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BBS2002 All cases - From Cradle to Grave
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These are all the cases from BBS2002. Including notes from the lecture
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Case 1
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Neurulation
The embryo begins as a flat disk with three distinct layers of cells called endoderm,
mesoderm, and ectoderm. The endoderm ultimately gives rise to the lining of many of the
internal organs (viscera).
● The mesoderm becomes the bones of the skeleton and the muscles, including
connective tissue, notochord, kidney, gonads and circulatory system.
● The endoderm forms the epithelial (inner) lining of the digestive tract, including the
stomach, colon, liver, pancreas, bladder, lung
● The ectoderm turns into the nervous system and the skin (epidermis (outer layer of
skin)), including hair, nails, brain, spinal cord and peripheral nervous system
At 17 days, the primitive embryonic CNS begins as a thin sheet of ectoderm. The neural
groove is formed from this sheet
as the
Directly beneath the primitive
streak, the mesoderm (the
middle germ layer) forms a thin
rod of cells known as the
notochord.
The notochord causes the
ectoderm above it to form a thick
flat plate of cells called the
neural plate. The neural plate
extends the length of the rostral-
caudal axis. The neural plate
then bends back on itself and
seals itself into a tube known as
the neural tube (later CNS) that
fits underneath the ectoderm.
The borders of where the neural
plate had been getting pulled
under with it, and become the
neural crest (later PNS). The
neural tube will become the
brain and spinal cord.
, 2
Making Tubes
Step 5: During gastrulation, the three germ layers form; the cell mass is now known as a
gastrula
Step 5a: The primitive streak forms
Step 6: The notochord is formed
Neurulation
Step 6: Tubes form, making a neurula
Step 6a: The notochord induces the formation of the neural plate
Step 6b: The neural plate folds in on itself to make the neural tube and neural crest
Step 7: The mesoderm has five distinct categories
The first step in the differentiation of the brain is the development, at the rostral end of the
neural tube, of three swellings called the primary vesicles --> the entire brain derives from
the primary vesicles of the neural tube.
Three-vesicle stage:
1. The prosencephalon = Forebrain
2. The mesencephalon = Midbrain and becomes the tectum and tegmentum with the
cerebral aqueduct in between
3. The rhombencephalon = Hindbrain is connected to the caudal neural tube, which
gives rise to the spinal cord
Five-vesicle stage: Each primary vesicle has secondary vesicles (as seen in the picture
above)
, 3
NOTE: The forebrain becomes the retina, optic nerve, thalamus, hypothalamus, third ventricle,
olfactory bulb, cerebral cortex, basal telencephalon, corpus callosum, cortical white matter,
and the internal capsule.
The nervous system is composed of two main classes of cells: neurons and glia. Glial cells
of the vertebrate CNS include three major types, microglia, astrocytes, and
oligodendrocytes. Microglia are derived from the bone marrow and will not be further
considered here. Astrocytes are multipolar cells whose processes interact with neuronal
synapses, as well as the capillary network; astrocytes form the blood-brain barrier.
Oligodendrocytes produce large, lamellar processes that make up the myelin sheath around
axons.
Neuronal Stem Cells
Neural stem cells (NSCs) are self-renewing, multipotent cells → generate neurons and glia
(primarily astrocytes, oligodendrocytes and neurons). Both the neurons, glia and crest cell
originate from the ectoderm. The Neuronal Stem Cells (NSC) are used in the Central
Nervous System (CNS) whilst the crest cells are used in the Peripheral Nervous System
(PNS).
● Some of these cells stay in the vertebrate, to produce neurons throughout life.
There are different types of neuronal cells:
● neuroepithelial cells (NECs),
● radial glial cells (RGCs),
● basal progenitors (BPs),
● intermediate neuronal precursors (INPs).
Neurogenesis doesn’t begin until there are enough NSCs (early stem cells are NECs and
RGCs). RGCs are in a niche in the ventricular zone, proliferation results in neurogenesis.
They form subclass INPs, which produce neurons (daughters produced directly).
Neurons do not form immediately new circuits, first, they need to migrate to the right plate
where they can form the cortexes.
Neuronal cell proliferation
The brain develops from the walls of the five fluid-filled vesicles, in the early stages consisting
of two layers: the ventricular zone (form ependymal cells) and the marginal zone (forms
white matter).
