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Development of the Nervous
System
Fourth Edition

Dan H. Sanes
Thomas A. Reh
William A. Harris
Matthias Landgraf
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Preface to the First Edition

The human brain is said to be the most complex object in The goal of this text is to provide a contemporary over-
our known universe, and the billions of cells and trillions view of neural development for undergraduate students or
of connections are truly wonders of enormous proportions. those who have some background in the field of biology.
The study of the way that the cellular elements of the ner- This intent is not compatible with a comprehensive review
vous system work to produce sensations, behaviors, and of the literature. A recent MEDLINE search of publications
higher-order mental processes has become a most produc- in the field of neural development [(neural or neuron or
tive area of science. However, neuroscientists have come nervous) and (development or embryology or maturation)]
to realize that they are studying a moving target: growth yielded 56,840 papers published between 1966 and 1999.
and change are integral to brain function and form the very We admit, up front, to having read only a fraction of these
basis by which we can learn anything about it. As the be- papers or of the thousands that were published before 1966.
havioral embryologist George Coghill pointed out, “Man is, As a practical matter, we made use of authoritative books,
indeed, a mechanism, but he is a mechanism which, within contemporary review articles, hallway conversations, and
his limitations of life, sensitivity and growth, is creating and email consultations to select the experiments that are cov-
operating himself.” To understand the brain, we need to un- ered in our text. Even so, we expect that important contribu-
derstand how this mechanism arises and the ways in which tions have been missed inadvertently. Therefore, advanced
it can change throughout a lifetime. students will find themselves quickly turning to specialized
The construction of the brain is an integrated series of texts and reviews. Another compromise that comes from
developmental steps, beginning with the decision of a few writing an undergraduate biology book well after the onset
early embryonic cells to become neural progenitors. As con- of the revolution in molecular biology is that all subjects
nections form between nerve cells and their electrical prop- now have a rather broad cast of molecular characters. In
erties emerge, the brain begins to process information and addition, the most instructive experiments on a particular
mediate behaviors. Some of the underlying circuitry is built class of molecules have often been performed on nonneu-
into the nervous system during embryogenesis. However, ral tissue. Even if we chose to cover only the genes and
interactions with the world continuously update and adapt proteins whose roles have been best characterized in the
the brain's functional architecture. The mechanisms by nervous system, most chapters would run the risk of sound-
which these changes occur appear to be a continuation of ing like a (long) list of acronyms. Therefore, we charted a
the processes that sculpt the brain during development. compromise between the need to update students and our
Since the text covers each of these developmental steps, it is strong inclination to hold their attention. The book does not
relatively broad in scope. contain exhaustive lists of molecular families, and the most
An understanding of the development of the nervous current articles must serve as an appendix to our text.
system has importance for biologists in a larger context. Among the many scientists who helped us through dis-
Studies of development have led to insights into the evo- cussions, unpublished findings, or editorial comment are
lutionary relationships among organisms. The dogma of (in alphabetical order) Chiye Aoki, Michael Bate, Olivia
phylogeny and ontogeny of the last century has been su- Bermingham-McDonogh, John Bixby, Sarah Bottjer, Martin
perseded by a deeper understanding of the ways in which Chalfie, Hollis Cline, Martha Constantine-Paton, Ralph
evolutionary change can be effected through changes in Greenspan, Voker Hartenstein, Mary Beth Hatten, Christine
development. The brain is no exception to these rules. We Holt, Darcy Kelley, Chris Kintner, Sue McConnell, Ilona
should expect that insight into the evolution of that which Miko, Ronald Oppenheim, Thomas Parks, David Raible,
makes us most human will be gained from an appreciation Henk Roelink, Edwin Rubel, John Rubenstein, David
of how developmental processes are modified over time. Ryugo, Nancy Sculerati, Carla Shatz, and Tim Tully.

