gary R. Lewin Bruce D. Carter
Department of Neuroscience Department of Biochemistry
Max-Delbrück-Center for Vanderbilt University School of Medicine
Molecular Medicine Nashville
Berlin Tennessee
Germany USA

ISSN 0171-2004 ISSN 1865-0325 (electronic)

ISBN 978-3-642-45105-8 ISBN 978-3-642-45106-5 (eBook)
DOI 10.1007/978-3-642-45106-5
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014933801

# Springer-Verlag Berlin Heidelberg 2014

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Preface

Neurotrophic factors can be broadly understood as any secreted factor that has
nourishing or sustaining effect on neurons. The archetypical neurotrophic factor is
nerve growth factor (NGF) which was first discovered in series of elegant embryo-
logical and biochemical experiments carried out by Rita Levi-Montalcini and her
colleagues. In the 1980s and 1990s, the work of Hans Thoenen, Yves-Alain Barde,
and others paved the way for the discovery of new members of this family BDNF,
NT-3, and NT-4. This family of neurotrophic factors became known as the
neurotrophins. In parallel to these discoveries, other neurotrophic factors were
discovered, notably the glial-derived neurotrophic factor (GDNF) which also
belongs to a small sub-family of factors which includes neurtrin, artemin, and
persephin. Our knowledge on the biology of neurotrophic factors has exploded in
the last 15 years and it has become apparent that members of the neurotrophin
family play important roles, not just in the development of the nervous system, but
in the normal physiology and pathophysiology of the brain. For this reason we have
chosen to largely restrict the focus of this new handbook of pharmacology volume
on neurotrophic factors to the biology of the neurotrophins NGF, BDNF, NT-3, and
NT-4. Research on the neurotrophins in the 1990s provided much hope that these
factors would show therapeutic potential in a wide variety of neurodegenerative
diseases from Alzheimer’s to Parkinson’s disease. It is probably fair to say that the
research emphasis has moved away from pursuing a role for neurotrophins in
neuroprotection. Nevertheless the last 15 years has witnessed outstanding progress
in understanding the functional roles of these neurotrophic factors and their
receptors in normal development and adult physiology, their mechanisms of action,
as well as their role in the pathophysiology of disease. This book provides critical
reviews of the role of neurotrophins and their receptors in a wide variety of diseases
including neurodegenerative diseases like Huntington’s, cognitive dysfunction,
psychiatric disorders such as clinical depression, Rett syndrome, motor neurone
disease, spinal cord injury, pain, metabolic disease, and cardiovascular disease. The
book also contains contributions from leaders in the field dealing with the basic
biology, transcriptional and post-translational regulation of the neurotrophins, and
their receptors. The last decade has witnessed a radical change in the view of
neurotrophins and their receptors, because of the discovery that the pro-peptide
forms of NGF and BDNF, in particular, have distinct biological effects mediated by
novel receptor constellations, including that of the VPS10p family transmembrane

v
vi Preface

receptor sortilin and the low-affinity neurotrophin receptor p75NTR. Thus there are
more molecular targets for manipulating neurotrophins available and more
validated disease processes in which neurotrophins play a relevant and powerful
role. Pharmaceuticals tailored to interfere with neurotrophin function have not only
been developed, but even show clinical efficacy in late stage clinical trials for the
treatment of pain. This book will review all recent areas of progress in the study of
neurotrophins and their biological roles. Importantly, world-renowned experts
explain the detailed and complex biology of these factors in the context of disease,
revealing future perspectives for new therapies based on neurotrophin signalling
and their downstream targets.
We are very excited about this book as it contains contributions from the leading
scientists in the field who bring a unique combination of expertise on the detailed
molecular mechanisms by which neurotrophins signal as well as perspectives on
their disease relevance. During the final stages of the production of this book, two
pioneers in the field of neurotrophin research, Rita Levi-Montalcini and Hans
Thoenen, sadly passed away. We both had the honour and the luck to benefit
from close scientific contact with Hans Thoenen in the formative years of our
research careers. We would like to dedicate this volume to the memory of these two
wonderful scientists, Rita Levi-Montalcini and Hans Thoenen.

