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CHAPTER 2 Meeting the Building Blocks 41
double-stranded DNA produce the ospring’s unique DNA.In the complex pro-
cess of assembling a single chromosome of DNA from the two parental chromo-
somes, errors can happen. In addition, errors in replication can result in
spontaneous mutations.
Here are the four most common mutations (single genes or larger regions of
chromosomes can be aected):
»
Point mutation: A point mutationoccurs when a single base pair is changed.
Although many point mutations are benign, others can also have functional
consequences, including alterations in encoded proteins or changes in gene
expression.
»
Deletion: A piece of a chromosome or partial sequence of DNA may be missing
from the single chromosome of the egg or sperm, resulting in deletion of the gene.
»
Duplication: In duplication, a partial sequence of DNA from one parent is
replicated twice or more.
»
Inversion: When inversion happens, a partial DNA sequence from one parent
is inserted in the wrong orientation in the ospring.
Genetically based nervous system disorders include sensory problems such as
blindness and deafness and motor disorders. Other identied genetic disorders
include Down syndrome, Fragile X syndrome, and Rett syndrome. Chapters 12
and18 describes these disorders in more detail.
Disorders that aect cognitive or mental functions are more complex, such as
autism spectrum disorder, attention decit hyperactivity disorder, schizophrenia,
and depression. Interactions between genes and environment are proposed to be
the basis of these disorders. Chapter18 also discusses these disorders.
Neurodevelopmental, neurological, and psychiatric disorders are among the most
challenging and signicant health problems in the United States today. This is
particularly true for neurodevelopmental disorders like intellectual disability and
autism spectrum disorders that aect children, neurodegenerative disorders such
as Alzheimer’s disease that aect the elderly, and depression that aects indi-
viduals in many age groups.
Modifying Genes: Yes or No?
One question that neurobiologists look to answer is whether broken genes can be
xed to cure or treat neurological disorders that have genetic components. The
following sections examine some areas of research.
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42 PART 1 Getting Started with Neurobiology
Researching on animals
Major research over the past three decades has involved genetic manipulation of
animals for experimental models for investigating human disorders. A few animal
lines have been studied with dierent genetic compositions that originally arose
from random mutations in ospring.
Selective genes have been removed (knock-outs), and mutant genes have been
replaced with normal genes (knock-ins). Many studies have also used brain or
neuron specic knock-outs or knock-ins to study brain-based disorders.
In genetically modied animal models, scientists modify the genome by changing
the DNA codons for single amino acids, multiple amino acids, or even entire genes.
These animal models have provided valuable information about brain disorders
that have led to the development of eective treatments.
Examining gene therapy
Human gene therapy (the general term for genetic manipulation in humans for
medical reasons) is currentlyavailable primarily for research studies. The FDA has
approved only a limited number of gene therapy treatments in the United States.
Human genetic manipulation may require silencing a gene that produces a harm-
ful protein and/or adding a gene to produce a functional one. This involves intro-
ducing exogenous DNA into a person’s cells. This DNA may come from another
organism or be synthesized in a lab. The presence of the blood-brain barrier poses
a signicant obstacle to overcome for gene therapy to treat disorders of the ner-
vous system. But there’s hope.
Delivering the genes
Gene therapy can be conducted in developed organisms in several ways:
»
Physically restrict the injection of the introduced DNA, such as in the eye to
treat blindness, so that the gene can’t get into any other body cells
»
Use a tissue or cell type-specic promoter with the DNA so that it’s only
expressed in particular tissues
Typically, the introduced DNA is packaged within a vector that’s used to transfer the
DNA inside cells within the body. One common vector is a modied virus because
viruses normally function by binding the cell membrane and inserting their DNA or
RNA into the cell. The contents of a virus can be modied to incorporate a human
gene. Also, exogenous DNA may be introduced that encodes a therapeutic protein
that works like a drug rather than the DNA corresponding to any actual human gene.
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CHAPTER 3 Constructing the Nervous System 43
Chapter3
Constructing the
Nervous System
A
new life starts when a zygote is formed when two gamete cells are com-
bined in sexual reproduction. The zygote divides and then its daughter
cells divide many times, migrate, and dierentiate to produce the entire
organism, including the nervous system.
