Part III: The stem cell concept

• A stem cell is defined as an undifferentiated cell that divides asymmetrically

to produce one cell that remains a stem cell and a second cell that can
undergo one or more paths of differentiation. Thus stem cells have self-
renewing potential.

• In some organs, such as gut, epidermis, and bone marrow, stem cells
regularly divide to replace worn-out cells and repair damaged tissues.

• In other organs, such as prostate and heart, stem cell divide only under
special physiological conditions such as response to stress or the need to
repair the organ.

• Stem cells are maintained in their undifferentiated state by interaction with

adjacent cells which constitute a protected microenvironment for signaling.
These support cells are known as niche cells.

• For example, blood-forming (hematopoietic) stem cells are located in the

bone marrow niche. Moreover, a bone marrow transplant represents the
first successfully demonstrated use of a “stem-cell therapy”.
Part Figure III.1 The stem cell concept

Hematopoietic stem cells

are multipotent and
contribute to the formation
of all the different blood
cell types as well as cells
of the immune system.
Part Figure III.2 Blood-forming (hematopoietic) stem cells and the bone marrow niche
Stem Cell Vocabulary

• There are (2) major divisions in terms of stem cell populations:

– (1) Embryonic stem cells which are derived from the inner cell mass of
blastocyst stage mammalian embryos. These cells are capable of producing all
the cells of the embryo and thus give rise to a complete organism.
– (2) Adult stem cells which are found in the tissues or organs that support that
organ once it has reached maturity. These cells have a more restricted
differentiation potential and are typically involved in replacing and repairing
tissues of a particular organ and thereby can only give rise to a subset of cell
types.

• The ability of a particular stem cell to generate numerous different types of

differentiated cells is referred to as stem cell potency.
– Totipotent cells are capable of forming every cell in the embryo as well as the
placenta
– Pluripotent cells have the ability to become all cell types except placenta
(embryonic stem cells)
– Multipotent cells are stem cells whose commitment is limited to a relatively
small subset of all possible cell types in the body (adult stem cells)
– Unipotent cells represent a subset of adult stem cells which are involved in
regenerating a very specific and singular cell type such as sperm cells.
Stem Cell Vocabulary

• Progenitor cells are related to stem cells, however

these cells are not capable of unlimited self-renewal as
is the case with stem cells. Rather, these cells have the
capacity to divide only a few times prior to differentiation.

• Progenitor cells are usually more differentiated than

stem cells and have become committed to a particular
type of cell.

• In many instances, stem cell division generates progeny

that become progenitor cells as is commonly seen in the
case of blood cells, sperm cells and the nervous system.
(Figs. III.1A and III.2).
Part Figure III.4 Example of the maturational series of stem cells, here applied to the differentiation
of neurons
Adult Stem Cell Niches

• Many tissues and organs contain stem cells that undergo

continual renewal and such stem cells must maintain the long-
term ability to divide, producing some daughter cells that are
differentiated and other daughter cells that remain stem cells.

• The ability of a cell to become an adult stem cells is

determined in large part by where it physically resides. The
continuously proliferating stem cells are housed in
compartments called stem cell niches.

• Stem cell niches regulate stem cell proliferation and

differentiation, usually by paracrine factor signals that are
produced by the niche cells. These factors retain the stem
cells in uncommitted state and once cells leave the niche, the
paracrine factors cannot reach them and the cells begin
differentiating.
Part Figure III.6 Stem cell niche in Drosophila testes

In Drosophila testes, the stem cells for sperm reside in a niche defined by a
population of somatic cells at the apical end of the testes known as hub cells.

Unpaired-b-gal

The division of the sperm stem cell is asymmetric, always producing one cell that
remains attached to the hub, and one unattached cell (gonialblast).

The somatic cells of the hub create this asymmetric proliferation by secreting the
paracrine factor Unpaired onto the attached stem cells which activates the JAK-
STAT pathway in germline stem cells in order to specify their self-renewal.
Part Figure III.6 Stem cell niche in Drosophila testes

Those cells that are distant from the paracrine factor, Unpaired, cannot receive the
signal, so they begin to differentiate into the sperm cell lineage.

Unpaired-b-gal

In the division of the stem cell, one centrosome remains attached to the cortex at
the contact site between between the stem cell and the somatic hub cells. The
other centrosome moves to the opposite pole, thus establishing a mitotic spindle
that will produce one daughter cell attached to the hub and one daughter cell away
from it.

