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Preface to Second Edition xi
Preface to First Edition xiii
Conventions and Commonly used Abbreviations xv
Introduction xix
About the Companion Website xxiii
1 Models and Methods for Studying Neural Development 1
1.1 What is neural development? 1
1.2 Why research neural development? 2
The uncertainty of current understanding 2
Implications for human health 3
Implications for future technologies 4
1.3 Major breakthroughs that have contributed to understanding developmental mechanisms 4
1.4 Invertebrate model organisms 5
Fly 5
Worm 7
Other invertebrates 11
1.5 Vertebrate model organisms 11
Frog 11
Chick 12
Zebrafish 12
Mouse 12
Humans 19
Other vertebrates 20
1.6 Observation and experiment: methods for studying neural development 23
1.7 Summary 24
2 The Anatomy of Developing Nervous Systems 25
2.1 The nervous system develops from the embryonic neuroectoderm 25
2.2 Anatomical terms used to describe locations in embryos 26
2.3 Development of the neuroectoderm of invertebrates 27
C. elegans 27
Drosophila 27
2.4 Development of the neuroectoderm of vertebrates and the process of neurulation 30
Frog 31
Chick 33
Zebrafish 35
Mouse 36
Human 43
2.5 Secondary neurulation in vertebrates 47
2.6 Formation of invertebrate and vertebrate peripheral nervous systems 47
Invertebrates 49
Vertebrates: the neural crest and the placodes 49
Vertebrates: development of sense organs 50
2.7 Summary 52
3 Neural Induction: An Example of How Intercellular Signalling Determines Cell Fates 53
3.1 What is neural induction? 53
3.2 Specification and commitment 54
3.3 The discovery of neural induction 54
3.4 A more recent breakthrough: identifying molecules that mediate neural induction 56
3.5 Conservation of neural induction mechanisms in Drosophila 58
3.6 Beyond the default model - other signalling pathways involved in neural induction 59
3.7 Signal transduction: how cells respond to intercellular signals 64
3.8 Intercellular signalling regulates gene expression 65
General mechanisms of transcriptional regulation 65
Transcription factors involved in neural induction 67
What genes do transcription factors control? 69
Gene function can also be controlled by other mechanisms 71
3.9 The essence of development: a complex interplay of intercellular and intracellular signalling 75
3.10 Summary 75
4 Patterning the Neuroectoderm 77
4.1 Regional patterning of the nervous system 77
Patterns of gene expression are set up by morphogens 78
Patterning happens progressively 80
4.2 Patterning the anteroposterior (AP) axis of the Drosophila CNS 81
From gradients of signals to domains of transcription factor expression 81
Dividing the ectoderm into segmental units 83
Assigning segmental identity - the Hox code 83
4.3 Patterning the AP axis of the vertebrate CNS 86
Hox genes are highly conserved 87
Initial AP information is imparted by the mesoderm 88
Genes that pattern the anterior brain 90
4.4 Local patterning in Drosophila: refining neural patterning within segments 91
In Drosophila a signalling boundary within each segment provides local AP positional information 92
Patterning in the Drosophila dorsoventral(DV) axis 94
Unique neuroblast identities from the integration of AP and DV patterning information 96
4.5 Local patterning in the vertebrate nervous system 97
In the vertebrate brain, AP boundaries organize local patterning 97
Patterning in the DV axis of the vertebrate CNS 99
Signal gradients that drive DV patterning 100
SHH and BMP are morphogens for DV progenitor domains in the neural tube 101
Integration of AP and DV patterning information 103
4.6 Summary 103
5 Neurogenesis: Generating Neural Cells 105
5.1 Generating neural cells 105
5.2 Neurogenesis in Drosophila 106
Proneural genes promote neural commitment 106
Lateral inhibition: Notch signalling inhibits commitment 106
5.3 Neurogenesis in vertebrates 107
Proneural genes are conserved 107
In the vertebrate CNS, neurogenesis involves radial glial cells 111
Proneural factors and Notch signaling in the vertebrate CNS 111
5.4 The regulation of neuronal subtype identity 114
Different proneural genes - different programmes of neurogenesis 114
Combinatorial control by transcription factors creates neuronal diversity 114
5.5 The regulation of cell proliferation during neurogenesis 117