In this chapter, we take you through how the nervous system develops from a
single fertilized zygote into its nal structures and how its components become
organized. We focus in on the brain’s neocortex. We highlight the generation of
neuronal and glial cells, axon outgrowth, and synapse formation and renement.
Chapter18 discusses neurodevelopmental disorders.
In eukaryotes, cell division occurs through the process of mitosis, in which the
DNA is copied and the cellular organelles are divided through cytokinesis. In
somatic cells, chromosomes exist in pairs— one set of chromosomes is inherited
from each parent. Humans have 22 pairs of somatic chromosomes (44 total) and
two sex chromosomes XX (typical female) or XY (typical male).
IN THIS CHAPTER
»
Seeing how cells divide and develop
»
Establishing the neural tube and
neural crest
»
Forming the brain regions and
spinal cord
»
Making neurons and glia from
progenitors
»
Creating and rening synapses
»
Generating the peripheral nervous
system
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44 PART 1 Getting Started with Neurobiology
Staging Early Development
In the reproductive organs (ovaries and testes), a dierent kind of cell division
occurs, called meiosis. It produces haploid cells called gametes or germ cells. During
meiosis, each gamete receives only one copy of each chromosome. During meio-
sis, chromosome crossover can result in gametes receiving a single chromosome
that is a mixture of both strands of the two parental chromosomes.
Crossover produces new chromosomes in each gamete. This new chromosome
contains parts of chromosomes from both of the parents. If the crossover occurs
within a gene, the DNA section that codes for a protein, a new gene can be pro-
duced. Each egg or sperm that the parent produces is unique. The following sec-
tions examine what occurs after fertilization in the next developmental stages.
Progressing from fertilization
Human development begins when the egg (ovum) is fertilized by the sperm and
produces a zygote with 46 chromosomes, one set received from each parent. The
zygote divides by mitosis and creates a group of cells called the inner cell mass
(ICM) at the blastula stage. The ICM is a totipotent stem cell population, meaning
that it can give rise to all types of cells in the embryo. The ICM then forms a two
layered disc of cells called the epiblast and hypoblast that are also totipotent
stem cells.
Partitioning in gastrulation
During gastrulation, cells in the epiblast undergo mitosis and migration (see
Figure3-1).
In the rst wave, epiblast cells divide and migrate toward the midline (called the
primitive streak). After they reach the streak, they crawl through a gap (called the
primitive groove) and migrate underneath the epiblast cells to form the endoderm.
The endoderm gives rise to the linings of digestive and respiratory organs.
In the next wave, cells divide and migrate to the midline through the groove and
on top of the endoderm cells to form the mesoderm. The mesoderm forms the
musculoskeletal and cardiovascular systems. The cells that remain on the top
divide but don’t migrate and form the ectoderm, which gives rise to the entire
nervous system and skin.
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CHAPTER 3 Constructing the Nervous System 45
Specifying the germ layers
Gastrulation also leads to the formation of the three major axes: anterior-
posterior, dorsal-ventral, and medial-lateral. As cells within the gastrula form
and continue to divide, they become specied, losing totipotency and form
pluripotent or multipotent stem cells that can give rise to several dierent tissues
and organs. Specication involves selective control of gene expression.
One mechanism that controls gene expression is epigenetics, which entails the
covalent modication of DNA and histones (see Chapter2). The pattern of epige-
netic modications becomes altered in subsequent divisions and reduces the
potency as the cells become specied.
Inducing the neural plate
At the end of gastrulation, a cylinder of mesoderm cells, called the notochord,
forms at the midline. The notochord secretes diusible molecules called morpho-
gens. These factors bind to target cells, control gene expression, and specify the
cells to adopt a particular cell fate. Secreted by the notochord, the neural-inducing
morphogens bind to and specify the overlying medial ectoderm cells to become
neural ectoderm and form the neural plate. The ectoderm cells farther away from
the midline don’t bind enough morphogen and become non-neural ectoderm that
form the skin and related tissues like teeth, hair, and nails.
FIGURE3-1:
Mammalian
gastrulation and
neurulation.
© John Wiley & Sons, Inc.
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46 PART 1 Getting Started with Neurobiology
The neural-inducing morphogens are secreted proteins called noggin, chordin, and
follistatin. They act by blocking the action of bone morphogenetic proteins (BMPs).
