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Neurodevelopment I
Neurogenesis
Reading:
BCP Chapter 23
Neurodevelopment
Neural development is an ongoing,
complex process involving
interactions between genes and the
environment. There can be dire
consequences when something goes
wrong.
Genetic and environmental causes of
nervous system disorders include:
•
•
gene copy number variation
mutations in genes (single nucleotide
polymorphisms) or regulation regions
 toxins, viruses (e.g., Zika), stress
Neurodevelopmental disorders:
autism; schizophrenia, Down syndrome,
fragile X, ADHD, dyslexia, verbal dyspraxia
Psychiatric Disorders:
anxiety, affective
Phases of Development
Ovum + Sperm = Zygote
Cell division (multiplication)
Neurogenesis
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Induction of the neural plate
Neural proliferation
Structure Formation
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Migration
Aggregation
Wiring the Brain
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Axon growth/synapse formation
Neuron death/synapse refinement
Germinal Stage
The germinal stage of embryogenesis, refers to the time from
fertilization to implantation in the
uterus. The germinal stage takes
around 8-10 days.
Potency: the ability to develop
into different cell types
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totipotent: fertilized egg  morula
pluripotent (embryonic stem cells):
blastocyst
multipotent; unipotent
At the end of the germinal stage,
there is a “Baby in a Compact
Disc”.
morula
Gastrulation
Neurulation
The third phase of development is neurulation, the stage at which the nervous
system emerges. The mammalian nervous system is derived from the ectoderm
– the outermost germ layer – of the embryo. In the third week of human
development, a neural plate forms along the dorsal side of the embryo. The
edges of this plate elevate and meet at the mid-line forming a neural tube. This
tube is the precursor of the central nervous system.
Neurulation stage
• Neural tube: CNS
• Inside tube: ventricles
and spinal canal
• Neural crest: PNS
• Somite: skull and
vertebrae
thebrain.mcgill.ca
Induction 1
A central question in developmental
biology is how form and pattern emerge
from the simple beginnings of a
fertilized egg. Are cell fates somehow
predetermined or do cells and tissues
interact with one another to orchestrate
developmental processes (induction)?
Embryonic induction was first shown
unambiguously by the results of
experiments conducted by Mangold and
Spemann (1924), wherein the
transplanted dorsal lip of one frog
blastopore induced a second neural
tube in a recipient frog embryo.
The dorsal lip – future mesoderm (the
notochord in humans) – is known as the
organizer.
Induction 2
Induction of the neural plate is caused not
by an excitatory signal from the mesoderm
but by blockade of an inhibitory one within
the ectoderm itself (a process called
disinhibition).
Prior to gastrulation, cultured regions of
ectoderm develop into epidermis. However,
if the cells are dissociated – separated by
removal of calcium from the medium – then
the cells become neurons. This suggests
that neural fate is actively suppressed by
cellular associations in ectoderm.
If bone morphogenetic protein (BMP) is
added to the dissociated culture dish, then
the cells again develop into epidermis.
Thus, BMP inhibits (prevents) a neural fate.
Induction 3
The current model of neural
induction is that the dorsal lip in
amphibians (notochord in
humans) releases several
molecules that interfere with the
BMP signals between overlying
ectodermal cells.
Ceberus (Cb), chordin (Chd),
noggin (Nd) and follistatin all
interfere with the activation of the
BMP receptor in ectoderm,
thereby blocking its anti-neural
effects. Thus, these chemical
signals “induce” this region of the
embryo to develop into neural
tissue ultimately generating the
brain and spinal cord.
Neural Tube
Following neurulation, the neural
tube forms two plates.
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•
In response to BMP released by the
overlying non-neural ectoderm, the
dorsal aspect of the tube develops into
a tissue known as the roof plate. It
then begins to release BMP (and Wnt).
In response to the release of sonic
hedgehog (SHH) from the underlying
notochord, the ventral part of the tube
becomes flattens into the floor plate. It
then begins to secrete SHH.
The cells between the two plates will
proliferate and differentiate into the
neurons in the brain and spinal cord.
Neural Proliferation 1
Neural Proliferation 2
Neural stem cell proliferation
(symmetric cell division) and
differentiation (asymmetric cell
division) is controlled by multiple
factors:
•
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morphogenetic factors
cell-to-cell signaling
Morphogens are soluble molecules
that diffuse and control cell fate
decisions in a concentrationdependent fashion.
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•
BMP
Wnt
dorsal plate: BMP, Wnt
ventral plate: SHH
In direct cell-to-cell signaling,
neighboring cells influence one
another. If one cell differentiates,
then it suppresses differentiation in
others via Notch (lateral inhibition).
SHH
Neural Proliferation 3
Gross Morphology
Proliferation and differentiation
cause the neural tube to change
its size and shape (morphology).
Shape changes are quite
pronounced at the rostral end of
the tube (future brain and
cerebellum), whereas they are
minor at the caudal end (future
spinal cord).
In temporal order, the rostral end
of the tube shows:
• first, three swellings which will
give rise to the forebrain,
midbrain and hindbrain
• second, five swellings which
give rise to major divisions of
the brain.
Forebrain
Milestones in the morphological
development of the forebrain
include:
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flexion forward (in humans)
posterior growth of the
telencephalic swellings such that
they lie over, lateral to and fuse
with the diencephalon
sprouting from the diencephalon
of optic stalks and cups that give
rise to the optic nerves and
retinas (for vision)
sprouting from the ventral surface
of the cerebral hemispheres of
the olfactory bulbs (smell)
Telencephalon surrounds the
lateral ventricles; diencephalon
is on either side of the third
ventricle.
Lateral
ventricles
Telencephalon
Third
ventricle
Diencephalon
Midbrain
Milestones in the morphological
development of the midbrain
include:
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the dorsal surface (tectum) shows
four bumps (colliculi)
the floor of the midbrain becomes
the tegmentum, and projection
fibers accumulate on the lateral
edges (cerebral peduncles;
pyramidal motor tracts)
the cerebral aqueduct narrows
Mesencephalon surrounds the
cerebral aqueduct.
Cerebral
peduncles
Hindbrain
Milestones in the morphological
development of the hindbrain
include:
•
•
in metencephalon (the rostral
hindbrain), tissue along the
dorsal-lateral wall grows to form
the rhombic lips, which then
expand further dorsally until they
fuse forming the cerebellum
in myelencephalon (the caudal
hindbrain), the ventral and lateral
walls swell such that the fourth
ventricle is at the roof, and
projection fibers (the pyramids)
pass along the ventral surface
Metencephalon surrounds the
fourth ventricle; myelencephalon
is below the fourth venticle.
Neuroplasticity in Adults
The mature brain continues to change
and adapt
 Experience can reorganize the
adult cortex (learning and memory)
 Neurogenesis (growth of new
neurons) is seen in the olfactory bulb
and hippocampus