ix
Preface to the Second Edition

The human brain—perhaps the most complex object in our changes in development. The brain is no exception to these
universe—is composed of billions of cells and trillions of rules, and we can expect that much insight into the evo-
connections. It is truly a wonder of enormous proportions. lution of that which makes us most human will be gained
Although we are far from a thorough understanding of our from an appreciation of how developmental processes are
brains, the study of the way that the cellular constituents of modified over time.
the nervous system, the neurons and glia, work to produce The goal of this text is to provide a contemporary over-
sensations, behaviors, and higher order mental processes view of neural development both for undergraduate stu-
has been a most productive area of science. However, more dents and for those who have some background in the field
and more, neuroscientists are realizing that we are studying of biology. This intent is not compatible with a comprehen-
the moving target of growth, and that changes are integral sive review of the literature. In the first edition, we noted
to brain function, forming the very basis for learning, per- that there were about 54,000 papers published in this field
ception, and performance. To comprehend brain function, between 1966 and 1999. Another 25,000 have appeared
we must understand how the circuits arise and the ways during the past 4 years (using the search string “neural or
in which they are modified during maturation. Santiago neuron or nervous” and “development or embryology or
Ramón y Cajal, one of the founders of modern neurosci- maturation” and 2000:2004). We charted a compromise be-
ence, was able to make his remarkable progress in studies tween the need to update students and our strong inclination
of the cellular makeup of the nervous system in large part to hold their attention. The book does not contain exhaus-
because of his work with the embryonic brain, choosing to tive lists of molecular families, and the most current review
study “the young wood, in the nursery stage…rather than articles must serve as an appendix to our text. Since the text
the…impenetrable…full grown forest.” does not encompass many exciting areas of research, stu-
The construction of the brain is an integrated series of dents will find themselves quickly turning to specialized
developmental steps, starting with the decision of a few texts and reviews.
early embryonic cells to become neural progenitors and Among those who helped us through discussion and
nearing completion with the emergence of behavior, which editorial comment are: Chiye Aoki, Michael Bate, Carla
is the scope of this book. Interactions with the world con- Shatz, Ford Ebner, Edward Gruberg, Christine Holt, Lynne
tinuously update and adapt synaptic connections within the Kiorpes, Vibhakar Kotak, Tony Movshon, Ron Oppenheim,
brain, and the mechanisms by which these changes occur Sarah Pallas, Sheryl Scott, Tim Tully, and Lance Zirpel.
are fundamentally a continuation of the same processes that Finally, we acknowledge our editor, Johannes Menzel,
sculpted the emerging brain during embryogenesis. with particular gratitude, for his help, advice, and
Studies of development have also led to insights about perseverance.
the evolutionary relationships among organisms. The
dogma of phylogeny and ontogeny of the last century has Dan H. Sanes
been superseded by our current deeper understanding of the Thomas A. Reh
ways in which evolutionary change can be effected through William A. Harris

xi
Preface to the Third Edition

In a field of science where the tools of investigation continue acceptance and included several new studies to convey the
to improve dramatically and the challenge is to understand excitement that is part of a field where very recent discover-
the construction of what is, arguably, the most complex ob- ies continue to have enormous impact. We were cautious,
ject in our known universe, it is not unexpected that this third however, about including too much of this new material for
edition of Development of the Nervous System required ex- two reasons. First, we wanted to keep the size of the book
tensive revision. Moreover, it has become increasingly clear the same. Second, experience has taught us that what is new
that in many respects the processes of neural development and exciting will not always turn out to be as pivotal for the
continue in the “mature” adult brain. Discoveries in adult field as it now appears. The future will be the best judge of
neurogenesis and plasticity have profound implications for which studies become classics and which studies will form
brain function throughout life. Moreover, abnormalities in the core of future textbooks.
developmental mechanisms lead to brain disorders that only Therefore, though we are enormously grateful to many
become manifest in adulthood. Our understanding of these colleagues (listed below) who have contributed advice
developmental processes holds the promise for emerging and material to this third edition, the choice of what to in-
therapies, such as deriving neurons and glia from embry- clude and what not to include was ours alone. We accept
onic stem cells. In this way, the study of neural development responsibility for any deficits in concept or coverage. Our
has never been more relevant. thanks go explicitly to the following people who helped
Experts in various subfields of neural development us with the third edition: Michael Bate, John Bixby, Steve
helped us by reviewing each chapter, telling us what they Burden, Martha Constantine-Paton, Ford Ebner, Gord
thought was missing, wrong, needed updating, or should be Fischell, John Flanagan, Francois Guillemot, Christopher
removed from the text. They also suggested where entire Henderson, Christine Holt, Chris Kintner, Lynne Kiorpes,
sections of the book should be approached afresh, empha- Alex Kolodkin, Vibhakar Kotak, Matthias Landgraf, Jeff
sizing new conceptual angles. We took most of their excel- Lichtman, Tony Movshon, Alan Roberts, John Rubenstein,
lent advice. However, we were mindful that many of the Peter Scheiffele, Josh Weiner, Ed Ziff, and Lance Zirpel. A
older studies in our field have stood the test of time, and special note of thanks goes to the editorial staff at Elsevier:
continue to serve as the core knowledge of neural develop- Clare Caruana, Mica Haley, Johannes Menzel, and Melissa
ment. This core still forms the storyline of the textbook. We Turner.
hope that those of you who were content with our second
edition, particularly for teaching purposes, will be comfort- Dan H. Sanes
able with the third edition. The book is built on the same Thomas A. Reh
foundation, yet we have embraced ideas that have gained in William A. Harris

