Neuro: 9:00 - 10:00
Thursday, January 8, 2009
Dr. Theibert
Development of the Nervous System
PNS – Peripheral Nervous System, CNS – Central Nervous System
Scribe: Brittney Wise
Proof: Laura Adams
Page 1 of 7
I. Introduction [S1]: This transcript goes along with the updated power point that is 43 slides
II. Development of the Nervous System occurs during both Prenatal and Postnatal periods [S2]
a. In humans, development of the nervous system begins early after fertilization and takes place both pre-natally
and post-natally.
b. Prenatally:
i. When gross sections of the brain are formed, so major regions of the CNS and PNS are formed.
ii. Majority of neuronal population is generated before birth but the brain is relatively small (350-400 grams)
iii. During this stage of development the brain is mostly controlled by intrinsic factors ( ex// genetic factors)
1. Not a lot of plasticity or experience that takes place prenatally
c. Post-natally:
i. A few neuronal populations are generated
ii. The majority of the glial cells, things like astrocytes and oligodendrocytes and microglia are actually formed
after birth
d. There’s a large increase in the volume and the mass of the brain; it triples between pre-natal and post-natal
development.
i. This is caused by a number of different activities including increases in dendritic branching or dendritic
arborization, the formation of synapses between neurons (between axons and dendrites) so
synaptogenesis, and then myelination of the axons by the oligodendrocytes.
ii. The adult brain is between 1200 and 1400 grams; there is a large increase in mass and metabolic activity
e. Post-natally, experience is affecting the development of the brain because the brain is very plastic right after
birth; this is when activity, synaptic transmission, can modulate the function and activity of different dendritic
spines and synapses.
III. Stages of Development of the Nervous System [S3]
a. There are 7 main stages of development of the nervous system beginning with fertilization:
i. First stage is the formation of the gastrula, so the initial embryonic development leads to gastrulation when
the germ layers are formed. This occurs really early in humans (before 2 weeks).
ii. This is followed by the process of neurulation in which the primordial nervous system is established and
this also occurs early (by 5 weeks in humans)
iii. After the neural tube is formed there is a significant proliferation of the neuronal glial precursor cells; this
occurs during a very extended period between about 5 weeks and 6 months; this doesn’t mean that for an
individual neuronal population it takes this long but that different neuronal populations are being generated
at different times during this period
iv. Once the neurons are generated they have to migrate to their final destination and many neurons
aggregate to form nuclei
1. This occurs after the cells have generated by mitosis, and again occurs over an extended period.
v. During migration the cells begin to differentiate into the individual neuronal phenotypes that they will
eventually become. They also put out their processes (axons and dendrites) and begin to form synapses.
1. This usually occurs about 4-5 months pre-natally, but then this period of differentiation occurs
extensively after birth.
vi. Once the axons and synapses have been formed, they can connect and form synapses, so synaptogenesis
occurs forming connections between the neurons, about 25 weeks and it continues into the adult
vii. Then there is refinement of synaptic pathways that occurs post-natally, this is very important. Some of the
neurons that are not properly connected can undergo apoptosis (this usually occurs post-natally)
IV. Initial Embryonic Development [S4]
a. During the earliest stage of embryonic development (after fertilization) the fertilized egg undergoes a series of
cell divisions and it forms the blastocyst. They blastocyst undergoes implantation and forms the embryonic disc.
In human development, this results in the formation of an inner cell mass, which is just a group of cells which
undergo morphological movements, and these cells will actually delaminate to form 2 different types of cells;
these are the epiblast and the hypoblast:
i. epiblast is the structure which is going to give rise to the embryo proper
ii. hypoblast will form the yolk sac
b. At this stage the epiblast is 2 layers and it’s just a disc of cells and these cells will undergo migrational
movements during gastrulation to form the embryo.
c. The trophectoderm are the cells that are lining the rest of the structure here, will end up forming the placenta.
V. Gastrulation involves cell migration [S5]
a. This involves the conversion of the epiblast, into the 3 primary germ layers. These cells actually crawl along the
surface of the disc and actually crawl inside, so the cells are actually undergoing migration.