Moreover, the cell adhesion molecules (Cadherins) also link the hub and stem cells
together.
Adult Stem Cell Niches

• The stem cell niche is a critical component of our phenotype,

and is responsible for regulating the ratio of cell division to cell
differentiation.

• This means that maintenance of such stem cell niches is

critical to our health. Too much stem cell differentiation
depletes the stem cells and promotes the phenotypes of aging
or decay. Too much stem cell division can cause cancers to
arise.

• Thus, stem cell niches provide microenvironments that

regulate stem cell renewal, survival and differentiation. Their
paracrine factors, cell adhesion molecules, and architecture
allow asymmetric cell division to regulate stem cell division vs.
differentiation.
CH. 9: The Emergence of the Ectoderm: Central Nervous System

• The ectoderm is divided into (3) major domains:

– (1) The surface ectoderm (primarily epidermis)
– (2) The neural crest (peripheral neurons, pigment, facial cartilage)
– (3) The neural tube (brain and spinal cord)

• There are at least (4) stages through which pluripotent cells of the blastula
become neural precursor cells known as neuroblasts
– (1) Competence: stage at which multipotent cells become neuroblasts if
they are exposed to the appropriate combination of signals
– (2) Specification: stage where cells have received the appropriate
signals to become neuroblasts, but progression along the neural
differentiation pathway can still be repressed by other signals.
– (3) Commitment (determination): stage where neuroblasts enter the
neural differentiation pathway and will become neurons even in the
presence of inhibitory signals.
– (4) Differentiation: stage where neuroblasts leave the mitotic cycle and
express those genes characteristic of neurons.
Figure 9.1 Major derivatives of the ectoderm germ layer (Part 1)
Figure 9.1 Major derivatives of the ectoderm germ layer (Part 2)
Figure 9.1 Major derivatives of the ectoderm germ layer (Part 3)
Constructing the Central Nervous System: Formation of the Neural Tube

• There are (2) major ways of converting the neural plate into a neural
tube:
– (1) In primary neurulation, the cells surrounding the neural
plate direct the neural plate cells to proliferate, invaginate, and
pinch off from the surface to form a hollow tube.
– (2) In secondary neurulation, the neural tube arises from the
coalescence of mesenchyme cells into a solid cord that
subsequently forms cavities that coalesce to create a hollow
tube.

In general, the anterior portion of the neural tube is made by

primary neurulation, while the posterior portion of the neural tube
is made by secondary neurulation.

The complete neural tube forms by joining these two separately

formed tubes together.
Figure 9.3 Dorsal view of neurulation in an amphibian embryo, showing early, middle, and late
neurulae in each case
Figure 9.3 Three views of neurulation in an amphibian embryo, showing early, middle, and late
neurulae in each case (Part 3)
Primary Neurulation

• The events of primary neurulation divide the original ectoderm into (3) sets
of cells (see Fig. 9.1):
– (1) the internally positioned neural tube, which will form the brain and
spinal cord;
– (2) the externally positioned epidermis of the skin; and
– (3) the neural crest cells

The neural crest cells form in the region that connects the neural tube and
epidermis, but they migrate to new locations where they will generate
the peripheral neurons and glia, the pigment cells of the skin, and
several other cells types.

• Primary neurulation can be divided into (4) distinct, but spatially and
temporally overlapping stages:
– (1) formation and folding of the neural plate
– (2) shaping and elevation of the neural plate
– (3) convergence of the neural folds, creating a neural groove
– (4) closure of the neural groove to form the neural tube
Figure 9.4 Primary neurulation: neural tube formation in the chick embryo (Part 1)

Folding begins as the medial hinge point

(MHP) cells anchor to the notochord and
change their shape.

The neural folds are elevated as the

presumptive epidermis continues to move
toward the dorsal midline.
Figure 9.4 Primary neurulation: neural tube formation in the chick embryo (Part 2)

Convergence of the neural folds occurs

as the dorsolateral hinge point (DLHP)
cells become wedge-shaped and the
epidermal cells push toward the center

The neural folds are brought into contact with one

another, and the neural crest cells link the neural
tube with the overlying epidermis. Neural crest cells
then disperse, leaving the neural tube separate from
the epidermis.
Closure of the Neural Tube

• In humans, there are probably three sites of neural tube closure.

