Cortical Development III:
Proliferation,
Migration, and
Differentiation
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Review From Last Time
• Asymmetric Cell Division
• Neurons can be generated by two types of cells: _____________ and ____________
• Cleavage plane [DOES / DOES NOT] reliably predict the mode of division
(that is, symmetric vs. asymmetric)
• Radial Glial Cells divide in the ____________, in a __________ orientation,
and this is division is usually [ASYMMETRIC / SYMMETRIC / BOTH]
• Intermediate Progenitor Cells divide in the _____________, in a _________
orientation, and this division is usually [ASYMMETRIC / SYMMETRIC /
BOTH]
Neuronal structure develops in 3 major stages
• Cell proliferation
• Cell migration
• Cell differentiation
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Cell differentiation
• The process by which a cell takes on the appearance and
characteristics of a neuron
• By the time a neuron extends its axons and dendrites, it has usually
acquired a fate; that is, the outcome of the developmental decision as
to what kind of cell it is
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Cell differentiation
• Developmental decisions:
• Is the cell excitatory, inhibitory, or modulatory?
• What neurotransmitter will it use?
• What presynaptic and postsynaptic connections will it make?
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Cell differentiation
• The bulk of evidence favors the view that neuronal differentiation is
based primarily on local cell-cell interactions followed by distinct
histories of transcriptional regulation via a code of transcription
factors expressed in each cell
• This means that a cell is influenced by its neighbors (cell-cell
interactions) and by its lineage (who its “parent” is)
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Cell differentiation
• The age of the precursor cell, its position within the ventricular zone,
and its environment at the time of division are also key factors that
determine a cell’s fate
• Discuss with your table, and then write on the board one example
from class or the text demonstrating how we know the following
factors determine a cell’s fate:
• “#1 Tables”: Age of precursor cell
• “#2 Tables”: Position in ventricular zone
• “#3 Tables”: Environment at the time of division
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Cell differentiation
• Further neuronal differentiation continues when the neural precursor
cell arrives in the cortical plate
• Layer V and layer VI cells have differentiated into recognizable
pyramidal cells before layer II cells have migrated into the cortical
plate
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Cell differentiation
• Neuronal differentiation occurs first
• Astrocyte differentiation occurs next, peaking around birth
• Oligodendrocytes are the last cells to differentiate
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10 2014
Gao et al., Cell
Cell differentiation
• Neuronal differentiation does not occur until the cell has migrated to its
final location
a) Short stubby processes form
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Cell differentiation
• Neuronal differentiation begins with the appearance of neurites sprouting
off the cell body
neurite
b) Immature processes called
“neurites” extend from the cell
body
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Cell differentiation
axon
c) One of the neurites becomes a
thin, rapidly growing axon
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Cell differentiation
dendrite
d) The sequence continues with
further axon outgrowth and
dendritic branching
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Cell differentiation
• Neuronal differentiation will occur even if the neuron is removed
from the brain during migration and grown in a dish
• This means that neuronal differentiation is programmed before the
cell reaches its final destination
• However, the architecture of cortical dendrites and axons depends on
cellular signals
What is this cellular signal?
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Cell differentiation
• A protein called semaphorin 3A, secreted in the marginal zone, is important
for differentiating the characteristic architecture of cortical neurons.
Marginal Zone
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Cell differentiation
• Semaphorin 3A repels growing axons, causing them to grow away from the
pial surface.
Marginal Zone
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Cell differentiation
• Semaphorin 3A also attracts growing dendrites, causing them to grow toward
the pial surface
Marginal Zone
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Summary
• Neural precursor cells migrate radially or tangentially
• Neocortex develops in an inside-out fashion
• Transcription factor gradients and thalamic inputs determine cortical
cytoarchitecture
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How far we’ve come…
• Formation of a polarized, layered embyro from an undifferentiated
blastocyst
• Organization of the body plan (i.e., patterning) via signaling gradients,
which activate highly specific expression of target genes
• Proliferation of stem cells
• Fate specification of newborn cells
• Neuronal migration in the embryonic cortex
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Wiring the brain
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• Once cells migrate to their final destination, they must make
connections with other cells
• How are these neural pathways formed?