Neuro: 9:00 - 10:00
Scribe: Brittney Wise
Thursday, January 8, 2009
Proof: Laura Adams
Dr. Theibert
Development of the Nervous System
Page 2 of 7
b. Initially they pile up at the primitive streak and then they crawl inside, underneath the overlying cells.
c. The primitive streak is a groove in the dorsal midline of the ectoderm and will eventually become the neural
groove as the cells crawl in.
d. This cell migration that allows for the formation of the individual germ layers.
VI. Gastrulation forms 3 primary germ layers [S6]
Endoderm
Cells that migrate 1st inside the embryo; forms the inner linings of both the digestive and respiratory
systems; they will also generate endocrine glands like the liver and the pancreas
Mesoderm
Cells that move in later; will end up lying on top of the endoderm; gives rise to muscle, the circulatory
system, bones/cartilage, epithelial cells of the internal organs, and the excretory system as well as the
gonads.
Ectoderm
Cells that remain on top and don’t crawl inside; give rise to the CNS and PNS as well as the epidermis
including the skin, nails, and the hair
VII. Formation of neural plate and notochord [S7]
a. After the formation of the primary germ layers you’ve got this trilaminate disc of cells with the 3 layers;
endoderm on bottom, mesoderm in the middle, and ectoderm on the top
i. ectoderm is the part that will give rise to the nervous system
ii. only part of the ectoderm will give rise to the CNS and PNS, and that’s the medial ectoderm
iii. the surrounding ectoderm will give rise to the skin.
b. On the dorsal side of the neural plate, is a structure that will give rise to all of the population of neurons, and
these cells will eventually become the progenitor cells that give rise to both the neurons and the glia.
c. At this stage of development (about 18 days in humans) you have the formation of what’s called the neural
plate.
i. This is not a homogeneous structure, the cells are already being distinguished, depending on what kind of
signaling molecules they have received, and it’s also not morphologically homogeneous.
ii. You can see that the neural plate is broad in the part of the region that’s going to become the head,
including the brain, and is much narrower in the region that’s going to eventually become the spinal cord.
d. After the formation of the neural plate, there is the formation of the notochord.
i. The notochord is a tissue that’s derived from the mesoderm that pinches up and it ends up underlying the
neural plate; the notochord specifies which part of the ectoderm will form nervous tissue or not.
VIII. Neural Induction (in Vertebrates) [S8]
a. There are specific signals from the mesoderm that specify to the overlying ectoderm to become the neural plate.
i. In mammals, the notochord is a transient structure (you can’t see it in the adult), but it’s critical in secreting
specific factors that will then determine that the neural plate will become nervous tissue.
b. What are these factors? We don’t exactly know what they are in humans, but genetic studies in amphibians and
in birds have actually given us an idea about what these signals might be.
c. Throughout the embryo there are a series of secreted proteins which are members of the BMP (Bone
Morphogenetic Protein) family of signaling molecules.
i. These proteins are called TGF. They were originally identified in cancer cells, so the T stands for
transforming growth factors.
ii. The TGF family of peptide growth factors are expressed throughout the embryo and there are receptors
for these proteins which are also expressed throughout the embryo.
iii. The TGFfamily of proteins are receptor kinases, they are serine-threonine kinases, and the way they is by
phosphorylating and activating the Smad proteins, which are transcription factors.
d. When the Smads are phosphorylated they can then move into the nucleus and induce transcription.
e. We know that there is TGFand BMP signaling throughout the embryo.
f. When the BMP signaling is activated, it inhibits the neuronal cell fate. So BMP is a specific inhibitor of cells
actually becoming neurons. It turns out that the inducers in the amphibian, also known as the “organizer” that
we think is something like the notochord in mammalian cells, releases factors which antagonize the BMP
signaling.
g. So they are inhibitors of BMP signaling and you have to block BMP signaling in order to induce the neural fate.
h. In frogs and chickens these secreted factors have been identified and are called noggin/chordin/follistatin.
i. What they do is block the TGFsignaling by either binding and acting as antagonist at the receptor, or they
bind to the ligand and tie them up.
i. In order to become/adopt the neural fate you have to inhibition of BMP signaling.
j. This suggests that the neural fate is really the default pathway and what happens in the rest of the embryo is
that you block the neural pathway and in order to get the neural pathway, you have to release that block or
release BMP inhibitors.