Failure of closure in different regions of the neural tube causes
different neural tube defects.

• Failure to close the posterior neuropore around day 27 of

development results in spina bifida, the severity of which depends
on how much of the spinal cord remains exposed.

• Failure to close sites 2 and 3 in the rostral neural tube keeps the
anterior neuropore open resulting in a lethal condition called
anencephaly in which the forebrain remains in contact with the
amniotic fluid and subsequently degenerates.

• Collectively, neural tube defects are quite common in humans

occurring at a rate of approximately 1 in every 1,000 live births.
Neural tube closure defects can, however, be detected during
pregnancy by various physical and chemical tests.
Figure 9.5 Neurulation in the human embryo

Still born infant

with
anencephaly
Closure of the Neural Tube

• The neural tube eventually forms a closed cylinder that separates

from the surface ectoderm.

• This separation appears to be mediated by differential expression of

cell adhesion molecules. Although cells that will become the neural
tube originally express E-Cadherin, they stop producing this protein
as the neural tube forms and instead synthesize N-cadherin and N-
CAM.

• As a result, the surface ectoderm and neural tube tissues no longer

adhere to each other.
Building the Brain: Differentiation of the Neural Tube

• Differentiation of the neural tube into the various regions

of the CNS (i.e. brain and spinal cord) occurs
simultaneously in three different ways:
– (1) On the gross anatomical level, the neural tubes and its
lumen bulge and constrict to form the chambers of the brain and
spinal cord.
– (2) At the tissue level, the cell populations in the wall of the
neural tube rearrange themselves to form different functional
regions of the brain and spinal cord.
– (3) On the cellular level, the neuroepithelial cells themselves
differentiate into the numerous types of nerve cells (neurons)
and supportive cells (glia) present in the body.
Brain/Spinal Cord: Anterior-Posterior Axis

• The early mammalian neural tube is a straight structure, however

even before the posterior portion of the neural tube has formed, the
most anterior portion of the tube is undergoing dramatic changes.

• In the anterior region, the neural tubes balloons into (3) primary
vesicles:
– (1) the forebrain (prosencephalon)
– (2) the midbrain (mesencephalon)
– (3) the hindbrain (rhombencephalon)
Brain/Spinal Cord: Anterior-Posterior Axis

• The prosencephalon becomes subdivided into the anterior

telencephalon and more posterior diencephalon.
– The telencephalon will eventually give rise to the cerebral
hemispheres
– The diencephalon will form the optic vesicles (future retina), as well as
the thalamic and hypothalamic brain regions which receive neural
input from the retina.

• The mesencephalon does not become subdivided, and its lumen

eventually becomes the cerebral aqueduct.

• The rhombencephalon becomes subdivided into the anterior

metencephalon and the posterior myelencephalon.
– The metencephalon will eventually give rise to the cerebellum, the part
of the brain responsible for coordinating movement, posture and
balance.
– The myelencephalon eventually becomes the medulla oblongata,
whose neurons generate the nerve centers responsible for pain relay,
auditory connections, tongue movement, and heart beat, as well as
respiratory and gastrointestinal movements.
Figure 9.9 Early human brain development (Part 1)
Figure 9.9 Early human brain development (Part 2)
Dorsal-ventral specification of the neural tube

• The neural tube is polarized along its dorsal-ventral axis. For example, in
the spinal cord, the dorsal region is the place where the spinal neurons
receive input from sensory neurons in the periphery, while in the ventral
region is where the motor neurons reside. In the middle, are numerous
interneurons that relay information between the sensory and motor neurons.

• The D-V polarity of the neural tube is induced by local paracrine signaling.

• The ventral pattern is imposed by the notochord, while the dorsal pattern is
induced by the overlying epidermis.

• Specification of the axis is initiated by (2) major paracrine factors: Sonic

hedgehog protein, originating from the notochord (ventral), and TGF-b
proteins, originating in the dorsal ectoderm (epidermis).

• In both cases, these factors induce a second signaling center within the
neural tube itself.
Dorsal-ventral specification of the neural tube

• Sonic hedgehog (Shh) is secreted from the notochord and induces the
medial hinge point cells to become the floor plate of the neural tube.

• These floor plate cells also secrete Shh, and this signal from the floor plate
cells forms a gradient that is highest at the most ventral portion of the neural
tube.