Signals that promote proliferation 117
Cell division patterns during neurogenesis 118
Asymmetric cell division in Drosophila requires Numb 118
Control of asymmetric cell division in vertebrate neurogenesis 121
In vertebrates, division patterns are regulated to generate vast numbers of neurons 122
5.6 Temporal regulation of neural identity 124
A neural cell's time of birth is important for neural identity 124
Time of birth can generate spatial patterns of neurons 126
How does birth date influence a neurons fate? 128
Intrinsic mechanism of temporal control in Drosophila neuroblasts 128
Birth date, lamination and competence in the mammalian cortex 129
5.7 Why do we need to know about neurogenesis? 133
5.8 Summary 133
6 How Neurons Develop Their Shapes 135
6.1 Neurons form two specialized types
of outgrowth 135
Axons and dendrites 135
The cytoskeleton in mature axons and dendrites 137
6.2 The growing neurite 138
A neurite extends by growth at its tip 138
Mechanisms of growth cone dynamics 139
6.3 Stages of neurite outgrowth 141
Neurite outgrowth in cultured hippocampal neuron 141
Neurite outgrowth in vivo 142
6.4 Neurite outgrowth is influenced by a neuron's surroundings 143
The importance of extracellular cues 143
Extracellular signals that promote or inhibit neurite outgrowth 143
6.5 Molecular responses in the growth cone 145
Key intracellular signal transduction events 145
Small G proteins are critical regulators of neurite growth 145
Effector molecules directly influence actin filament dynamics 147
Regulation of other processes in the extending neurite 148
6.6 Active transport along the axon is
important for outgrowth 149
6.7 The developmental regulation
of neuronal polarity 149
Signalling during axon specification 149
Ensuring there is just one axon 151
Which neurite becomes the axon? 152
6.8 Dendrites 153
Regulation of dendrite branching 153
Dendrite branches undergo
self?]avoidance 154
Dendritic fields exhibit tiling 155
6.9 Summary 156
7 Neuronal Migration 157
7.1 Many neurons migrate long distances during formation of the nervous system 157
7.2 How can neuronal migration be observed? 157
Watching neurons move in living embryos 158
Observing migrating neurons in cultured tissues 158
Tracking cell migration by indirect methods 158
7.3 Major modes of migration 164
Some migrating neurons are guided by a scaffold 164
Some neurons migrate in groups 165
Some neurons migrate individually 168
7.4 Initiation of migration 169
Initiation of neural crest cell migration 170
Initiation of neuronal migration 170
7.5 How are migrating cells guided to their destinations? 170
Directional migration of neurons in C. elegans 171
Guidance of neural crest cell migration 173
Guidance of neural precursors in the developing lateral line of zebrafish 174
Guidance by radial glial fibres 174
7.6 Locomotion 176
7.7 Journey's end - termination of migration 179
7.8 Embryonic cerebral cortex contains both radially and tangentially migrating cells 182
7.9 Summary 184
8 Axon Guidance 185
8.1 Many axons navigate long and complex routes 185
How might axons be guided to their targets? 185
The growth cone 187
Breaking the journey - intermediate targets 188
8.2 Contact guidance 190
Contact guidance in action: pioneers and followers, fasciculation and defasciculation 191
Ephs and ephrins: versatile cell surface molecules with roles in contact guidance 191
8.3 Guidance of axons by diffusible cues - chemotropism 194
Netrin - a chemotropic cue expressed at the ventral midline 195
Slits 195
Semaphorins 198
Other axon guidance molecules 198
8.4 How do axons change their behavior at choice points? 199
Commissural axons lose their attraction to netrin once they have crossed the floor plate 199
Putting it all together - guidance cues and their receptors choreograph commissural axon pathfinding at the ventral midline 202
After crossing the midline, commissural axons project towards the brain 205
8.5 How can such a small number of cues guide such a large number of axons? 207
The same guidance cues are deployed in multiple axon pathways 208
Interactions between guidance cues and their receptors can be altered by co?]factors 208
8.6 Some axons form specific connections over very short distances, probably using different mechanisms 209
8.7 The growth cone has autonomy in its ability to respond to guidance cues 209