IX. Neurulation [S9]
a. After induction is neurulation: this is the process by which the neural tube is formed
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Thursday, January 8, 2009
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Dr. Theibert
Development of the Nervous System
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i. Neural tube will give rise to all of the neurons and glial cells in the CNS
ii. The region of cells that are right around the neural tube as it is folding together is going to give rise to most
of the neurons and glial cells in the PNS. These arise from a structure called the neural crest.
b. During primary neurulation, there is actually a constriction and bending of the cells within the neural plate and
there are a couple of places where these bends take place.
i. These cells undergo very dramatic shape changes and they buckle inwards which allows for the cells in the
midline, in the neural groove region, to move down.
ii. This elevates the neural folds above it.
c. The margins of the neural folds are going to give rise to the neural crest cells, which are also a transient
structure that will give rise to the neurons and glial cells of the PNS.
d. [S10] Neurulation begins around day 18 or 19 in the human and the way that this begins is through the
formation of the neural groove at the midline of the neural plate. This continues to buckle inward, until about the
4th week of development.
e. [S11] These shape changes in the neural plate allow for the cells to come together at the tops of the neural
folds and these shape changes allow for specific cell-cell interaction to occur. It turns out, that the interaction
between the cells when they come together at the margins of the neural fold, are mediated by specific cell
adhesion molecules.
i. So, precursors to neurons express a specific type of cell adhesion molecule called N-CAM (or neural cell
adhesion molecule).
ii. They also express another type which is called N-cadherin.
iii. It’s the specific interaction between the N-cadherin and N-CAM’s, which will allow for the neural tube to
come together and form.
f. On the overlying ectoderm (the cells that are not going to become part of the neural tube) a different kind of cell
adhesion molecule called E-cadherin and different types of CAM’s are expressed. This allows the overlying
ectoderm cells to come together.
g. After neurulation the neural tube will pinch off from the surrounding ectoderm and it separates from this nonneural tissue, which will become the epidermis.
X. Primary Neurulation [S12]
a. Neurulation has 2 different stages: there is Primary and Secondary neurulation. During Primary Neurulation, the
neural folds begin to come together and fuse, and they fuse in the middle of the embryo 1 st at about the level of
the 4th somite. This is interesting because the neurulation process begins in the middle of the embryo and then
it takes places both rostrally and caudally during development.
b. The neural tubes will then fuse at different times along their length. Once they have begun to fuse they will
leave 2 openings/holes at each end called neural pores.
i. These neural pores will eventually close. The anterior (also called the rostral neural pore) will close about
day 23 or 24.
ii. The caudal neural pores will close a few days later, after the embryo has begun to undergo some other
morphological changes in its curving.
iii. The improper closure of these neural pores will lead to neural tube defects which can be mild or quite
severe depending on the extent of the opening. This can lead to significant problems for children.
XI. Secondary Neurulation [S13]
a. We don’t know much about secondary neurulation, but it occurs at the caudal most end of the neural tube.
b. This part of the neural tube doesn’t derive from the neural ectoderm, but actually comes from the primitive
streak region called the mesodermal caudal eminence.
c. This tissue will sink down or cavitate and will eventually join the posterior neuropore after the posterior
neuropore has begun to form. It eventually will become the very base of the spinal cord and will become
continuous with the neural tube.
XII. What are Neural Tube Defects? [S14]
a. The most common neurological malformation in humans.
b. Occurrence from about 1-2 per 1,000 live births.
c. Can be very serious birth defects, because the spinal cord or the brain and the projecting coverings of these
organs can be exposed to the outer environment. Depending on which neuropore is not closing or which one
has errors, will determine what kind of neural tube defect there is.
d. If the anterior neural plate does not close, it will lead to a condition known as anencephaly. This is usually very
devastating, and most babies are usually stillborn if they have this condition or will only survive for a few days.
e. Spina Bifida is a result of the failure of the posterior neural tube to fuse and to close properly. This is the most
common congenital neurological tube defect.
i. We know that the supplement of folic acid during pre-natal care significantly reduces the incidence of
Spina Bifida about %75. We don’t understand the mechanism of this but it’s thought that the
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Scribe: Brittney Wise
Thursday, January 8, 2009
Proof: Laura Adams
Dr. Theibert
Development of the Nervous System
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developmental defect here involves cell adhesion molecules or transcription factors and that somehow the
folic acid is able to help override the defects in their expression.