Berlin, Germany Gary R. Lewin

Nashville, TN Bruce D. Carter
Contents

Part I The Neurotrophin Family

NGF, BDNF, NT3, and NT4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

M. Bothwell
Deciphering Proneurotrophin Actions . . . . . . . . . . . . . . . . . . . . . . . . . . 17
B.L. Hempstead
Spatiotemporal Intracellular Dynamics of Neurotrophin
and Its Receptors. Implications for Neurotrophin Signaling
and Neuronal Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
F.C. Bronfman, O.M. Lazo, C. Flores, and C.A. Escudero
Neurotrophins: Transcription and Translation . . . . . . . . . . . . . . . . . . . 67
A.E. West, P. Pruunsild, and T. Timmusk

Part II Neurotrophin Receptors

Trk Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

Katrin Deinhardt and Moses V. Chao
The Biological Functions and Signaling Mechanisms of the p75
Neurotrophin Receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
B.R. Kraemer, S.O. Yoon, and B.D. Carter
Sortilins in Neurotrophic Factor Signaling . . . . . . . . . . . . . . . . . . . . . . 165
S. Glerup, A. Nykjaer, and C.B. Vaegter

Part III The Biology of Neurotrophins

Neurotrophins in the Regulation of Cellular Survival and Death . . . . . 193

Claire Ceni, Nicolas Unsain, Michele P. Zeinieh, and Philip A. Barker
BDNF and Synaptic Plasticity, Cognitive Function, and Dysfunction . . . 223
B. Lu, G. Nagappan, and Y. Lu

vii
viii Contents

Nerve Growth Factor and Nociception: From Experimental

Embryology to New Analgesic Therapy . . . . . . . . . . . . . . . . . . . . . . . . . 251
Gary R. Lewin, Stefan G. Lechner, and Ewan St. John Smith
Neurotrophins and the Regulation of Energy Balance
and Body Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283
M. Rios
The Biology of Neurotrophins: Cardiovascular Function . . . . . . . . . . . 309
Costanza Emanueli, Marco Meloni, Wohaib Hasan, and Beth A. Habecker
Neurotrophin Signalling and Transcription Programmes
Interactions in the Development of Somatosensory Neurons . . . . . . . . . 329
F. Marmigère and P. Carroll

Part IV Neurotrophins in Pathological Conditions

Huntington’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

Chiara Zuccato and Elena Cattaneo
Motoneuron Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411
M. Sendtner
Neurotrophic Factors in Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . 443
Vanessa S. Boyce and Lorne M. Mendell
Neurotrophins and Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . 461
E. Castrén
Brain-Derived Neurotrophic Factor and Rett Syndrome . . . . . . . . . . . . 481
D.M. Katz
Modulation of Neurotrophin Signaling by Monoclonal Antibodies . . . . 497
A. Rosenthal and J.C. Lin
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513
 Part I
The Neurotrophin Family
NGF, BDNF, NT3, and NT4

M. Bothwell

Abstract
The discovery of nerve growth factor (NGF) was a seminal event in history of
research in developmental neurobiology. The further discovery that NGF was
just one of a family of structurally similar growth factors, neurotrophins,
provided important insights into the way nerve cells communicate, during
development of the nervous system, and in neuroplasticity, memory, and
learning in the adult nervous system. Four neurotrophins, NGF, brain-derived
neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4),
regulate a wide variety of neural functions, acting upon p75NTR, TrkA, TrkB,
and TrkC receptors.