xiii
Preface to the Fourth Edition

It is apparent to students and authors alike that the lit- rally occurring neuron cell death, with most contemporary
erature has grown exponentially in all scientific disciplines. research being directed at the mechanisms that underlie the
To illustrate this, we plotted an estimate of the cumulative pathological basis of necrosis.
number of developmental neuroscience publications from Although there has been a huge growth in our knowl-
1967 to the present using a fairly inclusive PubMed search edge of the details, especially at the edges of the field, we
string. Some of this growth is due to a boom in technological have endeavored to retain the size of the book and so have
advances, especially in fields such as genetics and neural kept our focus on the fundamentals by sometimes bring-
imaging. Other factors, such as the increase in worldwide ing in clearer and more modern examples, and sometimes
expenditure on scientific research, have led to an increase in bringing in more up-to-date or integrative interpretations.
the number of active laboratories. We have not, therefore, shied away from the frontiers of the
field and have also tried, when possible, to show the bound-
aries between what is well known and what is not.
All of the figures in the Fourth Edition have been revised
or drawn anew by our talented artist, Elizabeth Morales. In
addition to those acknowledged in previous editions, we are
grateful to these colleagues who have contributed advice
and material to this fourth edition: Hermann Aberle and
Sergi Simo. And a special note of thanks to the editorial
team at Elsevier: Pat Gonzalez and Natalie Farra.
Finally, we owe a profound debt of gratitude to the many
scientists who authored the primary research studies or re-
view articles that we read, too few of which are cited in the
book. Among these, we pay tribute to colleagues who, dur-
ing the past 50 years, authored the major textbooks in the
field of developmental neurobiology:

Marcus Jacobson (1970, 1978, 1991) (2005, with

Mahendra S. Rao) Developmental Neurobiology,
Whatever its source, this dramatic increase suggests Editions 1–4
that undergraduate textbooks face a significant challenge in Raymond D. Lund (1978) Development and Plasticity
remaining up to date. However, our sense is that the core of the Brain: An Introduction
concepts and seminal research findings remain relatively Ira Black (1984) Cellular and Molecular Biology of
stable. The overall goal of a revised text is to rebalance the Neuronal Development
presentation, increasing coverage in areas where novel in- Dale Purves and Jeff W. Lichtman (1985) Principles of
sights have arisen, and minimize coverage of data that have Neural Development
become less pivotal to an introductory text. For example, M.C. Brown and W.G. Hopkins, R.J. Keynes (1991)
when we first wrote about the field of synapse formation, Essentials of Neural Development
research on the neuromuscular junction provided the best, Michael Brown, Roger Keynes, Andrew Lumsden
and occasionally the only, insights. However, molecular (2002) The Developing Brain
and genetic studies now provide a cogent understanding of Susan E. Fahrbach (2013) Developmental Neuroscience,
the mechanisms that support central synapse formation. In A Concise Introduction
contrast, there has been little movement in the field of natu- Lynne Bianchi (2017) Developmental Neurobiology