Growth cones can still navigate when severed from their cell bodies 209
Local translation in growth cones 210
8.8 Transcription factors regulate axon guidance decisions 211
8.9 Summary 212
9 Life and Death in the Developing Nervous System 215
9.1 The frequency and function of cell death during normal development 215
9.2 Cells die in one of two main ways: apoptosis or necrosis 217
9.3 Studies in invertebrates have taught us much about how cells kill themselves 219
The specification phase 221
The killing phase 221
The engulfment phase 222
9.4 Most of the genes that regulate programmed cell death in C. elegans are conserved in vertebrates 222
9.5 Examples of neurodevelopmental processes in which programmed cell death plays a prominent role 224
Programmed cell death in early progenitor cell populations 224
Programmed cell death contributes to sexual differences in the nervous system 225
Programmed cell death removes cells with transient functions once their task is done 227
Programmed cell death matches the numbers of cells in interacting neural tissues 230
9.6 Neurotrophic factors are important regulators of cell survival and death 232
Growth factors 232
Cytokines 235
9.7 A role for electrical activity in regulating programmed cell death 235
9.8 Summary 237
10 Map Formation 239
10.1 What are maps? 239
10.2 Types of maps 239
Coarse maps 241
Fine maps 242
10.3 Principles of map formation 243
Axon order during development 244
Theories of map formation 245
10.4 Development of coarse maps: cortical areas 246
Protomap versus protocortex 246
Spatial position of cortical areas 247
10.5 Development of fine maps: topographic 248
Retinotectal pathways 248
Sperry and the chemoaffinity hypothesis 250
Ephrins act as molecular postcodes in the chick tectum 252
10.6 Inputs from multiple structures: when maps collide 253
From retina to cortex in mammals 254
Activity?]dependent eye?]specific segregation: a role for retinal waves 254
Formation of ocular dominance bands 257
Ocular dominance bands form by directed In growth of thalamocortical axons 257
Activity and the formation of ocular dominance bands 259
Integration of sensory maps 260
10.7 Development of feature maps 261
Feature maps in the visual system 261
Role of experience in orientation and direction map formation 263
10.8 Summary 264
11 Maturation of Functional
Properties 265
11.1 Neurons are excitable cells 266
What makes a cell excitable? 266
Electrical properties of neurons 267
Regulation of intrinsic neuronal
physiology 269
11.2 Neuronal excitability during development 271
Neuronal excitability changes dramatically during development 271
Early action potentials are driven by Ca2+, not Na+ 271
Neurotransmitter receptors regulate excitability prior to synapse formation 273
GABAergic receptor activation switches from being excitatory to inhibitory 273
11.3 Developmental processes regulated by neuronal excitability 275
Electrical excitability regulates neuronal proliferation and migration 275
Neuronal activity and axon guidance 277
11.4 Synaptogenesis 277
The synapse 278
Electrical properties of dendrites 278
Stages of synaptogenesis 280
Synaptic specification and induction 281
Synapse formation 285
Synapse selection: stabilization and withdrawal 286
11.5 Spinogenesis 286
Spine shape and dynamics 287
Theories of spinogenesis 289
Mouse models of spinogenesis: the weaver mutant 290
Molecular regulators of spine development 291
11.6 Summary 293
12 Experience?]Dependent Development 295
12.1 Effects of experience on visual system development 296
Seeing one world with two eyes: ocular dominance of cortical cells 296
Visual experience regulates ocular dominance 297
Competition regulates experiencedependent plasticity: the effects of darkrearing and strabismus 299
Physiological changes in ocular dominance prior to anatomical changes 301
Cooperative binocular interactions and visual cortex plasticity 304
The timing of developmental plasticity: sensitive or critical periods 305
Multiple sensitive periods in the developing visual system 306
12.2 How does experience change functional connectivity? 307
Cellular basis of plasticity: synaptic strengthening and weakening 309
The time?]course of changes in synaptic weight in response to monocular deprivation 310
Cellular and molecular mechanisms of LTP/LTD induction 312