Keywords
Neurotrophin • NGF • BDNF • NT3 • NT4 • Evolution

1 Historical Background: Discovery of NGF and Other

Neurotrophins

1.1 Discovery of NGF

The discovery and biochemical and functional characterization of nerve growth

factor (NGF), by Rita Montalcini, Viktor Hamburger, and Stanley Cohen, was
decades ahead of its time, in more ways than we can easily appreciate today. The
discovery that the trophic effect of innervated tissues on sympathetic and sensory
neuronal development was mediated by a diffusible factor (Levi-Montalcini and
Hamburger 1953) was conceptually ground-breaking, and the successful isolation
of this NGF from mouse salivary gland was remarkable given the primitive tools for

M. Bothwell (*)
University of Washington, Seattle, WA, USA
e-mail: mab@[Link]

G.R. Lewin and B.D. Carter (eds.), Neurotrophic Factors, Handbook of 3

Experimental Pharmacology 220, DOI 10.1007/978-3-642-45106-5_1,
# Springer-Verlag Berlin Heidelberg 2014
4 M. Bothwell

protein fractionation that were available at the time. It is also remarkable that the
importance of NGF for neurons in vivo was established almost immediately by
demonstrating that injection of NGF antibody caused death of sympathetic neurons
(Cohen 1960). The precocious nature of these studies can only be understood by
contrasting this to the history of experimentation with a variety of other growth
factors that were discovered subsequently, since the loss-of-function experiments
required to demonstrate the importance in vivo of other growth factors usually
lagged the initial discovery of those growth factors by a decade or more.
It is hard to appreciate also, from a modern perspective, that the concept that a
protein released by one cell could control the differentiation of neighboring cells
was revolutionary at the time of discovery of NGF. Indeed, the possibility that NGF
could be “instructive” for neuronal differentiation, rather than merely being “per-
missive” was still a hotly debated subject when the author of this chapter entered
the field of NGF research in 1975.
The seed for the discovery of NGF was planted by the pioneering work of Viktor
Hamburger in which it was shown that surgical removal of the wing buds of chick
embryos reduced the ultimate number of motor neurons in the lateral motor column
of the spinal cord and of sensory neurons in the dorsal root ganglia at segmental
levels responsible for innervation of the missing target tissue, while transplantation
of supernumerary limb buds had the opposite effect of allowing development of
more motor neurons and sensory neurons (Hamburger 1934, 1939). Thus was born
the so-called neurotrophic hypothesis, stating that “Each part of the peripheral field
controls directly [development of] its own nervous center” along with the idea that
some signal or substance must move from the axon terminus to the neuronal cell
body to convey this signal.
The work of Rita Levi-Montalcini, initially independently (Levi-Montalcini and
Levi 1943) and subsequently in collaboration with Viktor Hamburger (Hamburger
and Levi-Montalcini 1949), demonstrated that these effects were not primarily an
effect on neurogenesis, as initially supposed, but rather, largely reflected the ability
of the innervated target to suppress developmental cell death of the innervating
neurons. Attempts to model the limb bud effects with small pieces of sarcoma
tumor, initially in vivo (Levi-Montalcini and Hamburger 1951), and subsequently
in vitro (Levi-Montalcini and Hamburger 1953), using newly available tissue
culture techniques demonstrated potent effects on development of sympathetic
neurons as well as sensory neurons and importantly established that the effects
were mediated by a diffusible factor. Subsequent studies revealed that a similar
activity was present at much higher concentrations in cobra venom and mouse
salivary gland, allowing the biochemical purification of the factors and importantly,
demonstrating that an antiserum to the NGF protein caused degeneration of the
nervous system of neonatal rodents (Cohen 1960; Cohen and Levi-Montalcini
1956). The later discovery that NGF was a member of a family of factors that
control survival of sensory neurons was presaged by Levi-Montalcini’s observation
that NGF promoted the survival of small mediodorsally located sensory neurons in
DRGs, while NGF had no effect on the larger ventrolaterally located sensory
neurons.
NGF, BDNF, NT3, and NT4 5