xv
Chapter 1

Neural Induction
DEVELOPMENT AND EVOLUTION OF from the egg cell through a series of cell divisions and their
NEURONS subsequent rearrangements. The eggs of animals are typi-
cally polarized, with differences in their cytoplasm from
Almost as early as multicellular animals evolved, neurons one “pole” to the other. In amphibians, for example, the
have been part of their tissues. Metazoan nervous systems eggs have an “animal pole” and a “vegetal pole” that can be
range in complexity from the simple nerve net of the jelly- distinguished by the concentration of yolk, the stored nutri-
fish to the billions of specifically interconnected neuron as- ent material necessary for sustaining the embryo as it devel-
semblies of the human brain. Nevertheless, the neurons and ops, in the vegetal pole. Once fertilized by the sperm, the
nervous systems of all multicellular animals share many egg cell undergoes a series of rapid cell divisions, known as
common features (Fig. 1.1). Voltage-gated ion channels are cleavages. There are many variations of cleavage patterns
responsible for action potentials in the neurons of hydras, as in embryos, but the end result is that a large collection of
they are in people. Synaptic transmission between neurons cells, the blastula, is generated over a relatively short pe-
in nerve nets is basically the same as that in the cerebral riod of time. In many organisms the cells of the blastula
cortex in humans. This book describes the mechanisms re- are arranged as a hollow ball, with an inner cavity known
sponsible for the generation of these nervous systems, high- as a blastocoel. The rearrangement of this collection of
lighting examples from a variety of organisms. Despite the cells into the primary (or germ) layers is called gastrula-
great diversity in the nervous systems of various organisms, tion. Gastrulation rearranges the blastula into an inner,
the underlying principles of neural development have been or endodermal, layer of cells, an outer layer of cells, the
maintained throughout evolution. ectoderm, and a layer of cells between the two other lay-
It is appropriate to begin a book concerned with the de- ers, known as the mesoderm (Gilbert and Raunio, 1997).
velopment of the nervous system with an evolutionary per- The middle layer can be derived from either the ectoderm
spective. The subjects of embryology and evolution have ­(ectomesoderm) or the inner layer (endomesoderm). During
long shared an interrelated intellectual history. One of the the process of gastrulation, the cells of the mesoderm and
major currents of late 19th-century biology was that a de- endoderm move into the inside of the embryo, often at a
scription of the stages of development would provide the single region, known as the blastopore. Once the endoderm
key to the path of evolution of life. The phrase “ontogeny and mesoderm are inside the ball, they usually obliterate the
recapitulates phylogeny” was important at the start of ex- blastocoel and form a new cavity, the archenteron, or primi-
perimental embryology (Gould, 1970). Although the care- tive gut. All animals fall into one of two classes on the basis
ful study of embryos showed that they did not resemble the of whether the mouth forms near the point of this blastopore
adult forms of their ancestors, it is clear that new forms are (protostomes) or at a distant site (deuterostomes). Once
built upon the structures of biological predecessors. One these three primary layers are established, the development
aim of this book is to show how an understanding of the of the nervous system begins. A more detailed description
development of the nervous system will give us insight into of the development of the other organ systems is beyond the
its evolution. It is also wise to remember, as Dobzhansky scope of this text. Nevertheless, one should keep in mind
pointed out, “nothing in biology makes sense except in the that the development of the nervous system does not take
light of evolution.” place in a vacuum but is an integral and highly integrated
part of the development of the animal as a whole.
The next three sections will deal with the embryology
EARLY EMBRYOLOGY OF METAZOANS
of several examples of metazoan development: nematode
The development of multicellular organisms varies substan- worms (Caenorhabditis elegans); insects (Drosophila me-
tially across phyla; nevertheless, there are some common lanogaster), and several vertebrates (frogs, fish, birds, and
features. The cells of all metazoans are organized as lay- mammals). The development of these animals is described
ers. These layers give rise to the various organs and tissues, because they have been particularly well studied for histori-
including the nervous system. These layers are generated cal and practical reasons. However, one should take these

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2 Development of the Nervous System