XIII. Segmentation of the Neural Tube [S15]
a. The neural tube is now formed and will undergo segmentation. This provides the initial structural segmentation
which is going to give rise to the primordial of the brain and the distinction between the brain and the spinal
cord. The initial constrictions take place in these regions here and give rise to the first 3 vesicles during
development: the forebrain, midbrain, and hindbrain.
b. These are called vesicles; these are macro-vesicles, not to be confused with things like micro-vesicles involved
in trafficking of proteins and synaptic vesicles. These are very large structures.
i. Forebrain – prosencephalon
ii. Midbrain – mesencephalon
iii. Hindbrain – rhombencephalon
c. The neural tube is a single cell layer that has specific cell-cell contacts and interactions (tight junctions and
adhesion junctions) and so the cells are differentially adhesive to sticking to each other and there are specific
tight junctions that take place at these regions.
d. There is a transient block between the neural tube and the presumptive spinal cord. The neural tube is filled
with fluid, but there is an increase in the volume of the fluid and this leads to an increase in fluid pressure and
depending on how tightly the cells are connected to each other in these tight junctions will then allow for the
ballooning out of specific regions within the neural tube.
XIV.
4th Week – Segmentation of the Neural Tube [S16]
a. As the neural tube is undergoing this segmentation is also bends. So you have a neural tube, which is on the
dorsal part of the embryo here, that is going to undergo 2 bends which are called flexures:
Cephalic flexure allows the forebrain to actually swing underneath where the hindbrain is
Cervical flexure
same direction as cephalic; will eventually form the distinction b/t the hindbrain and the spinal cord
XV. Segmentation of Neural Tube [S17]
a. After the initial segmentation and while the embryo is undergoing these flexures and bends, there is a second
segmentation process which will allow for the production of 5 secondary vesicles.
b. The prosencephalon will become subdivided into the telencephalon and the diencephalon.
c. The mesencephalon doesn’t really change.
d. The rhombencephalon will become subdivided into the metencephalon and the myelencephalon.
e. This occurs at about 5 weeks in human development.
XVI.
Added slide (chart showing (c) secondary brain vesicles and (d) adult brain structures ) [S18]
a. The telencephalon will generate the cerebrum which includes the cerebral hemispheres, the cerebral cortex,
including all of the white mater as well as the basal nuclei.
b. The diencephalon gives rise to the thalamus, hypothalamus, and epithalamus.
c. The mesencephalon, metencephalon, and myelencephalon will all give rise to different parts of the brain stem.
i. Mesencephalon will give rise to the midbrain
ii. Metencephalon will give rise to the pons
iii. Myelencephalon will give rise to the medulla
d. It’s through these 5 vesicles, that the production of the major structural regions of the brain is formed.
XVII. 8 Weeks [S19] There are further subdivisions in the morphological changes at about 8 weeks. She just wanted
to point out at this stage, the neural tube is still only one cell thick and is called a neuro-epithelium. It’s a germinal
neuro-epithelium because it will give rise to all of the different neural populations and glial populations within the CNS.
XVIII. Cavities within the tube form ventricles [S20]
a. In addition to forming the major structures of the brain, cerebral cortex, and cerebellum, and all of those regions,
these 5 vesicles also distinguish the ventricles, which will eventually form.
b. So it’s the cavities and the single cell layer in this drawing (which is a tube like cross section filled with fluid), all
of which will give rise to the major ventricles.
XIX.
Added slide (chart showing (c) secondary brain vesicles and (e) adult neural canal regions) [S21]
a. The cavity that is generated by the telencephalon will give rise to the lateral ventricles.
b. The cavity that is generated by the diencephalon will give rise to the 3 rd ventricles.
c. The cerebral aqueduct arises from the cavity in the mesencephalon.
d. The 4th ventricle will arise from the cavities in the metencephalon and myelencephalon.
e. Remember that the spinal cord, which is posterior to this region, also has a central cavity as well which is
derived from the neural tube.
XX. Added another picture of 2 brains [S22]
a. This figure of the adult brain will give you a little anatomical coordinates so you can see all of the ventricular
system. Understanding how these ventricles are derived during development actually helps you remember
them easier.