BMPs and their receptors are expressed throughout the gastrula where they control
transcription factors that increase expression of non-neural genes and inhibit
expression of neural commitment genes. By blocking BMP signaling, the neural-
inducing morphogens increase neural commitment gene expression. Other growth
factors, such as broblast growth factor, are also implicated in neural induction.
Forming the Neural Tube in Neurulation
The next stage, neurulation, involves the transformation of the neural plate into
the neural tube (see Figure3-1). In this process, which the following sections dis-
cuss, two longitudinal folds at the edges of the neural plate cause the lateral
regions to elevate, forming a neural groove between the folds. The neural groove
deepens, which causes the neural folds to come together at the dorsal midline.
Closing the neural tube
The neural folds join through cell-cell adhesion, which closes the neural tube.
Ectodermal cells at the outer margins of the neural fold coalesce at the dorsal
aspect of the tube and become the neural crest cells. The non-neural ectoderm
joins to form a sheet above the neural crest and neural tube. The neural tube gives
rise to neurons and glia in the central nervous system (CNS), while the neural
crest gives rise to neurons and glia in the peripheral nervous system (PNS). The
non-neural ectoderm forms the skin and related structures.
Failure of the neural tube to close normally can produce neural tube defects, which
are the most common congenital birth defects aecting the nervous system.
Chapter12 describes neural tube defects.
Separating into regions
After the neural tube closes, the cephalic (anterior) end of the tube divides into
three vesicles:
»
Forebrain: The forebrain (also referred to as the prosencephalon) divides into
the following:
•
Telencephalon (cerebrum): The telencephalon consists of the cerebral
cortex and underlying white matter (derived from the dorsal telencephalon,
or pallium) and the basal ganglia (derived from the ventral telencephalon,
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CHAPTER 3 Constructing the Nervous System 47
or subpallium). The amygdala is derived from both the pallium and
subpallium.
•
Diencephalon: This consists of the thalamus, hypothalamus, and retina.
»
Midbrain: The midbrain (also called the mesencephalon) doesn’t divide further,
though there are a specialized areas within it. The midbrain consists of the
tectum, tegmentum, and cerebral peduncles, among other structures.
»
Hindbrain: The hindbrain (also known as the rhombencephalon) divides into
the following:
•
Metencephalon: The pons and cerebellum develop from the
metencephalon.
•
Myelencephalon: The myelencephalon forms the medulla.
During development, the mammalian hindbrain is composed of eight
swellings called rhombomeres.
A second morphological change further divides the forebrain and hindbrain. In
Figure3-2, you can see these main vesicles and the embryonic nervous system at
several key stages.
The walls of the neural tube vesicles give rise to the neurons and glial cells in the
CNS.The uid lled inside becomes the brain’s ventricle system. The posterior
part of the neural tube forms the spinal cord and its cavity becomes the central
canal.
FIGURE3-2:
Structures of the
developing
nervous system.
© John Wiley & Sons, Inc.
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48 PART 1 Getting Started with Neurobiology
In cold-blooded vertebrates such as amphibians and reptiles, the three brain ves-
icles are approximately equal in size, as they are in early mammalian ontogeny.
However, in mammals, the forebrain became increasingly enlarged during evolu-
tion, becoming the dominant percentage of total brain mass, especially in pri-
mates and large mammalian species.
After the neural tube has closed and undergone the morphological changes to
form the vesicles, the cells of the neural tube proliferate, migrate, and dierenti-
ate. These developmental processes have been well studied in the developing
cerebral cortex.
Meeting the neocortex
Older types of cerebral cortex include archicortex and paleocortex (together
referred to as allocortex) and mesocortex in the limbic system (refer to Chapter11).
The neocortex evolved in mammals and is the most recent cerebral cortex to
evolve. The neocortex consists of excitatory glutamatergic and inhibitory
GABAergic neurons arranged in six layers. The layers are numbered from the outer
layer 1 at the surface, to layer 6 at the border with the underlying cerebral white
matter.
The entire neocortex develops using a common set of developmental programs.
These programs generate structures capable of processing inputs from all ve
senses, executing programs for voluntary motor control, and providing language
and executive functions.