The proliferative zones surrounding the ventricles are the major regions involved in the
production of neural cells in the cerebral cortex as well as other regions of the central nervous
system
● neural precursor cells give rise to many different types of tissue and are also called
neural stem cells
, 4
In humans, the neocortical neurons are born between week 5-24 of gestation (pregnancy),
with a peaking rate of 250.000 new neurons per minute during the process of neurogenesis
and continue to be generated in adult life in restricted regions of the adult brain.
● New brain cells/connection are made when old cells are damaged or die.
Hippocampus creates new cells without the constraint of age/time. It maintains its
central function by quickly replacing dying cells. These new cells are made in the
dentate gyrus of the hippocampus (glial and granule cells). The number of new cells
+ its creation frequency declines with age.
● The hippocampus is only for MEMORY, hence why this keeps on making new neuronal
cells.
Cell proliferation
1. First position: A cell in the ventricular zone extends a process that reaches upward
toward the pia.
2. Second position: The nucleus of the cell migrates upward from the ventricular surface
toward the pial surface (in the marginal zone) → the cell’s DNA is copied.
3. Third position: The nucleus, containing two complete copies of the genetic
instructions, settles back to the ventricular surface.
4. Fourth position: The cell retracts its arm from the pial surface.
5. Fifth position: The cell divides in two, either symmetrical or asymmetrical:
, 5
The cell division is either asymmetric or symmetric --> the neural stem cells divide
symmetrically at first to expand the population of the neuronal precursors and later on the NSC
will divide asymmetrically
● During symmetric division, the progenitor cell generates two additional progenitor
cells --> they remain in the ventricular zone to divide again.
● During asymmetric division, either the progenitor cell (P) generates a neuron (N) and
a glial cell (G) OR give rise to another progenitor cell and a neuron. This mode of
division contributes to the generation of neurons at early stages of development, and
of glial cells at later stages, typical of many regions of the CNS.
○ These daughter cells will migrate towards the cortex (where it will no longer
divide)
○ NOTE: that the radial glial cells = progenitor cells that generate both neurons
and astrocytes in addition to their role in neuronal migration.
Ventricular zone precursor cells repeat this pattern until all the neurons and glia of the cortex
have been generated
Cell fate is regulated by differences in gene expression during development, which is
regulated by transcription factors.
Notch-1 and Numb are transcription factors that
migrate to different poles of ventricular zone precursor
cells.
● During vertical/symmetrical division, Notch-1
and Numb proteins act similarly.
● During horizontal/asymmetrical division,
Notch-1 stops the daughter cells from dividing
and migrates them away from the ventricular
zone, whilst Numb inhibits the migration of
daughter cells.
Cell migration
● Many daughter cells migrate by slithering along with radial glial cells (thin fibres) that
radiate from the ventricular zone toward the pia, providing the scaffold on which the
cortex is built.
, 6
● The immature neurons, called neuroblasts, follow this radial path from the ventricular
zone toward the surface of the brain through the radial movement of the soma within
the fibre that connects the ventricular zone and pia.
● When the cortical assembly is complete, the radial glia withdraws their radial
processes.
● Not all migrating cells follow the path provided by the radial glial cells
● About one-third of the neuroblasts wander horizontally on their way to the cortex.
● The neuroblasts destined to become subplate cells are among the first to migrate away
from the ventricular zone.
The first cell to migrate away from the dorsal ventricular zone to the cortical plate, are destined
to reside in a layer called the subplate. As these differentiate into neurons, the neuroblasts
destined to become layer VI cells migrate past and collect in the cortical plate. This process
repeats until all layers from VI to I of the cortex have differentiated. The subplate neurons then
disappear.
Notice that each new wave of neuroblasts migrates right past those in the existing cortical
plate. In this way, the cortex is said to be assembled inside-out.
● This orderly process can be disrupted by a number of gene mutations.
Three major programs for the migration of neurons.
1. Radial migration is moving of central neurons along unbranched processes of radial
glial cells.
2. Tangential migration is moving along axonal tracts
3. Free migration is in PNS without tracts.
Each radial glial cell has one basal end foot in the ventricular zone at the apical surface and
processes that terminate in multiple end-feet at the pial surface of the brain. Leading process
, 7
of neuron wraps around the shaft of radial glial cell, then nucleus translocates step-wise to the
cytoplasm of the leading process. Then lattice forms cage around the nucleus and its
movement depends on the basal body. Adhesive receptors (integrins) promote neuronal
extension on radial glial cells.