Caenorhabditis elegans
The development of C. elegans, a nematode worm, high-
lights the shared lineage of the epidermal and neural cell
fates. These animals have been studied primarily because
of their simple structure (containing only about 1000 cells),
their rapid generation time (allowing for rapid screening
of new genetic mutants), and their transparency (enabling
lineage relationships of the cells to be established). These
nematodes have a rigid cuticle that is made of collagenous
proteins secreted by the underlying cells of the hypodermis.
The hypodermis is analogous to the epidermis of other ani-
mals, except that it is composed of a syncytium of nuclei
rather than of individual cells. C. elegans has a simple ner-
vous system, composed of only 302 neurons and 56 glial
cells. These neurons are organized into nerve cords. The
nerve cords are primarily in the dorsal and ventral sides of
the animals, but there are some neurons that run along the
lateral sides of the animal as well. The nematodes move by
a series of longitudinal muscles, and they have a simple di-
gestive system.
Nematodes have long been a subject for developmental
biologists’ attention. Theodore Boveri studied nematode
embryology and first described the highly reproducible
pattern of cell divisions in these animals in the late 1800s.
Boveri’s most famous student, Hans Spemann, whose
work on amphibian neural induction will be described
below, worked on nematodes for his Ph.D. research. The
modern interest in nematodes, however, was motivated by
Sydney Brenner, a molecular biologist who was searching
for an animal that would allow the techniques of molecu-
lar genetics to be applied to the development of metazoans
FIG. 1.1 Neurons throughout the evolution of multicellular organisms (Brenner, 1974).
have had many features in common. All animals other than colonial flagel- Because of the stereotypy in the pattern of cell divisions,
lates and sponges have recognizable neurons that are electrically excitable
and have long processes. The Cnidarians have nerve networks with electrical
the lineage relationships of all the cells of C. elegans have
synapses, but synaptic transmission between neurons is also very ancient. been determined (Sulston et al., 1983). The first cleavage
produces a large somatic cell, the AB blastomere, which
examples as representative, not as definitive. The necessity gives rise to most of the hypodermis and the nervous sys-
of studying many diverse species has become critical to the tem and the smaller germline P cell, which in addition to the
understanding of the development of any one species. gonads will also generate the gut and most of the muscles
of the animal (Fig. 1.2). Subsequent cleavages produce the
germ cell precursor, P4, and the precursorcells for the rest
DERIVATION OF NEURAL TISSUE
of the animal: the MS, E, C, and D blastomeres (Fig. 1.2),
The development of the nervous system begins with the and these cells all migrate into the interior of the embryo,
segregation of neural and glial cells from other types of while the AB-derived cells spread out over the outside of the
tissues. The many differences in gene expression between embryo completing gastrulation (Fig. 1.3). The next phase
neurons and muscle tissue, for example, arise through the of development is characterized by many cell divisions and
progressive narrowing of the potential fates available to a is known as the proliferation phase. Then an indentation
blast cell during development. The divergence of neural and forms at the ventral side of the animal marking the begin-
glial cells from other tissues can occur in many different ning of the morphogenesis stage, and as this indentation
ways and at many different points in the development of an progresses, the worm begins to take shape (Fig. 1.3). At this
organism. However, the cellular and molecular mechanisms point, the worm has only 556 cells and will add the remain-
that are responsible for the divergence of the neural and ing cells (to make a total of 959) over the four larval molts.
glial lineages from other tissues are remarkably conserved. The entire development of the animal takes about 2 days.
 Neural Induction Chapter | 1 3