1.2 Discovery of the Neurotrophin Gene Family

The sensory ganglia that are segmentally distributed along the trunk of vertebrates
derive from the neural crest, but many cranial sensory ganglia derive instead from
epithelial placodes. Target-derived trophic factors are required for developmental
survival of both neural crest-derived and placode-derived peripheral sensory
neurons, yet NGF only promotes survival of neural crest-derived sensory neurons.
Such observations motivated experiments leading to the discovery and molecular
cloning of brain-derived neurotrophic factor (BDNF) as a trophic factor for
placode-derived sensory neurons (Barde et al. 1982). Nucleotide sequence analysis
revealed that NGF and BDNF were structurally related (Leibrock et al. 1989).
Several teams of investigators recognized independently that short highly
conserved regions of NGF and BDNF transcripts permitted the design of primers
for polymerase chain reaction that would jointly amplify both NGF and BDNF
sequences and employing these primers discovered additional members of the NGF
gene family—neurotrophin-3 (NT3) (Hohn et al. 1990; Jones and Reichardt 1990;
Maisonpierre et al. 1990; Rosenthal et al. 1990) and neurotrophin-4 (NT4)
(Berkemeier et al. 1991; Hallbook et al. 1991; Ip et al. 1992). The fourth mamma-
lian neurotrophin identified was variously named NT4 or NT5, according to
whether the discoverers included a previously described fish neurotrophin in their
numbering scheme. As a compromise between the alternative nomenclatures, the
fourth mammalian neurotrophin is frequently referred to as NT4/5. It will be called
NT4 in this chapter. Some fish possess an additional neurotrophin family member,
while birds lack NT4. The term neurotrophin was originally coined to describe
members of the NGF gene family. A few present day investigators use the term
“neurotrophin” as a synonym for “neurotrophic factor.” Most investigators prefer to
reserve the term “neurotrophin” for its original purpose, as a means to refer to NGF
gene family members collectively.

2 Neurotrophin Structure

Mature neurotrophins exist as noncovalently associated dimers of ~13,500 Da

protomers (Bothwell and Shooter 1977; Radziejewski et al. 1992). The affinity of
the dimeric NGF association is sufficient to prevent dissociation even at the pM
concentrations at which NGF acts physiologically (Bothwell and Shooter 1977) and
this is probably also true for the other neurotrophins. High resolution structures
have been determined for each of the neurotrophins (Butte et al. 1998; McDonald
et al. 1991; Robinson et al. 1999). Each neurotrophin subunit has a backbone
consisting of two pairs of antiparallel β-strands generating an elongated shape
and stabilized by three disulfide bonds. The structure has been referred to as a
cystine knot, and a similar folding organization has been observed in several other
growth factors, including TGF-beta and PDGF family members (McDonald and
Chao 1995). The highly conserved interaction interface of the neurotrophin dimers
permits the formation of heterodimers between different neurotrophins in vitro but
6 M. Bothwell

evidence is lacking for the existence of such heterodimers in vivo (Jungbluth

et al. 1994; Philo et al. 1994; Robinson et al. 1995).
Early studies of the biochemistry of NGF placed particular attention on the high
molecular weight complex in which NGF could be isolated from mouse submaxil-
lary salivary gland (Greene et al. 1969; Nichols and Shooter 1985). The sedimenta-
tion velocity of this complex was 7 svedbergs—accordingly the complex was
known as 7S NGF. Curiously, this complex was ultimately found to represent
NGF (known at the time as low molecular weight NGF, 2.5S NGF or beta-NGF)
in association with alpha and gamma subunits which represent two different
members of the glandular kallikrein family of proteases (Bothwell et al. 1979;
McDonald and Blundell 1991). The physiological relevance of the high molecular
weight complex of NGF is unclear, as this form of NGF appears to exist only in
mouse, and in mouse, only in salivary glands. The manner in which this peculiar
biological adaptation of NGF may have evolved in mice is discussed below.