Producing Neural Cells
After closure of the neural tube, the tube is a single layer of neural stem cells,
called neuroepithelial cells (NECs). The entire brain and spinal cord develop from the
NECs. The NECs rst undergo symmetrical divisions to self-renew in the ventric-
ular zone, the region adjacent to the developing ventricles. After a sucient num-
ber of NECs are formed, the NECs divide asymmetrically to form a daughter NEC
and a daughter progenitor cell, called a radial glial cell (RGC) or radial glial
progenitor.
RGCs were named because they initially express astrocyte cell markers and some
RGCs guide the migration of developing neurons. However, RGCs are the neural
progenitors that form all the excitatory glutamatergic neurons and some glia in
the cerebral cortex. There are dierent subtypes of progenitors, including apical
RGCs that self-renew and can also give rise to basal RGCs and intermediate pro-
genitor cells (iPCs).
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CHAPTER 3 Constructing the Nervous System 49
Early in cortical development some apical RGCs extend a process all the way to the
outer region, called the pial surface, and provide the guidance for migrating cells.
Apical RGCs are located in the ventricular zone, basal RGCs are found in the adja-
cent subventricular zone, and iPCs can be located in both regions. The following
sections discuss the migration of RGCs along radial glia.
Migrating along radial glia
In one type of division, an apical RGC can give rise to a daughter apical RGC and a
daughter neuron, sometimes called a neuroblast. The neuron migrates to its spe-
cic layer in the cortex, using the processes of RGCs to guide it along its path. As
development proceeds, other neurons are generated from basal RGCs and iPCs.
As the cerebral cortex develops, it forms in an inside-out manner, which means
that the deepest layer 6 forms rst, then layer 5, layer 4, and so on. The neurons
that form the outer layers must migrate past the neurons that have already formed
the inner layers. After neurons have reached their nal position in their cortical
layer, they dierentiate into a specic neuronal type.
Research suggests that each RGC, and the neurons produced from it, form a fun-
damental unit of organization called the cortical minicolumn. A minicolumn con-
sists of about 100 neurons that are interconnected vertically through the six
cortical layers in a standard way. Figure3-3 depicts minicolumns at various stages
of the development of the neocortex. Several hundred million minicolumns con-
stitute the neocortex in humans. We provide more information on cortical mini-
columns in Chapter11.
Generating inhibitory interneurons
Cortical excitatory glutamatergic neurons are produced from RGCs in the dorsal
region of the telencephalon segment of the neural tube. In contrast, cortical
GABAergic inhibitory interneurons are generated from a ventral tube subregion
called the ganglionic eminence (GE). Inhibitory interneurons migrate tangentially
(parallel to the ventricular surface) to reach their appropriate location in the cor-
tex, independent of radial glial bers. They migrate into the developing cortical
layers after excitatory neurons have migrated to their specic layers.
In the cerebral cortex and most brain regions, neurogenesis occurs primarily pre-
natally. In a few brain regions, particularly the cerebellum and hippocampus,
neurogenesis continues postnatally. In the adult brain generation of new
neurons (adult neurogenesis) occurs in the dentate gyrus of the hippocampus and
olfactory bulb.
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50 PART 1 Getting Started with Neurobiology
Going to gliogenesis
RGCs also give rise to glial cells, which are important in myelination, supporting
neurons, surrounding the blood brain barrier, and producing the ventricles (refer
to Chapter 1). A subpopulation of RGCs generate ependymal cells that line the
ventricles and form the choroid plexus. In the developing neocortex, gliogenesis
typically follows neurogenesis and gives rise to oligodendrocytes and astrocytes.
However, the mechanisms underlying the switch from neurogenesis to gliogene-
sis or the identity of the RGCs haven’t been well characterized.
A pool of neural stem or progenitor cells is maintained in the cerebral cortex post-
natally and into adulthood. Neural stem or progenitor cells in the subventricular
zone may give rise to new glial cells to replace damaged glia. They may also give
rise to brain tumors, especially gliomas, the most common malignant primary
brain tumor. Brain tumors cause an estimated 19,000 cancer-related deaths in the
United States each year. Research to identify the stem or progenitor origin of brain
tumors may lead to early detection techniques and the design of therapies to treat
brain cancer.
FIGURE3-3:
Radial glia and
neural migration
form neocortex
minicolumns.
© John Wiley & Sons, Inc.
https://t.me/med1917
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