Biology 458: Developmental Neurobiology

Jan-Apr 2021

Learning Objectives: Wk 1
- Understand the sequence of events in neural development
- Understand the Major techniques we use to test which genes and
proteins may be used during an event in development
- Understand the model organisms that have revealed some of the
genes driving these mechanisms
- Begin to consider the concepts of balancing nature versus nurture
in neural development
 Biology 458: Developmental Neurobiology
Quick overview

Syllabus – all on Canvas, will be updated in a couple of weeks.

BIOL 458 – Developmental Neurobiology Winter 2019

Instructor: Dr Jane Roskams (roskams@zoology.ubc.ca)

TAs: Jesse Fox (jfox@can.ubc.ca), Shruti Kochhar (shruti31@student.ubc.ca),
Jennifer Kim (jenn_kim@outlook.com)

Textbook: Development of the Nervous System: Reh et al, 3rd edition (e-book).

We will explore how the nervous system arises from embryonic germ layers and
how it attains its adult form. The focus will be on the vertebrate nervous system
(e.g. mammals, frogs, fish, birds), and general principles and examples of
processes will also be drawn from invertebrates (e.g. fruit fly, nematode worm).
This course will also try to make you think, and
change your own brain in the process!
Brain “Development” - Mendel vs
Darwin vs Lamarck
The outcome of NEURAL
DEVELOPMENT – You!
 What Made Messi the best
soccer player in the world?

n A. His parents? (genetics? innate?)

n B Where he was born?
n C. When he was born?
n D. Where he migrated to? (FC
Barcelona?)
n E. What he ate (nutrition? Medical
help?)?
n F. How he was guided trained - by Yo Yo Ma
Messi
the people next to him?
(neighbors? Coaches?)
n G. The work he put in?
 Specification of Determination and Maintenance of
neural tissue proliferation of appropriate # of cells
specific neurons and (developmental cell
glia (cell fate) death)
Regional (pattern)
formation of nervous
system structures Neural cell Activity-dependent
differentiation to synaptic refinement
adult phenotype
Determination and
Plasticity and Learning
proliferation of neural
progenitor cells Local and distant
communication Neuronal and glial
(axonal growth & responses to adult
pathway formation) tissue damage (neural
Cell migration to
correct location cell repair)
within tissue Functional
(guidepost cells) connectivity Neural cell aging and
(synaptogenesis) CNS degeneration
 NEURAL DEVELOPMENT in
the embryo

Outline Part 1- Building

n 1. Induction of the Neural Plate
n 2. Neural Proliferation
n 3. Migration and Aggregation

n 4. Axon Growth and the Formation of

Synapses
n 5. Neural Death and Synapse Rearrangement

THEN: Where do we separate ourselves

from the other animals?
 Induction of the Neural
Plate - ectoderm
n During the development of the embryo, the
first observable step in the development of
the nervous system is the induction of the
neural plate
n About 3 weeks after conception, a patch of
ectoderm on the dorsal surface of the
embryo becomes distinguishable from the
rest of the ectoderm
n This patch is the neural plate, and it
eventually develops into the nervous system
Why is the neural plate/tube in the middle?
 Induction of the Neural
Plate
n Prior to induction of the neural plate, the cells
of the dorsal ectoderm are totipotential
n if they are transplanted to a new site in the
embryo, they develop in the same way as cells at
the new site
n these cells are called embryonic stem cells
n After neural plate induction, the cells lose
some of their totipotentiality
n They can develop into any kind of neural cell,
but not any other kind of cell. These cells are
said to be pluripotent neural stem cells
What is driving these changes? How do we test it?
Neural Proliferation
n After the neural tube is formed, the
developing nervous system cells rapidly
increase in number
n In the CNS, Cell division occurs in the
ventricular zone of the neural tube
(the zone next to the ventricle)
n Then they migrate into other layers
 Migration and Proliferation
n Cells migrate away from the ventricular zone along a
temporary network of radial glial cells, which are
present in only the developing neural tube
n The cells of the neocortex migrate in an inside-out
pattern
n The deepest layers form first so that the cells of the
superficial layers must migrate through them
n Migration of the cells of the neural crest is of
particular interest because these cells ultimately form
the PNS, and thus many have a long way to migrate

What is driving this? How do we test it?