3 Neurotrophin Receptors

The four mammalian neurotrophins interact with four receptors; p75NTR, TrkA,
TrkB, and TrkC. The function of these multiple receptors is complex, as p75NTR
and Trk receptors can function independently, but in neurons that express both
p75NTR and Trk receptors, the receptors interact physically and functionally in ways
that may alter the signaling properties of each. The structure and signaling functions
of these receptors are discussed in detail elsewhere in this book. Briefly, all four
neurotrophins, both as proneurotrophins and as mature fully processed
neurotrophins, can bind and activate signaling by p75NTR, whereas the Trk
receptors prefer to bind mature neurotrophins and are selective for particular
neurotrophins. NGF preferentially binds and activates TrkA, NT3 preferentially
binds and activates TrkC, and BDNF and NT4 preferentially bind and activate
TrkB. For this reason, BDNF and NT4 are typically functionally redundant in
mammals, and reflecting this redundancy, the NT4 gene has apparently been lost
during evolution of birds. NT3 is the most promiscuous of the neurotrophins as
alternative splicing of the TrkA transcript can generate forms of TrkA that are
effectively activated by NT3 (Clary and Reichardt 1994). Importantly, however,
NGF and NT3 are not functionally equivalent with respect to TrkA activation, as
they influence TrkA signaling differently (Harrington et al. 2011).
One or more of the four neurotrophin receptors are expressed in a wide variety of
types of neurons and glia in both the central and peripheral nervous system and also
in a variety of non-neural cell types. Thus, neurotrophins have an extraordinary
range of biological functions, with the neurotrophin preference of various cell
populations being determined by the particular neurotrophin receptor or receptors
they express.
NGF, BDNF, NT3, and NT4 7

4 Neurotrophin Processing and Secretion

Like most other secreted biologically active polypeptides, protein synthesis of

neurotrophins occurs in the rough endoplasmic reticulum, where the proneuro-
trophins are packaged into secretory vesicles. Proneurotrophins, which range
from about 210 to 270 amino acid residues in length, are processed within these
vesicles by proteases of the proprotein convertase family (Seidah et al. 1996),
producing the mature neurotrophins which are about 120 residues in length. In
the case of BDNF, the cleaved prodomain is stored with and cosecreted with mature
BDNF (Dieni et al. 2012). Whether this pro-peptide has any biological function,
and whether the pro-domains of other neurotrophins are secreted, is unknown. In
some cases, vesicular processing of neurotrophins is incomplete, leading to secre-
tion of unprocessed pro-neurotrophins from which the mature neurotrophin may be
released by plasmin and matrix metalloproteinases following secretion (Lee
et al. 2001).
The seminal experiments that lead to the proposal of the “neurotrophic hypothe-
sis” and the discovery of neurotrophins examined neuronal populations that
innervated non-neural peripheral target tissues. However, in many cases, and
particularly in the central nervous system, the neurotrophin-producing innervated
target cell may also be a neuron. Neurotrophin secretion by neuronal and
non-neuronal cells differs in several important ways that were not immediately
appreciated by investigators. Firstly, neurons (and neuroendocrine cells) have
distinct regulated and constitutive secretory pathways, whereas non-neuronal cell
types typically have only the constitutive secretory pathway (Kelly 1985). Thus,
while the manner of secretion of the four neurotrophin is similar in non-neural cell
types, in neurons, this is not the case, as NGF, NT3, and NT4 traffic mainly through
the constitutive secretory pathway in neurons and neuroendocrine cells, whereas
BDNF selectively traffics through the regulated secretory pathway (Farhadi
et al. 2000; Griesbeck et al. 1999; Hibbert et al. 2003; Mowla et al. 1999). This
distinction is particularly important in the context of BDNF functions in learning
and memory, where control of BDNF secretion by neural activity is likely to be
essential, as discussed elsewhere in this book. The second important distinction
between neurons and many non-neural cell types is that neurons are highly
polarized cells. Initially, no doubt with a mindset influenced by early studies of
neurotrophic functions with non-neural neurotrophin-producing cells, the expecta-
tion was that neurons would secrete neurotrophins principally at the
somatodendritic membrane domains, as these are normally the site of axonal
synaptic contacts. However, in neurons, much of BDNF secretion follows the
same secretory pathway as neuropeptides, being packaged in dense core vesicles,
which are transported anterogradely down axons and secreted at the axon terminus
(Conner et al. 1997; Dieni et al. 2012; von Bartheld et al. 1996; Zhou and Rush
1996).
Two proBDNF-binding proteins have been implicated in directing proBDNF to
the regulated secretory pathway, carboxypeptidase E (Lou et al. 2005), and sortilin
(Chen et al. 2005). Importantly, a common allelic variant of the human BDNF gene