• The dorsal fates of the neural tube are established by proteins of the TGF-b
superfamily, especially BMP4 and BMP7 as well as dorsalin and activin.
The epidermis establishes a secondary signaling center by inducing BMP4
expression in the roof plate cells of the neural tube.

• The BMP4 protein from the roof plate induces a cascade of TGF-b proteins
in adjacent cells.

• The dorsal sets of cells are thus exposed to higher concentrations of TGF-b
proteins and at earlier times, when compared to the more ventral neural
cells.
Figure 9.13 Dorsal-ventral specification of the neural tube (Part 1)
Figure 9.13 Dorsal-ventral specification of the neural tube (Part 2)

The neurons of the spinal cord are given their

identities by their exposure to these Shh and TGF-
b gradients. The amounts and types of paracrine
factors present causes different transcription
factors to be activated in the nuclei of these cells
depending upon their position in the neural tube.
Dorsal-ventral specification of the neural tube

• These paracrine factors interact to instruct the synthesis of different

transcription factors along the D-V axis of the neural tube.

• In the case of the ventral neural tube, a gradient of Shh specifies different cell
identities as a function of its concentration.

• The gradient of Shh specifies the ventral tube by activating and inhibiting the
synthesis of particular transcription factors.
Figure 9.13 Dorsal-ventral specification of the neural tube (Part 4)

TGF-b (dorsalin)

Pax7 (dorsal neural

tube

Pax6

Nkx6.1

Shh (ventral/notochord)
Motor neurons induced by Shh
concentration gradient
Figure 9.14 Cascade of inductions initiated by the notochord in the ventral neural tube (Part 1)

• Cell adjacent to the floor plate that receive high concentrations of Shh
synthesize Nkx6.1 and Nkx2.2 transcription factors and become ventral V3
neurons. Cells dorsal to these, exposed to slightly less Shh and slightly more
TGF-b produce Nkx6.1 and Pax6 and become motor neurons.

• With progressively less Shh the next two groups of neurons become V2 and
V1 interneurons.
Dorsal-ventral specification of the neural tube

• The importance of Shh in inducing and patterning the ventral portion of the neural
tube can be demonstrated experimentally.

• If notochord fragments are taken from one embryo and transplanted to the lateral
side of a host neural tube, the host neural tube will form another set of floor plate
cells at its side.

• These ectopic floor plate cells can then induce the formation of motor neurons on
either side of them.
Differentiation of Neurons in the Brain

• The human brain consists of more than 1011 neurons associated

with over 1012 glial cells.

• The neuroepithelial cells of the neural tube give rise the (3) main
types of cells.
– (1) First they become the ventricular (ependymal) cells that
remain integral components of the neural tube line and that
secrete the cerebrospinal fluid.
– (2) Second, they generate the precursors of the neurons that
conduct electric potentials and coordinate our bodily functions,
thoughts and sensations.
– (3) Third, they give rise to the precursors of the glial cells that
aid in constructing the nervous system, provide insulation around
the neurons, and that may be important in memory storage.
Differentiation of Neurons in the Brain

• The brain contains a wide variety of neuronal and glial subtypes.

• The fine, branching extensions of the neuron that are used to

receive incoming electrical impulses from other neurons are called
dendrites.

• Some neurons develop only a few dendrites whereas other cells

such as Purkinje neurons develop very extensive dendritic arbors.

• For example, in cortical neurons at birth there are very few

dendrites, however during the first year of human life there is a
dramatic increase in the number of these receptive processes.

• During this year, each cortical neuron develops enough dendritic

surface to accommodate as many as 100,000 synapses providing
connections to adjacent neurons.
Differentiation of Neurons in the Brain

• The average cortical neuron connects with 10,000 other neural cells
and the pattern of synaptic contact enables the human cortex to
function as the center for learning, reasoning, and memory as well
as to develop the capacity for symbolic expression and to produce
voluntary responses to interpreted stimuli.

• Another important feature of a developing neuron is its axon.

Whereas dendrites are often numerous and do not extend far from
the neuronal cell body or soma, axons may extend 2-3 feet.

• For example, the pain receptors on your big toe must transmit their
messages all the way to your spinal cord.