PNS Migration and Aggregation

n Neural crest cells transplanted to a new part of the

neural crest migrate to the destination that is
appropriate for cells in the new location
n Thus, the migration routes must be encoded in the
medium through which they travel rather than in the
cells themselves
n Many different types of chemicals signals have been found that
guide the migration of future PNS neurons
n Once migration is complete, cells must aggregate
correctly to form various neural structures
n Align themselves with other neurons in the area to form the
structures of the nervous system

What is driving this? How do we test it?

 Axon Growth and the
Formation of Synapses
n Once the aggregation of developing neurons is complete,
axons and dendrites grow out from the neurons
n Growing to the correct target is particularly difficult for
axons that have a long way to grow
n Studies in which the same recognizable developing neuron
has been labeled in different subjects
n demonstrate that the axons of some particular neurons grow to the
same destination by the same route in every member of a species
n this accurate axon growth seems to be directed by a growth cone
at the growing axon tip

What is driving this? How do we test it?

Axon Growth and the
Formation of Synapses
n Three hypotheses have been proposed to
explain how growth cones make their way to
their correct destination:
n (1) the chemoaffinity hypothesis,
n (2) the blueprint hypothesis, and
n (3) the topographic-gradient hypothesis
n Axon growth is often studied in
regenerating neurons
n It is assumed that axonal growth and regrowth
are guided by the same mechanisms
 Chemoaffinity Hypothesis
n the hypothesis that the target of each growing axon
has a specific chemical that draws the axon to it

n Sperry’s eye-rotation regeneration experiments

remain the classic example of data supporting the
chemoaffinity hypothesis
 Blueprint hypothesis
n The undeveloped nervous system contains
physical and chemical trails that growth cones
follow to their correct destinations
n Only the first axon that grows into an area must have
the ability to reach its correct target
n The others appear to follow the pioneer growth
cone's route (fasciculation)
n if a pioneer axon growth cone is destroyed by a laser, few
of the other neurons in the nerve reach their correct
destinations.
 Topographic-Gradient
Hypothesis
n Axon growth from one topographic array to another
(i.e., retina to optic tectum) is guided by the relative
position of the cell bodies and terminals
n In other words the terminal ends of the axons line
themselves on the structure that they are going
to, in the same way the cell bodies are arranged
on the structure they originated from

n Neuronal connections are arranged topographically

such that the spatial organization of neurons is
preserved by their terminals in the targets.
 Summary:
n Evidence on axon growth and
regeneration suggests that a variety of
mechanisms can guide axon growth and
regeneration
n All three of the hypotheses we have
discussed may be in operation
n Where does nature vs. nurture
come in?
Brain Connectivity – How Complex?

How many synaptic connections does a

typical multipolar neuron in your brain
make?
A. 25
B. 50
C. 500
D. 1,000
E. 10,000
 What does Multi Mean ??

Multipolar neurons usually have...

A. Multiple axons and multiple dendrites
B. Multiple dendrites and a single axon
C. Multiple axons and a single dendrite
D. Multiple soma (cell bodies)
E. Not sure... Perhaps my neurons are not
multipolar enough?
 Neuron Death and
Synapse Rearrangement
n Dogma: Up to 50% of neurons that
develop die during the course of normal
development
n Neurons that make incorrect connections
are more likely to die
n Suggests that cell death increases the overall
accuracy of synaptic connections (selective
pruning)
 Neuron Death and
Synapse Rearrangement
n Evidence suggests neurons die because they fail to
compete successfully for some life-preserving factor
supplied by their target:
e.g. Neurotrophins such as nerve growth factor

n Most of this cell death is due to apoptosis

n Preprogrammed (active) cell death is better than passive
cell death (necrosis)

n In addition, there is synapse rearrangement

n its effect is to focus the output of each neuron on fewer
postsynaptic neurons
What is driving this? How do we test it?
 Rest of the Course?
Outline - Part 2 - Using and Sculpting the NS
n 1.What do Glia Do?
n 2. How do Synapses change as we learn?

n 3. What else influences learning?

n 4. What underlies “plasticity?”

n 5. When does the brain STOP developing?

All of these things are driven by molecules,

pathways, cell-cell interaction and stimulation
(activity). First, we must learn how to test
mechanisms at play!
What animal models have been used to study neural development
(what are some advantages or disadvantages – 2 of each ) ?

1. Nematode (worm)
2. Fruit Fly
3. Chicken
4. Frog
5. Mouse
6. Zebrafish
7. Yeast