the egg, but they then move out toward the surface and a
process known as cellularization occurs, and the nuclei are
surrounded by plasma membranes. At this point the embryo
is known as a cellular blastoderm.
The major part of the nervous system of Drosophila
arises from cells in the ventrolateral part of the cellular blas-
toderm (Fig. 1.4, top). Soon after cellularization, the ventral
furrow, which marks the beginning of gastrulation, begins
to form (Fig. 1.4, middle). At the ventral furrow, cells of
the future mesoderm fold into the interior of the embryo.
The process of invagination occurs over several hours, and
the invaginating cells continue to divide and eventually will
give rise to the mesodermal tissues of the animal. As the
mesodermal cells invaginate into the embryo, the neuro-
genic region moves from the ventrolateral position to the
most ventral region of the animal (Fig. 1.4). The closing
of the ventral furrow creates the ventral midline, a future
site of neurogenesis. On either side of the ventral midline
FIG. 1.2 The nervous system shares a common cellular lineage with the is the neurogenic ectoderm, tissue that will give rise to the
ectoderm. The cell divisions that generate the C. elegans nematode worm ventral nerve cord (Fig. 1.5). A continuation of the neuro-
are highly reproducible from animal to animal. The first division produces genic region into the anterior of the embryo is called the
the AB blastomere and the P1 blastomere. The germ line is segregated into procephalic neurogenic region and gives rise to the cerebral
the P4 blastomere within a few divisions after fertilization. The subsequent
divisions of the AB blastomere go on to give rise to most of the neurons
ganglia or brain.
of the animal, as well as to the cells that produce the hypodermis—the Drosophila neurogenesis begins in the neurogenic
epidermis of the animal. region; some cells enlarge and begin to move from the
outside layer into the inside of the embryo (Fig. 1.5). At
The neurons of C. elegans arise primarily from the AB the beginning of neurogenesis, the neurogenic region is
blastomere, in lineages shared with the ectodermally de- a single cell layer; the first morphological sign of neuro-
rived hypodermis. An example of one of these lineages is genesis is that a number of cells within the epithelium be-
shown in Fig. 1.3. The Abarpa blastomere can be readily gin to increase in size. These larger cells then undergo a
identified in the 100-min embryo through its position and shape change and squeeze out of the epithelium. This pro-
lineal history. This cell then goes on to give rise to 20 ad- cess is called delamination and is shown in more detail in
ditional cells, including 9 neurons of the ring ganglion. The Fig. 1.5. The cells that delaminate are called neuroblasts
progeny of the Abarpa blastomere, like most of the progeny and are the progenitors that will generate the nervous sys-
of the AB lineage, lie primarily on the surface of the embryo tem. In the next phase of neurogenesis, each neuroblast
prior to 200 min of development. At this time, the cells on divides to generate many progeny, known as ganglion
the ventral and lateral sides of the embryo move inside and mother cells (GMCs). Each GMC then generates a pair
become the nervous system, whereas the AB progeny that of neurons or glia. In this way, the entire central nervous
remain on the surface spread out to form the hypodermis. system of the larval Drosophila is generated. However,
Most of the neurons arise in this way; of the 222 neurons the Drosophila nervous system is not finished in the larva,
in the newly hatched C. elegans, 214 arise from the AB lin- but rather additional neurogenesis occurs during meta-
eage, whereas 6 are derived from the MS blastomere and 2 morphosis. Sensory organs, like the eyes, are generated
from the C blastomere. from small collections of cells in the larva (called imaginal
discs) that undergo a tremendous amount of proliferation
Drosophila during metamorphosis to generate most of what we recog-
nize as an adult fly.
The development of the fruit fly, Drosophila, is character-
istic of many arthropods. Unlike the embryos of the nema- Vertebrates
tode, where cleavage of the cells occurs at the same time
as nuclear divisions, the initial rounds of nuclear division All vertebrate embryos develop in a fundamentally simi-
in the Drosophila embryo are not accompanied by corre- lar way, though at first appearance they seem to be quite
sponding cell divisions. Instead, the nuclei remain in a syn- different. In this section we will review the development
cytium until just prior to gastrulation, 3 h after fertilization. of several different vertebrates: amphibians, fish, birds,
Prior to this time, the dividing nuclei lie in the interior of and mammals. In all of these animals, multiple cleavage
4 Development of the Nervous System

FIG. 1.3 The next phase of development of the C. elegans worm also highlights the shared lineages of hypodermis and neurons. (A and B) During
gastrulation, the MS, E, C, and D blastomeres all migrate into the interior of the embryo, while the progeny of the AB blastomeres spread out over the
external surface. (B) Once the embryo starts to take form, sections through the embryo show the relationships of the cells. (C) The neurons are primarily
derived from the ventrolateral surface, through the divisions of the AB progeny cells. As these cells are generated, they migrate into the interior and form
the nerve rings. (D) A typical lineage is also shown. The Abarpa blastomeres undergo 5 rounds of division, to generate 9 neurons and 10 hypodermal cells.
Neural lineages are shown in red.
 Neural Induction Chapter | 1 5

FIG. 1.5 The neuroblasts of the Drosophila separate from the ectoderm
by a process known as delamination. The neuroblasts enlarge relative to
the surrounding cells and squeeze out of the epithelium. The process oc-
curs in several waves; after the first set of neuroblasts has delaminated
from the ectoderm, a second set of cells in the ectoderm begins to enlarge
and also delaminates. The delaminating neuroblasts then go on to generate
several neurons through a stereotypic pattern of asymmetric cell divisions.
The first cell division of the neuroblast produces a daughter cell known as
the ganglion mother cell, or GMC. The first ganglion mother cell divides
to form neurons, while the neuroblast is dividing again to make another
GMC. In the figure, the same neuroblast is labeled through its successive
stages as Nb, while the GMCs are numbered successively as they arise.