• One of the fundamental concepts of neurobiology is that the axon is

a continuous extension of the nerve cell body.
Figure 9.15 Diagram of a motor neuron

Electrical impulses are received by

dendrites, and the stimulated neuron
transmits impulses through its axon to its
target tissue.

The axon is the cellular process by which the

neuron sends its signals. The growth cone of the
axon is both a locomotor and a sensory apparatus
that actively explores the environment and picks
up directional cues telling it where to go.
Ultimately, the growth cone will form a synapse
with the axon’s target tissue (e.g. dendrite or
muscle)
Differentiation of Neurons in the Brain

• Nerve outgrowth is led by the tip of the axon, called the growth cone.
During outgrowth the growth cone does not proceed in a straight line, but
rather can respond to directional cues as it moves across the substrate.

• The growth cone moves by the elongation and contraction of pointed

filopodia called microspikes. These microspikes contain actin
microfilaments which are oriented in bundles parallel to the long axis of the
axon.

• Within the axon itself, structural support is provided by microtubules.

• As in most migrating cells, the exploratory microspikes of the growth cone

attach to the substrate and exert a force that pulls the rest of the cell
forward and axons will not grow if the growth cone fails to advance.

• In addition to their structural role in axonal migration, the microspikes also

have a sensory function. Fanning out in the front of the growth cone, each
microspike samples the microenvironment and sends signals back to the
soma.
Figure 9.16 Axon growth cones

Microtubules
Actin microfilaments
Differentiation of Neurons in the Brain

• Neurons transmit electric potentials from one region of the body to another. The
action potentials typically go from the dendrites into the soma, where they are
focused into the axon.

• To prevent dispersal of the action potential and to facilitate its conduction to the
target cell, the axon is insulated at intervals by glial cells.

• Within the CNS, axons are insulated at intervals by processes that originate
from a type of glial cell called an oligodendrocyte.

• Oligodendrocytes wrap themselves around the developing axon and then

produce a specialized cell membrane called a myelin sheath.

• In the peripheral nervous system, myelination (the process of wrapping an axon

in the myelin sheath) is accomplished by a glial cell type called a Schwann cell.

• Action potentials are propagated along the axon at sites known as nodes of
Ranvier which represent those intervals in which there is a space with no myelin
sheath. Action potentials “hop” from node-to-node via a phenomenon known as
saltatory conduction.
Figure 9.17 Myelination in the central and peripheral nervous systems
Differentiation of Neurons in the Brain

• The myelin sheath is essential for proper neural function and

demyelination of nerve fibers is associated with convulsions,
paralysis, and certain debilitating neurological disease states
such as multiple sclerosis.

• There are also mouse mutants where subsets of neurons are

poorly myelinated. For example in the trembler mutant
mouse, the Schwann cells are unable to produce a particular
protein component such that myelination is deficient in the
peripheral nervous system but normal in the CNS.

• Conversely, in the mouse mutant jimpy, the CNS is deficient

in myelin, while the peripheral nerves are unaffected.
Differentiation of Neurons in the Brain

• Axons are specialized for secreting specifical chemical

neurotransmitters across the synaptic cleft which is the
small gap between a pre-synaptic axon and a post-synaptic
dendrite or target cell (e.g. a muscle at the neuromuscular
junction).

• Some neurons develop the ability to synthesize and secrete

acetylcholine, while others develop the enzymatic pathways
for making and secreting epinephrine, norepinephrine,
octopamine, serotonin, g-aminobutyric acid (GABA), or
dopamine.

• Each neuron must activate those genes responsible for

making the enzymes that can synthesize its specific
neurotransmitter.
Tissue Architecture of the Central Nervous System

• The neurons of the brain are organized into layers (cortices) and
clusters (nuclei) each having different functions and connections.

• The original neural tube is composed of a germinal

neuroepithelium which is a layer of rapidly dividing neural stem
cells one cell layer thick.

• When a cell of the germinal neuroepithelium is ready to generate

neurons (instead of more neural stem cells), the plane of division
shifts.

• Instead of having both cells remain attached to the luminal surface

of the neural tube, one of the two daughter cells becomes detached
and one remains connected to the luminal surface.

• The cell connected to the luminal surface remains a stem cell

whereas the other cells migrates away from the luminal surface and
differentiates.
Figure 9.18 Neural stem cells in the germinal epithelium (Part 1)

Neural
Stem
Cells
Spinal Cord and Medulla Organization

• As the cells adjacent to the lumen continue to divide, the migrating cells form a
second layer around the original neural tube.