Synaptic changes that mediate the expression of LTP/LTD and experiencedependent plasticity 314 Metaplasticity 318
Spike?]timing dependent plasticity 320
12.3 Cellular basis of plasticity: development of inhibitory networks 322
Inhibition contributes to the expression of the effects of monocular deprivation 322
Development of inhibitory circuits regulates the time?]course of the sensitive period for monocular deprivation 323
12.4 Homeostatic plasticity 324
Mechanisms of homeostatic plasticity 325
12.5 Structural plasticity and the role of the extracellular matrix 327
12.6 Summary 328
Glossary 329
Index 349
Neural development is the process by which the nervous system grows from its first beginnings in the embryo to its completion as a mature functioning system. The mature nervous system contains two classes of specialized and closely interacting cells: neurons and glia. Neurons transmit signals to, from and within the brain: their axons transmit electrical signals and they communicate with other cells via synapses. There are many types of neuron with specialized shapes and functions, with cell bodies that vary in diameter from only a few micrometers to around 100 micrometers and with axons whose lengths vary from a few micrometers to more than 1 meter. There are also different types of glial cell. The interactions between neurons and glia are very precise and they allow the nervous system to function efficiently. Figure 1.1 shows a beautiful example of the complex structures created by interacting neurons and glia, in this case a microscopic view of a labelled node of Ranvier, which allows rapid signalling in the nervous system.
Figure 1.1 A node of Ranvier: these highly organized structures, formed as a result of interactions between axons and glia, are essential for speeding up the transmission of electrical signals along axons. In this single fibre from the mouse spinal cord, sodium channels (blue) are sandwiched between the regions where axons and glia form junctions (called axoglial junctions) (green), which are, in turn, flanked by potassium channels (red). This picture is courtesy of Peter Brophy and Anne Desmazieres, University of Edinburgh, UK.
The great molecular, structural and functional diversity of neurons and glia is acquired in an organized way through processes that build on differences between the relatively small numbers of cells in the early embryo. As more and more cells are generated in a growing organism, new cells diversify in specific ways as a result of interactions with pre-existing cells, continually adding to the organism's complexity in a highly regulated manner. The development of an organism is a bit like the development of human civilization (allowing for the obvious difference that organismal development repeats over and over again). In both, population size and sophistication (be it humans on earth or cells in an organism) grow hand-in-hand, each stage adding further layers of complexity to previously generated structures, functions and interactions. The mechanisms that regulate cellular actions and interactions during development are often described using terms commonly applied to human activities. We shall highlight this at several places throughout the book where analogies might be helpful.
To understand how organisms develop we need to know how cells in each part of the embryo develop in specific and reproducible ways as a result of their own internal mechanisms interacting with an expanding array of stimuli from outside the cell. Many laboratories around the world are researching this area. Why?
One reason for researching neural development is that we still know relatively little about it. In this book we shall try to explain some of the main events that occur during neural development and, in particular, the mechanisms by which those events are brought about, in so far as we understand them. It is important, however, to appreciate that much of what we present, particularly our understanding of molecular mechanisms, is best thought of as continually evolving hypotheses rather than established facts. The biologist Konrad Lorenz once stated that 'truth in science can be defined as the working hypothesis best suited to open the way to the next better one'; this is highly appropriate in developmental neurobiology.