FIG. 1.4 The nervous system of the Drosophila is derived from the ven-
trolateral region of the ectoderm. The embryo is first (top) shown at the blas- Amphibian eggs have a distinct polarity with a nutrient-
toderm stage, just prior to gastrulation. The region fated to give rise to the
nervous system lies on the ventral-lateral surface of the embryo (red). The in-
rich yolk concentrated at the “vegetal” pole and a relatively
volution of the mesoderm at the ventral surface brings the neurogenic region yolk-free “animal” pole. After fertilization, a series of rapid
closer to the midline. Scattered cells within this region of the ectoderm then cell divisions, known as cleavages, divide the fertilized
enlarge, migrate into the interior of the embryo, and divide several more times egg into blastomeres. The cleavage divisions proceed less
to make neurons and glia. These neurons and glia then condense into the rapidly through the vegetal hemisphere, and by the time
ganglia of the mature ventral nerve cord (or CNS) in the larva and the adult.
the embryo reaches 128 cells, the cells in the animal half
are much smaller than those of the vegetal half (Fig. 1.6).
d­ ivisions generate a large number of cells from the fertilized The embryo is called a blastula at this stage. The relatively
oocyte. However, while gastrulation in all of these animals simple blastula is then transformed into the more complex,
is basically conserved, the details of the cellular movements three-layered organization by gastrulation. During this
during this phase can look quite different. phase of development, cells on the surface of the embryo
6 Development of the Nervous System

FIG. 1.6 The development of the central nervous system, brain, and spinal cord in a frog embryo is shown from the egg cell to the adult. After a series
of cleavage divisions produce a blastula, a group of cells known as the involuting marginal zone, or IMZ, grow into the interior of the embryo at a point
known as the blastopore. This process of gastrulation is shown in two cross sections. The involuting cells go on to form mesodermal tissues (blue) and
induce the cells of the overlying ectoderm to develop into neural tissue, labeled as the neurogenic region (red). After the process of neural induction, the
neurogenic region is known as the neural plate and is now restricted to giving rise to neural tissue. A cross section of the embryo at the neural plate stage
shows the relationships between the tissues at this stage of development. The neural plate goes on to generate the neurons and glia in the adult brain and
spinal cord.

move into the center of the blastula through the blastopore next two chapters. For now, suffice it to say that this tube
(Fig. 1.6). In amphibians the first cells to invaginate occur at of cells gives rise to nearly all the neurons and glia of the
the dorsal side of the blastopore (Fig. 1.6). The dorsal side frog. Another source of neurons and glia is the neural crest,
of the blastopore has a special significance for the process a group of cells that arises at the junction between the tube
of neural induction and much more will be said about this and the ectoderm (Fig. 1.7). The neural crest is the source of
process later in this chapter. most of the neurons and glia of the peripheral nervous sys-
The cells that first migrate through the blastopore lead tem, whose cell bodies lie outside the brain and spinal cord.
a large number of cells from the surface of the embryo into This tissue is unique to vertebrates, and has the capacity to
the interior (Fig. 1.6). Most of these cells will give rise to generate many diverse cell types; we will have more to say
mesodermally derived tissues, like muscle and bone. The about the neural crest in later chapters.
first cells to involute crawl the farthest and produce the me- The complex tissue rearrangements that occur during
soderm of the anterior part of the animal (i.e., the head). gastrulation in the amphibian occur in other vertebrates in
The later involuting marginal zone (IMZ) cells produce fundamentally the same way. However, the details of these
the mesoderm of more posterior regions, including the tail movements can be quite different. Much of the difference
of the tadpole. At this point in development, the cells that in cell movements lies in differences in the amount of yolk
will make the nervous system (called the neural plate) still in the egg. Fish and bird embryos have a substantial amount
largely resemble the rest of the ectoderm; however, soon of yolk and since the cleavage divisions proceed more
the neural plate begins to fold onto itself to form a tube- slowly through the yolk, these animals have many more
like structure, called the neural tube (Fig. 1.7). Much more cleavage divisions in the animal pole than in the vegetal
will be said about the neural tube and its derivatives in the pole. In zebrafish embryos, the blastomeres are situated at
 Neural Induction Chapter | 1 7