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Thursday, January 8, 2009
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Dr. Theibert
Development of the Nervous System
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XXI.
Patterning along the rostral-caudal axis [S23]
a. Along the axis of the neural tube, these different vesicles are giving rise to different parts of the brain and we
know that neurons in the cerebral cortex are very different from neurons in the cerebellum.
b. One of the ways that these neurons are differentiated is through the selective expression of different
transcription factors and one of the best characterized transcription factor families that regulate transcription and
eventually the specific differentiation of neurons, are a family of proteins called the HOX genes.
c. HOX derives its name from homeobox domain containing gene, or also called homeotic genes, originally
identified in vertebrates like drosophilia development.
i. HOX genes are expressed along the rostral-caudal axis of the neural tube and are selectively expressed.
ii. It’s thought that this selective and sequential expression of these transcription factors that is then going to
determine the fate of the individual neurons that are expressing them.
iii. Transcription factors are proteins which bind to specific regions within the promoter region of the DNA and
affect differential gene expression or differential gene transcription. The reason that a cortical neuron is
different than a cerebellar neuron is really due to the different kinds of voltage gated ion channels and cell
adhesion molecules and synaptic transmitter molecules that it synthesizes. These are determined by the
expression of certain transcription factors.
XXII. Neural tube also patterned along its D/V axis [S24]
a. In addition to being patterned around the rostral-caudal axis, the neural tube is also patterned along its
dorsal/ventral axis.
b. This type of patterning is generated by 2 different structures.
c. We heard about the notochord, and what the notochord does is to produce a specific type of secreted
extracellular factor which is called Sonic Hedgehog. Sonic Hedgehog was originally identified in drosophila
development (flies have abnormal bristle formation which makes them look like hedgehogs) and it turns out that
there are vertebrate and human homolog’s of Sonic Hedgehog.
i. Sonic Hedgehog’s induction is initially expressed in the floor plate of the neural tube and it will actually
stimulate additional Sonic Hedgehog expression and there is a gradient of Sonic Hedgehog expression
from the region of the floor plate up to the dorsal region.
ii. Again, it’s thought that it is the specific activation of gene expression, through signaling molecules like
Sonic Hedgehog, that are going to determine the individual types of neurons that will differentiate in this
region of the spinal cord, whether a neuron will become an interneuron and be synapsed with sensory
neurons or become a motor neuron.
XXIII. Errors in Development [S25] Additional errors in early development have been attributed to a disruption of Sonic
Hedgehog signaling.
a. One of these is quite a rare defect called Holoprosencephaly, where the lobes of the brain do not separate from
each other and can actually be a devastating congenital defect.
b. Some holoprosencephaly can be caused by mutations in the Sonic Hedgehog gene, others have been shown to
be caused by fetal alcohol syndrome, and the causes of others are unknown.
c. In addition to neural tube defects there can be substantial errors at this stage of development which are caused
by defects in signaling molecules.
XXIV. Separation of Sensory and Motor Neurons in Spinal Cord and Brain Stem [S26]
a. This type of dorsal-ventral patterning is also reflected as I mentioned in the types of neurons that are produced
in the spinal cord.
b. In the spinal cord, in the dorsal-ventral axis, the neural tube in the spinal cord region is divided into 2 left and
right alar plates (so the alar plates are in the dorsal region) and 2 basal plates. These 2 plates are joined in the
midline at the roof plate and the floor plate.
c. Different kinds of neurons, ex// sensory neurons will synapse on interneurons in the alar plate, whereas motor
neurons are present in the basal plate.
XXV. Picture (diagram showing 6 pictures a-f) [S27]
a. After the neural tube is formed, it’s just a single cell thick, but it has already undergone these morphological
changes. After the tube has formed you have the processes of neurogenesis and glial-genesis (sp?) which is
going to allow for the expansion of these neural epithelial cells into a billion or so neurons.
b. After these neurons have been generated they have to migrate their target region within the brain and then they
have to differentiate into the specific types of neurons and glial cells.
i. After they have differentiated, they will put out axons and dendrites, which will allow for the synapses to
form between these 2 processes.
c. There are more neurons made than are needed so there is a period of cell death or apoptosis that will occur.
And after birth there is pruning of these synapses, which is dependent on experience, or synaptic refinement.
