PNS Peripheral Nervous System, CNS Central Nervous System

Neuro: 9:00 - 10:00Scribe: Brittney Wise

Thursday, January 8, 2009Proof: Laura Adams

Dr. TheibertDevelopment of the Nervous SystemPage1 of 7

PNS – Peripheral Nervous System, CNS – Central Nervous System

Introduction [S1]: This transcript goes along with the updated power point that is 43 slides
Development of the Nervous System occurs during both Prenatal and Postnatal periods [S2]
In humans, development of the nervous system begins early after fertilization and takes place both pre-natally and post-natally.
Prenatally:
When gross sections of the brain are formed, so major regions of the CNS and PNS are formed.
Majority of neuronal population is generated before birth but the brain is relatively small (350-400 grams)
During this stage of development the brain is mostly controlled by intrinsic factors ( ex// genetic factors)
Not a lot of plasticity or experience that takes place prenatally
Post-natally:
A few neuronal populations are generated
The majority of the glial cells, things like astrocytes and oligodendrocytes and microglia are actually formed after birth
There’s a large increase in the volume and the mass of the brain; it triples between pre-natal and post-natal development.
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.
The adult brain is between 1200 and 1400 grams; there is a large increase in mass and metabolic activity
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.
Stages of Development of the Nervous System [S3]
There are 7 main stages of development of the nervous system beginning with fertilization:
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).
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)
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
Once the neurons are generated they have to migrate to their final destination and many neurons aggregate to form nuclei
This occurs after the cells have generated by mitosis, and again occurs over an extended period.
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.
This usually occurs about 4-5 months pre-natally, but then this period of differentiation occurs extensively after birth.
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
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)
Initial Embryonic Development [S4]
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:
epiblast is the structure which is going to give rise to the embryoproper
hypoblast will form the yolk sac
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.
The trophectoderm are the cells that are lining the rest of the structure here, will end up forming the placenta.
Gastrulation involves cell migration [S5]
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.
Initially they pile up at the primitive streak and then they crawl inside, underneath the overlying cells.
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.
This cell migration that allows for the formation of the individual germ layers.
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

Formation of neural plate and notochord [S7]
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
ectoderm is the part that will give rise to the nervous system
only part of the ectoderm will give rise to the CNS and PNS, and that’s the medial ectoderm
the surrounding ectoderm will give rise to the skin.
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.
At this stage of development (about 18 days in humans) you have the formation of what’s called the neural plate.
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.
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.
After the formation of the neural plate, there is the formation of the notochord.
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.
Neural Induction(in Vertebrates) [S8]
There are specific signals from the mesoderm that specify to the overlying ectoderm to become the neural plate.
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.
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.
Throughout the embryo there are a series of secreted proteins which are members of the BMP (Bone Morphogenetic Protein) family of signaling molecules.
These proteins are called TGF. They were originally identified in cancer cells, so the T stands for transforming growth factors.
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.
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.
When the Smads are phosphorylated they can then move into the nucleus and induce transcription.
We know that there is TGFand BMP signaling throughout the embryo.
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.
So they are inhibitors of BMP signaling and you have to block BMP signaling in order to induce the neural fate.
In frogs and chickens these secreted factors have been identified and are called noggin/chordin/follistatin.
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.
In order to become/adopt the neural fate you have to inhibition of BMP signaling.
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.
Neurulation [S9]
After induction is neurulation: this is the process by which the neural tube is formed
Neural tube will give rise to all of the neurons and glial cells in the CNS
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.
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.
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.
This elevates the neural folds above it.
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.
[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.
[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.
So, precursors to neurons express a specific type of cell adhesion molecule called N-CAM (or neural cell adhesion molecule).
They also express another type which is called N-cadherin.
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.
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.
After neurulation the neural tube will pinch off from the surrounding ectoderm and it separates from this non-neural tissue, which will become the epidermis.
Primary Neurulation [S12]
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 1st 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.
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.
These neural pores will eventually close. The anterior (also called the rostral neural pore) will close about day 23 or 24.
The caudal neural pores will close a few days later, after the embryo has begun to undergo some other morphological changes in its curving.
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.
Secondary Neurulation [S13]
We don’t know much about secondary neurulation, but it occurs at the caudal most end of the neural tube.
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.
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.
What are Neural Tube Defects? [S14]
The most common neurological malformation in humans.
Occurrence from about 1-2 per 1,000 live births.
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.
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.
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.
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 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.
Segmentation of the Neural Tube [S15]
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.
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.
Forebrain – prosencephalon
Midbrain – mesencephalon
Hindbrain – rhombencephalon
The neural tubeis 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.
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.
4th Week – Segmentation of the Neural Tube [S16]
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