Some of our understanding is incomplete or may be shown by future experiments to be inaccurate. We have tried to highlight issues of particular uncertainty or controversy and to indicate the limits of our knowledge, since it is at least as important and interesting to acknowledge what we do not know as it is to learn what we do know. Much of the excitement of developmental neurobiology arises from the mystery that surrounds Nature's remarkable ability to create efficiently and reproducibly neural structures of great power.
One reason that we still know relatively little about the mechanisms of neural development is the sheer size and complexity of the finished product in higher animals. During the development of the human brain, for example, about 100 billion cells are generated with about 1000 trillion connections between them; if this number of connections is hard to visualize then consider that it might roughly equal the number of grains of sand on a small beach. Although cells and connections with similar properties can be grouped together, there is still great variation in their molecular make-ups, morphologies and functions throughout the nervous system. In reading this book you will see that many of our hypotheses about neural development are formulated at the level of tissues or populations of cells rather than individual cells and their connections, particularly in higher mammals. Only in very simple organisms containing a few hundred neurons (e.g. in some worms) do we fully understand where each cell of the adult nervous system comes from and even then we do not know for sure what mechanisms determine how each cell and its connections develop. We still have a long way to go to gain a profound understanding of the molecular and cellular rules that govern the emergence of cells of the right types in the right numbers at the right places with the right connections between them functioning in the right ways.
Just because we do not know much about a subject is not sufficient reason to want to invest time and resources in researching it further. However, there are many practical reasons for wanting to know more about the ways in which the nervous system develops. A better understanding should help us to tackle currently incurable diseases of the nervous system. Many congenital diseases affect neural development1 but their causes are often unknown; some examples of such diseases will be given later in this and in subsequent chapters. Numerous relatively common psychiatric and neurological diseases, such as schizophrenia, intellectual disabilities, autisms and some forms of epilepsy (Figure 1.2), are now thought to have a developmental origin, but the mechanisms are poorly understood. Knowledge of how cancers form should be helped by a better understanding of normal development; the uncontrolled growth of cancer cells is often attributed to abnormalities of the same molecules and mechanisms that control growth during normal development. Regarding the development of possible new treatments, it has been suggested that a diseased brain might be repaired by replacing dysfunctional genes or implanting new cells into the nervous system. Implanted cells would need to recapitulate a developmental programme allowing their survival and functional integration into the nervous system and its circuitry. How this might be achieved is currently unclear, but research on normal developmental mechanisms might help.
Figure 1.2 Schizophrenia, intellectual disabilities, autisms and epilepsies are neurological disorders affecting about 3-7% of people. Based on epidemiological and neurobiological evidence, schizophrenia is now believed to be a neurodevelopmental disorder with a large heritable component. Many possible susceptibility genes have been identified, but how abnormalities of these genes cause the symptoms of the disease is unknown. Similarly, autism spectrum disorders and intellectual disabilities are highly heritable and many of the known genetic causes seem to regulate the formation of synapses. Malformations of cerebral cortical development are among the commonest causes of epilepsy. Some are large defects that would be obvious to the naked eye whereas others would only be seen at a microscopic or molecular level. They are a consequence of a disruption of the normal steps of cortical formation, for example defective migration of neurons, and can be environmental or genetic in origin. A large number of malformations of cortical development have been described, each with characteristic pathological and clinical features. An example of a large congenital defect causing epilepsy is shown in the scan of a patient's brain on the right (between the arrows): for comparison, a scan of the brain of a normal person is shown on the left. This picture is courtesy of Professor John S. Duncan and the National Society for Epilepsy MRI Unit, UK.
Another, perhaps unexpected, motivation for understanding how the brain develops comes from the drive to revolutionize computer technology, to improve robotics and to generate autonomous machines able to make decisions. The application of current manufacturing methods to build much more complex computers than exist at present will need to overcome exponential increases in the production cost of ever smaller and faster circuits. In contrast, evolution has produced brains of enormous computing power that self-construct with great efficiency. Can lessons...
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