Avian embryos are an extreme example of a “yolky”

egg. We all know how much yolk is in a chicken egg. The
large amount of yolk makes it difficult for the cells to di-
vide as they do in frogs, and so the cell cleavage divisions
do not penetrate into this yolk, but are instead restricted to
the relatively yolk-free cytoplasm at the animal pole. These
cleavages lead to a disc of cells, called the blastodisc, which
is essentially floating on the yolk; think of this as a more
extreme version of what happens in the zebrafish. However,
instead of these cells “surrounding” the yolk, as happens in
fish during epiboly, the developing chick embryo continues
to sit on the surface of the yolk. After sufficient numbers
of cells are generated in the blastodisc, the process of gas-
trulation occurs. The invagination of mesoderm occurs in
this disc through a blastopore-like structure known as the
“primitive streak.” During this invagination, future meso-
derm cells migrate into the interior of the embryo (Fig. 1.9).
The nervous system is induced to form over the involut-
ing mesodermal cells, much like in frogs and fish. Another
structure, called Hensen’s node, is at the posterior end of
the primitive streak and is analogous to the dorsal lip of the
blastopore of amphibians.
What about mammalian embryos, which have essen-
tially no yolk and derive all their nourishment from the pla-
centa? The cleavage divisions of mammalian embryos are
complete (Fig. 1.10), and there is no obvious animal or veg-
etal pole in the egg. However, after a sufficient number of
divisions, when the blastula forms, there are cells on the in-
side of the ball, called the inner cell mass, that produce the
embryo, whereas the cells on the outside of the ball make
the placenta and associated extra-embryonic membranes.
FIG. 1.7 The neural plate (light red) rolls up into a tube separating from Even though they lack yolk, mammalian embryos undergo
the rest of the ectoderm. The involuting cells condense to form a rod- a process of gastrulation that is similar to the avian embryo
shaped structure—the notochord—just underneath the neural plate. At the in that the developing mesodermal cells migrate through
same time, the neural plate begins to roll up and fuse at the dorsal margins.
the primitive streak to reach the interior (Fig. 1.10). The
A group of cells known as the neural crest (bright red) arises at the point
of fusion of the neural tube. primitive streak runs along the anterior-posterior axis of the
embryo, and the ectoderm laying above the ingressing me-
sodermal cells becomes the neural plate and subsequently
the top of the egg, and as development proceeds these cells the neural tube, much like that described above for the other
divide and spread downward over the surface of the yolk vertebrate embryos. Although the processes of early neu-
cells; this downward spreading is called epiboly. When ral development seem to vary dramatically from insects
epiboly is about 50% complete (when the spread reaches to people, we will see in this chapter and throughout the
the equator), there is a transient pause as the process of gas- book that the underlying molecular mechanisms are highly
trulation begins at the future dorsal margin of the embryo, conserved.
which is at this point called the shield (Fig. 1.8). The shield
begins to thicken as gastrulation commences. Prospective INTERACTIONS WITH NEIGHBORING
mesodermal cells delaminate, move inside the ectodermal
TISSUES IN MAKING NEURAL TISSUE
layer, and begin migrating back toward the animal pole.
The rest of the ectoderm then continues its migration to As we have seen, the three basic layers of the embryo—
the vegetal pole until the yolk is completely enveloped the endoderm, mesoderm, and ectoderm—arise through
at 100% epiboly. As the dorsal mesodermal cells migrate the complex movements of gastrulation. These movements
toward the animal pole on the shield side, the ectoderm also create new tissue relations. For example, after gas-
above becomes committed to a neural fate and a definitive trulation in the frog, mesoderm now sits underneath the
neural plate begins to form. ectoderm. Experiments performed in the early part of the
FIG. 1.8 Development of the zebrafish embryo. The zebrafish embryo develops primarily on top of a large ball of yolk. The cleavages are confined to
the dorsal side. After multiple cleavage divisions, the cells migrate over the yolk in a process called epiboly. Once the cells have enclosed the yolk, the
development of the nervous system proceeds much like that described for the frog. Neural tissue is colored red. (After Kimmel et al., 1995.)

FIG. 1.9 Development of the chick embryo. The blastoderm (area opaca) sits on top of the large yolk and is the result of a large number of cleavage
divisions. At the start of gastrulation, cells move posteriorly (arrows) and migrate under the area opaca. The embryo begins to elongate in the anterior-
posterior axis, and the region where the cells migrate underneath the area opaca is now called the primitive groove and then primitive streak. The cells
migrate into the blastocoel to form the mesoderm. At the anterior end of the primitive streak an enlargement of the streak is called Hensen’s node. Later
stages of chick embryo development show the expanding nervous system in red.