XXVI. Proliferation/Neurogenesis [S28]
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Dr. Theibert
Development of the Nervous System
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a. Proliferation is the stage at which all the neurons and glial cells are born. After the neural tube is closed it forms
these neural epithelial cells, and these cells are going to undergo mitogenesis (sp?) and cell proliferation.
During this period there are 2 different types of cell cleavage that can take place:
i. Vertical cleavage – generates 2 identical daughter cells which will be able to go on and form additional
cells, so they stay as precursor cells and form additional stem cells
ii. Horizontal cleavage – occur in some cells at later stages of development; one cell after the split will migrate
away and one cell will stay and form a stem cell; this is the type of cleavage that allows cells to migrate
away from the neural epithelium
b. [S29] During the proliferation, there are specific zones that are generated.
c. The ventricular zone is the region where the progenitor cells will be dividing. They start dividing symmetrically
about day 28.
d. After this, some of the cells will undergo this asymmetric cell division and the Neurogenesis starts. During this
tremendous production, or mitogenic phase, of the neurons there can be a high rate of neurons produced, about
250,000 per minute.
XXVII. Adult Neurogenesis in Humans [S30] Takes place in embryonic development and takes place in adults as well;
so new neurons can be developed in the adult CNS system.
a. These are generated by progenitor cells that exist in the sub-ventricular layer, which is close to the ventricular
layer lining the ventricles. In particular, there are 2 types of neurons:
i. Hippocampal neurons (dentate gyrus neurons in the hippocampus)
ii. Olfactory neurons can be generated by the olfactory bulb
XXVIII. Migration in CNS [S31]
a. The cells have undergone their last division, their asymmetric division, and then once they are produced they
will migrate out and aggregate with other neurons to form specific neuronal layers within the cerebral cortex or
specific nuclei in other parts of the brain.
b. The migrating cells have stopped proliferating and many of these neurons will use specific guidance cells called
radial glial cells in order to make their movement from the ventricular zone out to their final destination
XXIX. Development of Layers of Cerebral Cortex [S32] Very well characterized
a. This development takes place in a very interesting pattern: an inside-out pattern
i. cells are being generated in the ventricular zone and then they migrate out towards the surface
b. The cells that are born first end up migrating into layers, ex// layer 6, these cells that are formed later will crawl
past these other cells to form the more superficial layers of the cerebral cortex
c. Neurons that are formed first (the oldest neurons) will form the deepest layer of the cortex
d. Neurons that are formed last will form the most superficial layer of the cortex
e. Most brain regions, more neurons are generated from the precursor cells than are need, so a lot of these cells
will compete for different trophic factors and secreted molecules and if they don’t receive signaling from these
molecules they will end up undergoing apoptosis; anywhere from 10-50% of neurons that are born during this
stage actually end up not making into the adult nervous system
XXX. Signaling Molecules [S33]
a. Many signaling molecules have been identified that mediate this migration process.
b. A protein called reelin (an extracellular matrix molecule) and 2 of its receptors, the LDL receptor and the ApoE
receptor (which you know from cholesterol regulation),are also expressed in developing neurons and they have
to bind to the reelin protein in order to mediate this proper development.
c. There is also a protein called megalin, and mice which are deficient in megalin show improper development,
similar to the Sonic Hedgehog developmental development and produces holoprosencephaly.
XXXI. Disorders of brain growth and migration [S34] There are number of extremely rare disorders associated with
brain proliferation and migration that have been identified:
a. Lissencephaly – also called “smooth brain”; there is a developmental defect in the migration of the neurons and
the brain does not end up developing the proper gyri or sulci so the brain look smooth
b. Microcephaly – thought to be a developmental defect in which the neurons proliferate or grow properly
c. Cortical heterotopias – displacement of normal brain structures, ex// grey matter is displaced into white matter
d. Encephalocele – caused by a hole in the skull and the brain herniates through the skull
XXXII. PNS Development [S35]
a. The PNS is composed of the somatic division (the primary motor and sensory neurons of the body) and the
autonomic division (composed of the sympathetic, parasympathetic, and enteric neurons).
b. Primary motor neurons are considered to be part of both the CNS and the PNS
i. The cell bodies of the motor neurons lie within the spinal cord and they are definitely generated as part of
the CNS but they extend axons out of the spinal cord which innervate muscles and glands.
c. Neural crest cells give rise to all the sensory neurons & the sympathetic, parasympathetic & enteric neurons.
