Describe the basic principles of neuralation
Occurs after gastrulation at the tri-laminar stage where there are the three layers of cells (ectoderm, mesoderm and endoderm).
Cells at the centre of the mesoderm differentiates as a result of being under the primitive streak into the notochord.
The notochord then induces a change in the ectoderm above it to form a structure called the neural plate.
Neural plate cells dive into the mesoderm to form a ring-like structure that pinches together and zips up to become the neural tube.
What are the cells forming the neural plate referred to?
What do these cells eventually form?
The neuroepithalial cells form the nervous system
Describe the neural tube
Is a hollow tube
Comprised of a thickness of only one layer
Where is the site of neural fold closure?
The centre or middle of the tube closes outwards towards the base of the neck and towards the base of the spine
What is meant by the rostral to caudal gradient in the formation of the nervous system?
The timing of the fusion of the neural tube is not the same along the length of the neural tube,
The rostral end (anterior) is older (it fuses before) than the caudal ends.
This is important to the the formation of the rest of the CNS following this stage
Describe the distinct stages in neural fold closure in terms of the embryo 
- The middle of the tube zippers up to the neck and to the base of the spine
- The crown then zips up towards the forehead and back of the skull
- The face and forehead zip up from below
- The base of the neck zips to the back of the skull
- The caudal end of the embryo zips up to the base of the spine
Describe 2 examples of disorders that can occur as a result of the failure of the neural fold closure
- SPINA BIFIDA occurs when there is a failure in closure of the caudal end of tube - step 5 (leaving a part of the nervous system exposed at the back)
- ANACEPHALY is a deadly disorder where failure of closure of the crown of the embryo occurs - step 2. This leaves the top of the head open and bathing in amniotic fluid and failure and disorganisation in developing the brain and skull.
What is the next step in neural tube development after closure?
This totally hollow tube at this stage (still one cell thic)
Rostral end of neural tube starts to swell and form 3 distinct vesicles. These vesicles go on to form the brain and the remainder of the tube becomes the spine.
What are the three major vesicles that are formed in segmentation of the neural tube?
(Note: don't really need to know the names just the consequences)
- Prosencephalon (forebrain)
- Mesencephalon (midbrain)
- Rhombencephalon (hindbrain)
The Prosencephalon (forebrain) undergoes further segmentation into 2 major parts. What are these parts and what do they become?
Telencephalon: cortex and basal ganglia
Diencephalon: thalamus and hypothalamus
The telencephalon further splits into 2 parts (left and right). What do these form?
The right and left cerebral hemispheres
The rhombencephalon (hindbrain) also undergoes further segmentation into further parts. What do these parts form?
(Note: don't need to know the names just the end result)
Pons and Medulla
Describe the formation of the retinae
Retinae forms as outgrowths of the brain (additional vescicles formed by the segmentation) that has been pushed out and is connected back to the origin by what becomes the optic nerve.
Describe the formation of the neural crest
As the neural fold closes in on itself to form the neural tube, a few cells from the ectoderm spill out and migrate away to form the neural crest
What is the major structure(s) formed by the cells of the neural crest?
THE PERIPHERAL NERVOUS SYSTEM
- Dorsal Root Ganglia
- Autonomic Ganglia (symp and parasymp)
- Enteric Ganglia
- Schwann Cells
(also melanocytes, muscle/cartilage/bone of the skull, jaws and face, pharynx, dentine)
Desribe neural crest migration
What is the significance of this in terms of pathology?
Cells of the neural crest have to migrate from their site to under the skin or to the site of the DRG and sympathetic ganglia (which is a potentially long way to go).
Because they have a long distance, there is a lot that can go wrong with their travels and lead to developmental and birth defects
What is the longest path that is needed to be taken by the neural crest cells?
The longest path is to form the cells of the enteric nervous system. Cells need to travel via the oesophagus down the elongating gut tube to populate the enteric nervous system.
This is stretching the migratory capacity of the cells and thus very little needs to happen in order for the process to go awry
Describe the neuroepithelium of the neural tube in terms of
- Cell layering
- Cell morphology
- Polarity of the cells
The neuroepithelium is a single cell layer thick that encloses a very large fluid filled space (otherwise hollow)
The cells are elongated and arranged in long and thin parallel strands of cells, each spanning the whole length of the layer.
The cells have a ventricular surface (lining the lumen or future ventricles) and an apical surface (beneath the ectoderm)
What is the preferred site of division of stem cells of the neuroepithelium?
Describe how this process of division occurred
The ventricular surface
The neuroepithelial cells would break their connections with the outer surface and shrink down into almost circular shaped cells at the base (ventricular surface).
They would then divide and the daughter cells would elongate and reattach themselves as long stretched cells once again.