Tangential migration is for the population of distinct regions of the brain. Its major cellular
substrate appears to be pre-existing axonal tracts that connect regions of a neuronal
generation with the final settling position of the neurons. In the developing cortex the axons of
cortical projection neurons reach the internal capsule when migratory neurons begin to enter
the neocortex; at this intersection immigrating neurons are tightly associated with the bundles
of axons that leave the cortex. Neurons that use tangential migration follow precise routes of
navigation and settling.
Cortical neurons originate from the cortical ventricular zone (excitatory) and medial ganglionic
eminence (inter). The peripheral nervous system derives from neural crest stem cells, a small
group of neuroepithelial cells at the boundary of the neural tube and epidermal ectoderm.
Soon after their induction neural crest cells are transformed from epithelial to mesenchymal
cells and begin to delaminate from the neural tube. They then migrate to many sites throughout
the body.
Neural crest cell migration does not rely on scaffolding and thus is called free migration. This
form of neuronal migration requires significant cytoarchitectural and cell adhesive changes
and differs from most of the migratory events in the central nervous system.
Cell differentiation
● The process in which a cell takes on the appearance and characteristics of a neuron
is called cell differentiation.
● neuroblast differentiation begins as soon as the precursor cells divide with the uneven
distribution of cell constituents.
● Further neuronal differentiation occurs when the neuroblast arrives in the cortical plate.
● Thus, layer V and VI neurons have differentiated into recognizable pyramidal cells
even before layer II cells have migrated into the cortical plate.
● Differentiation of the neuroblast into a neuron begins with the appearance of neurites
sprouting off the cell body.
● At first, these neurites all appear about the same, but soon, one becomes recognizable
as the axon and the others as dendrites. Differentiation will occur even if the neuroblast
, 8
is removed from the brain and placed in tissue culture. This means that differentiation
is programmed well before the neuroblast arrives at its final resting place.
Neuronal differentiation
occurs first, followed by
astrocyte differentiation that
peaks at about the time of
birth. Oligodendrocytes are
the last cells to differentiate.
Axon growth - The
Growth Cone
● Once the neuroblast has migrated to take up its appropriate position in the nervous
system, the neuron differentiates and extends the processes that will ultimately
become the axon and dendrites.
● At this early stage, however, the axonal and dendritic processes appear quite similar
and collectively are still called neurites. The growing tip of a neurite is called a growth
cone (Figure 23.9) which is specialized in identifying appropriate pathways for neurite
elongation.
, 9
● The leading edge of the growth cone consists of flat sheets of membrane called
lamellipodia
● Extending from the lamellipodia are
thin spikes called filopodia, which
constantly probe the environment,
moving in and out of the
lamellipodia.
● Growth of the neurite occurs
when a filopodium, instead of
retracting, takes hold of the
substrate (the surface on which it
is growing) and pulls the
advancing growth cone forward.
● Obviously, axonal growth cannot
occur unless the growth cone is able
to advance along the substrate. An
important substrate consists of
fibrous proteins that are deposited in
the spaces between cells, the
extracellular matrix. Growth occurs
only if the extracellular matrix
contains appropriate proteins.
○ An example of a permissive
substrate is the glycoprotein laminin. The growing axons express special
surface molecules called integrins that bind laminin, and this interaction
promotes axonal elongation. Permissive substrates, bordered by repulsive
ones, can provide corridors that channel axon growth along specific pathways.
● Travelling down such molecular highways are also aided by fasciculation, a
mechanism that causes axons growing together to stick together. Fasciculation is due
to the expression of specific surface molecules called cell-adhesion molecules
(CAMs). The CAMs in the membrane of neighbouring axons bind tightly to one
another, causing the axons to grow in unison.
, 10
Generation of synapses
When the growth cone (growing tip of a neurite) comes in contact with its target, a synapse is
formed
● The first step appears to be the induction of a
cluster of postsynaptic receptors under the site
of nerve-muscle contact. This clustering is
triggered by an interaction between proteins
secreted by the growth cone and the target
membrane.
● At the neuromuscular junction, one of these
proteins, called Agrin, is deposited in the
extracellular space at the site of contact called
the basal lamina.
○ This agrin binds to MuSK (muscle-
specific kinase = a receptor in the muscle
cell membrane)
○ MuSK communicates with the Rapsyn,
which appears to act as a shepherd to
gather the postsynaptic acetylcholine
receptors (AChRs) at the synapse.
● The size of the “flock” of receptors is regulated
by another molecule released by the axon, called
neuregulin, which stimulates the receptor gene
expression in the muscle cell
● The interaction between axons and target occurs
in both directions and the induction of the
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