Developmental and Systems Neurobiology
Spring 2002
Lecture 2
How do nervous systems come to be? In this lecture we will examine the
developmental events that give rise to the brain and spinal cord and the
molecular signaling pathways that are used to establish the identity of different
kinds of neurons.
As is the case for all dells generated during development, the nervous system
arises from intrinsic programs within cells, dictated by inheritance from maternal
cytoplasm, and influences from neighboring cells. During development cells and
their processes migrate and so are subject to changing influences from new
neighbors.
The nervous system is formed from an interaction between two types of tissues:
mesoderm and ectoderm. These, in turn, are formed during a characteristic
series of cell movements that most vertebrate embryos undergo: gastrulation.
Let’s review early development through gastrulation. using development of the
frog, Xenopus laevis, as an easily understood example.
The egg is divided into two regions, the animal and vegetal poles that are easily
recognized by pigments. These regions contain different proteins and
messenger RNAs deposited by the mother and localized within the egg
cytoplasm by identifying molecular tags that permit transport to particular regions
by intrinsic motors (not that different from the problem of anterograde and
retrograde transport discussed in this week’s recitation).
How do we know this? Doug Melton at Harvard, for example, separated the
animal and vegetal poles and isolated different pools of mRNAs in each. These
can be size fractionated, copied into DNA for stability (cDNA) and sequenced.
Some of these messages turn out to be important for cell fates.
The animal pole defines the future dorsal region of the embryo and the vegetal
pole the future ventral region. When the sperm enters the egg it sets up the
future anterior posterior axis of the embryo. After fertilization, the core cytoplasm
of the egg rotates relative to the external cytoplasm. The sperm entry point will
be posterior and the point opposite it (recognizable by a change in color due to
rotation called the grey crescent)>
September 14, 1999 Neurobiology II W3005y Darcy B. Kelley
Lecture 3: The Formation of the Nervous System
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I. Morphogenesis of different regions of the central nervous system.
A, All regions of the CNS originate from the neural tube.
B. The amount of cell proliferation (and death) and the programs of cell migration
are different at different levels of the A/P axis leading to differences in size and
shape (both within one species and across species).
C. Development of the mammalian brain.
1. The eye (neural retina) is an outpouching of the neural tube.
2. Cell death shapes the optic stalk.
3. The telencephalon undergoes marked cell proliferation and migration.
II. An overview of neural development
A. The nervous system originates from the neural epithelium, a flattened sheet of
cells on the dorsal surface of the early embryo.
B. The neural epithelium thickens to form the neural plate and the plate then rolls
up to form the neural tube.
C. Within the neural tube, cells proliferate (and die), migrate, extend (and retract)
processes and differentiate, forming (and breaking) synaptic connections.
D. Different patterns of proliferation and migration characterize different
anterior/posterior locations in the developing nervous system.
III. How does the neural epithelium form in the first place?
"It is not birth, marriage or death, but gastrulation, which is truly the most
important time in your life." Lewis Wolpert, in Slack, From Egg to Embryo, 1983.
A. Gastrulation is important because it establishes three main types of cells in the
embryo: ectoderm, mesoderm and endoderm.
B. The nervous system arises, for the most part, due to an interaction between
mesoderm and ectoderm (neural induction) that changes ectoderm into
neurectoderm, the progenitor of the neural tube and of neural crest.
C. The mesoderm is patterned (contains positional information) and that pattern
is transmitted to the neurectoderm through vertical and planar signals.
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HOW DO WE KNOW THIS? The Spemann/Mangold experiments
A. Hilde Mangold transplanted the dorsal lip of the blastopore from a pigmented
salamander (donor) to an unpigmented (host).
B. Two embryos ("Siamese" joined at the ventral midline) form from one host and
contain a duplicated neuraxis.
C. Mangold and Spemann originally distinguished donor from host by the
presence of absence of pigment; the same experiment has been repeated using
dye injected donor cells with the same result.
D. Spemann concluded from this experiment that the dorsal lip of the blastopore
is an "organizer" for neural development.
E. Exogastrulae and what they tell us.
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IV. How does the rest of the nervous system form?
A. There are three sources of neurons: neural tube, neural crest and placodes.
B. Placodes are thickened areas of epithelium some of whose cells become
neurons.
• Olfactory neurons derive from the olfactory pit or placode.
• The hair cells of the inner ear derive from the otic placode.
C. Neural crest is a multipotent stem cell population that derives from the lateral
margins of the neural plate.
1. Neural crest is migratory and different patterns of migration are associated
with different cell fates.
• Neural crest cells migrating under the epidermis form melanocytes (pigment
cells), and cartilages of the head (among other cell types).
• Neural crest cells migrating between the developing somites (embryonic
structures that give rise to muscle, dermis and cartilage) and the notochord (a
rod-like midline embryonic structure) give rise to neurons: part of the dorsal root
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ganglia and autonomic neurons as well as neurosecretory cells of the adrenal
gland.
• Some neural crest cells migrate into the gut where they form a separate
nervous system, the enteric nervous system.
V. Cell type specification in the nervous system
A. Neuron or g;lial cell?
B. Positional information and cell fate: dorsal vs. ventral; anterior versus posterior
VI. How do cells proliferate? The neural tube, a case study.
A. Cells in the neural tube for a pseudostratified epithelium. It looks like there are
many layers of cells but actually cell nuclei are simply at different deep
(ventricular)/superficial (pial) positions.
B. Cells whose nuclei are closest to the pial surface are in S-phase and are
duplicating their DNA.
C. The nuclei then drop to the ventricular surface, the cell divides and the cycle
can start again.
D. At some point a neural precursor cell in the neural tube will withdraw from the
cell cycle; that point in time is called the cell birthday of the neuron.
E. The newly formed neuron can break its attachment to the ventricular surface
and migrate away.
F. Cell proliferation, process extension and migration account for the thickening
of the neural tube.
G. Different patterns of cell migration characterize different parts of the central
nervous system.
1. In the spinal cord, neurons move on out as they are born.
2. In the cortex, newly born neurons migrate past older neurons.
3. In the cerebellum, the oldest cells stay put next to the ventricle. Some neural
precursor cells migrate to the pial surface where they give rise to neurons. The
newest neurons formed at the pial surface (a secondary germinal epithelium)
migrate towards the ventricle.
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HOW DO WE KNOW THIS? Using tritiated thymidine to trace neuronal birthdays
and patterns of migration.
1. Thymidine is incorporated into DNA during S-phase.
2. If a cell produces a terminally differentiated daughter at its next division, that
cell will retain 1/2 of the tritiated thymidine incorporated into the mother cell,
forever.
3. If the cell continues to divide, the radioactivity will be diluted. At some point it
will no longer be detectable.
4. How Pasko Rakic mapped the birthdays and migration patterns of cells in the
rhesus monkey cortex.
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Glossary
exogastrula- an embryo that has been placed in a hypertonic solution during
gastrulation. Cells fail to enter at the blastopore (invaginate) but instead move out
(evaginate) and form a sac-like structure.
urodele- salamanders, for example.
patterning- establishing the AP (also DV and ML) axes.
epidermis- a superficial layer of the skin derived from ectoderm.
planar signals- signals that "run around" the dorsal lip of the blastopore.
vertical signals- signals from the underlying mesoderm to the ectoderm.
morphogenesis- formation of something that looks like a NS or a neuron.
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