• How do axons find their correct targets?
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The three phases of pathway formation
Visual system example.
How does a developing retinal ganglion cell axon
find its way to the correct location in the LGN?
1. Pathway selection
2. Target selection
3. Address selection
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The three phases of pathway formation
Visual system example.
How does a developing retinal ganglion cell axon
find its way to the correct location in the LGN?
1. Pathway selection
 The retinal ganglion cell axon has 3 choices:
• Enter the ipsilateral optic tract
• Enter the contralateral optic tract
• Enter the contralateral optic nerve
 If the RGC is in the nasal retina, its axon must
enter the contralateral optic tract
 If the RGC is in the temporal retina, its axon
must enter the ipsilateral optic tract
 The RGC axon will never enter the other optic
nerve
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The three phases of pathway formation
Visual system example.
How does a developing retinal ganglion cell axon
find its way to the correct location in the LGN?
1. Pathway selection
 The retinal ganglion cell axon has 3 choices:
• Enter the ipsilateral optic tract
• Enter the contralateral optic tract
• Enter the contralateral optic nerve
 If the RGC is in the nasal retina, its axon must
enter the contralateral optic tract
 If the RGC is in the temporal retina, its axon
must enter the ipsilateral optic tract
 The RGC axon will never enter the other optic
nerve
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The three phases of pathway formation
Visual system example.
How does a developing retinal ganglion cell axon
find its way to the correct location in the LGN?
2. Target selection
 Now that the RGC axon has made its way to
the thalamus, it has to decide which thalamic
nucleus to innervate (i.e., it must innervate
the LGN)
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The three phases of pathway formation
Visual system example.
How does a developing retinal ganglion cell axon
find its way to the correct location in the LGN?
3. Address selection
 Now that the axon has landed in the LGN, it
must innervate the correct LGN layer (and
coordinate with other developing axons to
establish the proper retinotopy)
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How do axons find their targets?
• Chemoaffinity hypothesis
-Chemical markers on growing axons are
matched with complementary chemical markers on
their targets to establish precise connections
-Axons are predetermined to find their targets
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How do axons find their targets?
• “Exuberant connection” hypothesis
-Axons at first connect to many targets (that is,
excess connections are made that are not retained)
-Axons are then pruned based on experience
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Two different hypotheses attempted to explain
how axons find their targets
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
Sperry surgically
rotated one of a
newt’s eyes so that
each retinal ganglion
cell looked at a
point in space that
was 180 degrees
different than the
point that it looked
at before surgery
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
He then severed
the optic nerve to
allow the retinal
ganglion cell axons
from the rotated
eye to re-grow into
the brain to form
connections with
their targets
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
After appropriate
time for
regeneration, he
used behavioral
experiments to test
what the newt saw
with its
manipulated eye
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
• If the chemoaffinity hypothesis is correct, then the projections should
grow to their original target, no matter how light shines on the retinal
ganglion cells, and the newt will see the world upside down.
• If the “exuberant connections” hypothesis is correct, then the
projections will find their targets based on experience, and the newt
will see the world correctly.
• Or, perhaps neither hypothesis is correct, and vision will be disrupted
in some way that was not predicted
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
Actual result: the newt
could see, but vision was
inverted in that eye
When new food was
provided at the surface of
the aquarium, the newt
would swim downward
instead of upward to fetch
it (the other eye was
removed prior to the
behavioral experiment, so
the newt was forced to
use the manipulated eye)
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Testing the chemoaffinity hypothesis:
Experiments by Roger Sperry (1943)
• The results of the experiment strongly suggested that retinal ganglion
cell axons carried specific information corresponding to their original
positions in the eye and use this information to find their targets in
the brain
• Even though the eye was inverted, the retinal ganglion cell axons still
found their original target locations in the brain
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How does the axon know where to make
connections?
Growth Cones
axon
c) One of the neurites becomes a
thin, rapidly growing axon
*The growing tip of a neurite has a
growth cone, which senses the
chemical environment and guide
the axon to make a connection
Growth Cones
Dan Felsenfeld, 1989
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