How does the generation of the cortex occur? (Describe how the layering of the cortex arises)
As more and more cells begin to emerge from the division of stem cells in the ventricular zone the cells begin to DIFFERENTIATE.
There is a radial migration of the daughter cells from the ventricular surface outwards towards the skin (top layer) where they are laid down).
This constant addition of cells from the innermost side of the brain to the outemost creats the layering down of distinctive layers of the cortex.
As the cortex thickens by this process of stem cell division and migration to the top, the migration distance becomes very long. How do cells know where to go and where to stop?
A population of the neuroepithelial cells maintain the connections on both the surface and the ventricular sides of the growing cortex from the beginning.
These are called radial glia
They act as a railroad track and direct new cells to the top. (They also have their own stem cell population)
Describe 2 examples of developmental disorders that can occur if there are errors in the migration and differentiation processes of the neuroepithelium
Problems with these processes cause profound mental retardation.
- Reelin Mutation: The molecules that are meant to guide, stimulate and direct the cells in migration are mutated and dysfuncational causing a disorganised layering of the cortex
- Lissencephaly (Doublecortin, DCX gene): Causes no organisation in migration leading to little distinction between white and grey matter and very large ventricles.
How is cell identity assigned to the migrating cells of the neuroepithelium?
By a process of induction.
Signals pass between structure or tissues through ligand and receptor signalling to induce particular responses to the cells (to tell them what the next step is in development)
The CNS is organised in a very complex way with a large number of different neurons, each requiring different pathways, target cells and signalling processes.
What is the main concept that underlies the development of the different types?
The physical presence of a cells in that microenvironment and the signals it is receiving from its neighbours is the major factor
Describe the first step in differentiation for the cells of neural tube. What is the main driver for this change?
The neural tube develops two specialised regions:
- Roof plate
- Floor plate
The roof plate on the dorsal aspect is specialised because of its relationship to the neural crest above it and the floor plate due to the relationship to the notochord below it
How is the major signalling molecule sonic hedgehog involved in spinal cord development
The Notochord releases sonic hedgehog (and other signalling molecules) to cause the neighbouring neural tube cells to differentiate into the floor plate.
The floor plate cells then create and release a diffusion gradient of sonic hedgehog which acts as an inductive element to induce the differentiation of neighbouring cells.
What is the significance of the floor plate cells producing and releasing sonic hedgehog compared to the roof plate cells producing noggin
It sets up a topography within the spinal cord
The floor plate induces the cells of the neural tube to become motor cells and thus creates the ventral horn while the roof cells remain as sensory (dorsal horn)
Describe the induction of the interneurons
The newly formed motor neurons release motor neuron factor that diffuses out to surrounding cells to cause them to differentiate into interneurons.
Are axons present when the neurons are first formed (differentiated)?
Axons are a key feature only of the mature neurons.
The axon needs to grow out and directed throughout the body to meet its target tissue
Does the laying down of axons through the embryo occur all at once or in a more progressive manner?
An initial scaffold of axon tracts are laid down by some pioneer axons which establish a basic pattern of the brain.
Later axons will then follow this basic pattern and they eventually coalesce into a series of axonal tracts forming the brain.
This process is sterotyped and is thus tightly regulated and predictable.
What is the axonal growth cone?
It is a concentration of actin (a motile protein) at the tips of the growing axon. The growth cone pulls the axon, steers it through many obstacles in the body and dragging a lengthening axon towards the target tissue.
The growth cone has a highly organised and dynamic cytoskeleton motor that has finger like projections able to feel its way/naviage and crawl through the body.
How do axons navigate their way through the body? (ie. how do they know where to go and how to get there?)
The cone is able to detect signals in the environment and follow them; detecting a concentration gradient and moving towards the source of it.
What is meant by the critical period of nervous system development?
The already described processes generate a crude and immature nervous system that is not fully wired up.
The critical period is the period of time where very important refinement processes to form permanent changes occurs to establish a MATURE and FUNCTIONAL nervous system.
These refining processes often occur postnatally
Describe, with reference to the cat blinding experiment the refining process of the visual system.
Temporarily blinding one eye of a cat from birth for six months causes the eye to be completely blind despite not having any physical deformities or abnormalities.
Closing both eyes for the same duration leads to no changes in visual ability.
This is because the blindness is cortical and permanent in nature. This means that the visual cortex takes information from both eyes and interdigitates patches in a 50/50 ratio. Bilnding 1 eye causes the cortex to reduce representation to that eye and so the cortex is then unable to interpret any information from that eye.
What effect does the timing of an eye closure have on the ability of the eye to work later?
The longer after birth the eye is closed, the less profound the blindness is.
Closure at or after 6 weeks of birth has no effect at all.
Thus this is the critical period where the left and right eyes are sorting out their wiring and refining the CNS into a mature relaying system.