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Dr. Theibert
Development of the Nervous System
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d. The other neurons in the PNS, the sensory epithelia in the nose, the ear, the lens, and the pituitary gland are
formed from regions that are outside of the neural plate called placodes.
XXXIII. PNS Development – slide #2 on this topic[S36]
a. During the formation of the neural tube, the region of the roof plate where these neurons have come together
ends up forming a population of cells which are called the neural crest cells.
b. Neural crest cells migrate away from the roof plate region and eventually become specific peripheral neurons.
c. As they are migrating away they start out as pluripotent cells but then they eventually differentiate into specific
neurons and glial cells.
d. They will form sensory neurons, the dorsal root ganglia, some cranial nerves, and some nerves of the
autonomic nervous system, Schwann cells (myelinating cells of the PNS), as well as pigment synthesizing cells
(melanocytes), and adrenal chromaffin cells.
e. So it generates in the PNS from the neural crest, it proliferates the sensory and sympathetic neurons as well as
neurons of the adrenal gland and the pigment generating cells of the skin.
XXXIV. Peripheral Nervous System Migration [S37]
a. Cell adhesion molecules are also involved in the differentiation and guidance of the neural crest cells to their
final destinations.
b. Extracellular matrix molecules, like laminin and fibronectin, which bind to cell surface receptors also allow for
these neurons to be specifically guided as they undergo their migration process to their final destinations.
XXXV. Differentiation/Determination [S38]
a. This involves both intrinsic and extrinsic cues:
i. Intrinsic cues – include things like transcriptional regulator, transcription factors; as the cells are migrating
to their final destination and once they have gotten to their final residence they can be regulated by specific
diffusible molecules, signals on the membranes, extracellular matrix proteins, and diffusible factors.
b. It’s the combination of these 2 determinants, what it has received and how it’s been activated transcriptionally
during development as well as the extracellular molecules that it encounters that’s going to determine the cell
fate and neuronal fate.
XXXVI. Target Selection [S39]
a. Once the neurons have been generated and are migrating out the neurons extend axons and a lot of chemicals
a lot of specific small molecules and proteins that have been identified that are required for axon guidance.
b. She wants us to know that there are different kinds of guidance cues that can both activate and inhibit specific
axonal outgrowth and guidance.
c. There are diffusible molecules that allow for the chemoattraction of axons or the chemorepulsion and it’s
combinations of both of these that will direct the axon at different periods to its final destination.
d. In addition there are cell surface molecules which the axon will encounter as it’s crawling along other cells which
will allow for attraction and repulsion for axons to reach their final destination and form the proper synapses.
XXXVII. Targeting/Synaptogenesis [S40]
a. The final stages are synaptogenesis and the refinement of synaptogenesis.
i. Synaptogenesis is the formation of the contact between an axon and its target cell.
ii. Its target cell can either be a muscle, a gland, or another neuron.
iii. If it contacts another neuron, there are different kinds of synapses. We normally think of an axon that
synapses on a dendrite but synapses can occur b/t axons and the cell body or axons and other axons.
b. The formation of synapses occurs late in fetal development and then continues substantially following birth into
early development and it occurs at different stages.
c. She gave us peak info about the peak periods of synaptogenesis that occur in different regions of the cortex.
d. Something interesting about synaptogenesis is that it depend on activity and experience, so after birth when a
child is beginning to responds to stimuli in the environment, this is going to affect synaptic transmission and
synaptic transmission will then affect synaptogenesis.
XXXVIII.
Synapse Elimination [S41]
a. Synapse refinement is the final stage where synapses are specifically pruned between axons and dendrites.
b. We know that this pruning is very important, because if this activity does not occur normally there can be
abnormal dendritic spines.
XXXIX. Spine and Synapse dysgenesis in mental retardation [S42]
a. If the dendritic spines don’t form normally there can be too many of them, there can be too many synapses or
too few and these types of synaptic dysgenesis and spine dysgenesis are highly correlated with specific
neurodevlopmental disorders such as Down’s Syndrome, mental retardation and autism.
XL. Critical Periods of Development [S43] – she didn’t cover this slide
[end 54:20 min]