• This layer becomes progressively thicker as more cells are added to it from the
germinal neuroepithelium.

• This new layer is called the mantle (or intermediate) zone, and the germinal
epithelium is now called the ventricular zone (and later the ependyma).

• The mantle zone cells differentiate into both neurons and glia. The neurons
make connections among themselves and send forth axons away from the
lumen, thereby creating a “cell-poor” marginal zone.

• Eventually the glial cells cover many of the axons in the marginal zone in myelin
sheaths, giving them a “whitish” appearance. Hence, the axonal marginal layer
is often called the white matter, while the mantle zone containing the neuronal
cell bodies, is referred to as gray matter.

• Thus, the human neural tube is segregated into (3) zones: ventricular,
mantle (or intermediate) and marginal.
Figure 9.19 Differentiation of the walls of the neural tube (Part 1)

Gray Matter White Matter

Lumen

In the spinal cord and medulla, the ventricular

zone remains the sole source of neurons and
glial cells and is the site of the neural stem
cells.
Figure 9.19 Differentiation of the walls of the neural tube (Part 2)

In the cerebellum, a second mitotic layer, the external granular

layer, forms at the region farthest removed from the ventricular
layer. Neuroblast from this layer migrate back into the
intermediate zone to from the internal granular layer.
Figure 9.19 Differentiation of the walls of the neural tube (Part 3)

In the cerebral cortex, the migrating

neuroblasts and glioblasts form a cortical plate
ultimately forming six layers in what is known
as the neocortex.
Spinal Cord and Medulla Organization

• In the spinal cord and medulla, this basic three-zone pattern

of ventricular, mantle, and marginal layers is retained
throughout development.

• When viewed in cross-section, the gray matter (mantle)

gradually becomes a butterfly-shaped structure surrounded by
white matter, and both become encased in connective tissue.

• As the neural tube matures, a longitudinal groove known as

the sulcans limitans divides the neural tube into dorsal and
ventral halves.

• The dorsal portion of the neural tube receives input from

sensory neurons, whereas the ventral portion is involved in
effecting various motor functions via motor neurons.
Figure 9.20 Development of the human spinal cord

A segment of the spinal cord

with its sensory (dorsal) and
motor (ventral) roots.
Cerebellar Organization

• In the cerebellum, some neuronal precursors enter the marginal zone to form
nuclei (clusters of neurons). Each nucleus works as a functional unit, serving as
a relay station between the outer layers of the cerebellum and other parts of the
brain.

• Other neuronal precursors migrate away from the germinal neuroepithelium.

These cerebellar neuroblasts migrate to the outer surface of the developing
cerebellum and form a new germinal zone, the external granular layer, near
the outer boundary of the neural tube.
Cerebellar Organization

• At the outer boundary of the external granular layer, neuroblasts proliferate and
come into contact with cells that secrete BMP factors.

• The BMPs specify the postmitotic cells of these neuroblasts to become a type of
neuron called granule cells. Granule cells migrate back toward the ventricular
zone, where they produce a region called the internal granular layer.

• Meanwhile, the original ventricular zone of the cerebellum generates a wide

variety of neurons and glial cells, including the distinctive and large Purkinje
neurons, the major cell type of the cerebellum.
Cerebellar Organization

• Purkinje neurons secrete Sonic hedgehog which sustains the

division of the granule cell precursors in the external granular
layer.

• Each Purkinje neuron has an enormous dendritic arbor that

spreads like a tree above the cell body or soma. A typical
Purkinje neuron may form as many as 100,000 synapses with
other neurons---more connections than any other type of
neuron that has been studied.

• Purkinje neurons are critical in the electrical pathway of the

cerebellum. All electric impulses eventually regulate the
activity of these neurons which are the only output neurons of
the cerebellar cortex.
Cerebellar Organization

• One mechanism thought to be important for positioning young

neurons in the developing mammalian brain is glial guidance.

• Throughout the cortex, neurons are seen to ride a “glial monorail” to

their respective destinations. In the cerebellum, the granule cell
precursors travel on the long processes of the Bergmann glia.

• This neuron-glia interaction involves reciprocal recognition between

glia and neuroblasts. The neuron maintains its adhesion to the glial
cell through a number of proteins, one of them an adhesion protein
called astrotactin.

• Moreover, the direction of this neuroblast migration appears to be

regulated by a complex series of events orchestrated by brain-
derived neurotrophic factor (BDNF), which acts as a paracrine
factor made in the internal granular layer as cells exit the ventricular
layer migrating outward.
Figure 9.21 Cerebellar organization

Sagittal section of a rat cerebellum. Purkinje

neurons populate the outer most layer and are
adjacent to the Bergmann glia and granule cells.

These neurons display complex dendritic arbors.

Figure 9.22 Neuron-glia interaction in the mouse

Sequential time-series photographs of a

neuron migrating on a cerebellar glial
process. The leading process of the
neuron has several filopodial extensions.
Cerebral Organization

• The three-zone arrangement of the neural tube is also modified in the

cerebrum. The cerebrum is organized in two distinct ways:
– (1) First, like the cerebellum, it is organized vertically into layers that
interact with one another. Certain neuroblasts from the mantle (or
intermediate) zone migrate on glial processes through the white matter
to generate a second zone of neurons at the outer surface of the brain.
This new layer of gray matter will become the neocortex.

For example, neurons in layer 4

of the neocortex receive their
major input from the thalamus (a
region that forms from the
diencephalon) whereas neurons
in layer 6 of the neocortex send
their major output back to the
thalamus.

• The neocortex eventually stratifies into (6) layers of neuronal cell bodies.
Each layer of the neocortex differs from the others in its functional
properties, the types of neurons found there, and the sets of connections
they make.
Cerebral Organization

• The three-zone arrangement of the neural tube is also modified in the

cerebrum. The cerebrum is organized in two distinct ways:
– (2) The second way that the cerebrum is organized relates to the fact
that in addition to the six vertical layers, the cerebral cortex is also
organized horizontally into more than 40 regions that regulate
anatomically and functionally distinct processes.

• For example, neurons in layer 6 of the visual cortex project axons to the
lateral geniculate nucleus of the thalamus, which is involved in vision, while
layer 6 neurons of the auditory cortex (located more anteriorly than the
visual cortex) project axons to the medial geniculate nucleus of the
thalamus, which functions in hearing.
Cerebral Organization

• Most of the neuroblast generated in the

ventricular zone migrate outward along radial
glial processes to form the cortical plate at the
outer surface of the brain.

• As in the rest of the brain, those neurons with

the earliest “birthdays” form the layer closest to
the ventricle, whereas subsequent neurons
travel greater distances to form the more
superficial layers of the cortex.
Stem Cells and Precursor Cells

• The stem cells of the neocortex are originally generated by

symmetrical division of the neural tube epithelium before
neurogenesis actually occurs.

• Initially, the proliferative layer of the mouse cortex forms the

ventricular zone (VZ). Shortly thereafter (around day 13), it
divides to give rise to a subventricular zone (SVZ) directly
outside it.

• Together these zones form the germinal strata that generate

the neuroblasts (neuronal precursor cells) that migrate into
the cortical plate and form the layers of neurons in the
neocortex.

• The VZ will form the lower (deeper) layer of neurons, while

the SVB will give rise to those cells that form the upper layer
of neurons.
Stem Cells and Precursor Cells

• There are (3) major progenitor cells in the germinal strata:

– (1) radial glial cells (RGCs) – these cells aren’t really glia but look like
them and are thought to be stem cells found in the VZ. At each division,
RGCs generate another RGC cell and a more committed cell.
– (2) short neural precursors (SNPs)
– (3) intermediate progenitor cells (IPCs)

• The more committed cells generated by RGC division can be either

neuroblasts (which divide to generate neurons) or IPCs, which migrate
to the SVZ.

• The SNPs also appear to generate neuroblasts, but from the VZ.

• A single stem cell in the ventricular layer can give rise to neurons and
glial cells in any of the cortical layers.
Figure 9.24 Cortical neurons are generated from three types of neural precursor cells: radial glia
cells, short neural precursors, and intermediate progenitor cells

RGCs and SNPs divide within the ventricular zone (VZ). SNPs are committed
neuroblast precursors.

IPCs divide away from the luminal surface in the SVZ. Most IPCs undergo
Neurogenic divisions, with a small fraction undergoing symmetrical proliferative
divisions (dotted line – this would be a stem cell-like division)