Development of neurons Flashcards
What stages do neurons have to go through?
Cellular determination, proliferation, migration to their correct locations, axonal project (axon sent out to make way through various tissues to connect to target), establishment of connection to target, pruning unnecessary connections, death of excess neurons that are generated during development.
What must be studied in order to understand development of the nervous system?
Development in general - look at fertilisation etc.
What are the layers of the gastrula?
Outer layer (ectoderm), inner layer (mesoderm), and further inner layer (endoderm).
What are the most important layers in development of the nervous system?
The ectoderm and the mesoderm.
How are cell of the ectoderm determined to become neurons?
Neural induction - these induction signals come from the mesoderm.
What happens when determination of neurons has occurred?
Cells of the ectoderm will differentiate to become neurons or remain as precursor cells.
When does migration of neuronal precursor cells occur?
Before differentiation to a neuron is complete.
What induction signals are present in the etoderm?
Signals that prevent formation of neurons - there are inhibiting signals. Neural induction is the inhibition of inhibition signals from the ectoderm in order to form neurons.
What is organogenesis?
The process in which different layers become rudimentary organs.
What does organogenesis involve?
Folding, splitting and dense clustering of embryonic cells.
What are the first rudimentary organs formed from organogenesis?
The neural tube and the neural crest.
What cell layer gives rise to the neural plate?
The ectoderm.
What do the neural tube and neural crest give rise to?
Most of the cells of the nervous system.
What is the neural tube formed from?
The folding inwards of the neural plate which is an area of the embryo that is determined in development.
What is the xenopus laevis?
The clawed frog.
What does it mean that the frog embryo is polar?
There is a ventral and dorsal surface.
What is the Spemann organiser?
A region of the mesoderm that contains cells that release neural inducers such as Noggin, Chordin, Follistatin and Cerebrus.
What happens if a region of the ectoderm (animal cap) is transplanted onto a second embryo?
The frog would grow a second nervous system.
What does fertilisation trigger intracellularly?
An influx of calcium that sweeps across the egg and causes a rapid release of cortical granules to form the fertilisation envelope to block polyspermy.
When are the vegetal and animal regions determined?
When the egg is fertilised - this is determined by the point of entry of sperm into the cell.
What does the vegetal pole allow, compared to the animal pole?
The vegetal pole allows the entry of calcium which plays a role in signalling inside the egg to change where molecules are distributed.
What does the point of entry of sperm also determine?
A second positional axis - ventral (where the sperm entered), and dorsal (opposite to the entry point).
What does cortical rotation do?
It mixes cytoplasmic determinants and creates the dorsal-ventral axis. It redistributes maternal cytosolic determinants that are partitioned in different dividing embryonic cells.
What is the grey crescent?
The future blastopore.
What forms the Nieuwkoop centre?
The dorsal-most vegetal region of the egg.
What are some of the proteins associated with cortical rotation?
VegT is initially associated with disheveled at the membrane. Cortical rotation separates these, and disheveled can interact with siamois. Siamois influence further effects and there is an area of separation where the Nieuwkoop centre.
What determines the animal/vegetal region?
Maternal determinants.
What determines the dorsal/ventral regions?
Sperm entry, cortical rotation.
What determines the anterior/posterior of the egg?
The spemann organizer.
What are the three major spatial axes formed by gradients of signalling molecules?
The animal/vegetal, dorsal/ventral and anterior/posterior.
What is the anterior/posterior axis important in?
Generates the axis in which the neural tube begins to form.
What is the organizer transplant experiment?
A region above the blastopore lip is excised and transplanted into the ventral side of the host. The host embryo then develops a secondary dorsal axis - this is first evident by a secondary neural plate. The secondary dorsal axis contains the same tissues as the primary dorsal axis.
What is significant about time in the organizer transplant experiment?
If it is done too late there will be no effect - there is a window of time where the induction process is occurring.
What will neural crest cells go on to form?
PNS, endocrine cells, pigment cells and connective tissue.
What is neurulation?
Closure of the neural tube.
What is the notocord?
An area that induces the floor plate.
What is the neural floor plate?
An area of rich source of neuronal morphogens and axonal cues.
What is the area that is the most influential in the development of the neural tube?
The notocord.
When does the neural plate form?
After gastrulation is completed.
What happens to the neural tube throughout development?
It narrows along its medial-lateral axis and the plate begins to roll into a tube.
What do cells at the midline of the neural tube produce?
A medial hinge point - MHP.
What happens as the neural tube forms and segregates into the embryo?
The neural crest cells emigrate from the dorsal aspect of the neural tube.
What structure does the neural tube have?
Anterior posterior - the anterior forms the forebrain, midbrain and the hindbrain and the posterior forms the segments of the spinal cord.
What is the central area of the neural tube called?
Ventricular zone of proliferation - cells in this area give rise to all the neural cells.
What happens if ectodermal cells from the embryo are dissociated into single cells in culture?
They will differentiate to form cells of the nervous system - neurons or glia.
What do factors regulate about neurons?
When or if ectodermal cells differentiate to neurons.
What can other factors have on neurons?
They can prevent neuronal determination and push ectodermal cells to other fates.
What are bone morphogenic proteins?
They are neural inhibitors.
Where do BMPs bind?
Receptors on ectodermal cells.
What does binding on BMP to its receptors result in?
Phosphorylation of a protein Smad-1.
What happens after BMP has bound to its receptor?
Smad-1 then binds to Smad4 which causes a change in transcription factor expression, resulting in the inhibition of expression of neural genes and activation of epidermal genes.
What effect do neural inducers have on BMP?
They inhibit BMP binding to its receptors.
Where are BMPs derived?
In the bone, but have an important role in the nervous system.
How is the induction of neural fate determined?
Inhibition of the action of BMPs.
What do neural precursor cells produce?
Express inhibitory proteins that bind neural inducers that act through receptors to inhibit the process that requires the BMP receptors and the Smad pathway - resulting in the formation of neural gene expression rather than epidermal expression.
How are neural cells differentiated from epidermal cells?
Epidermal cells - the Smad pathway will be active and there will be activation of epidermal genes and inhibition of the expression of neural genes.
How is BMP regulated in the ventral side of the embryo?
The ectoderm expresses BMP receptors which induce it to become the epidermis.
How is BMP regulated on the dorsal side of the embryo?
The organizer releases inhibitors of BMP - noggin, chordin and follistatin.
When does proliferation of precursor cells occur?
During and after determination.
What does proliferation result in?
Cells that are determined to be neurons. This are called neuroblasts. It is in this form that the cells will migrate.
In what form will cells migrate to form neurones?
Neuroblasts.
In terms of numbers of cells, what does proliferation result in?
More cells than necessary in the adult nervous system.
What happens to cells that are involved in proliferation that do not become fully determined?
They are able to continue to divide - they are stem cells.
What happens to the stem cells involved in proliferation?
They can divide to make more stem cells or may become progenitor cells.
What happens to progenitor cells in proliferation?
They can differentiate further or divide.
What happens to neural progenitor cells?
They can divide but as differentiation continues that will become fewer in number until most of the daughter cells are neuroblasts that are terminally differentiated - they will eventually become neurons.
What are the properties of stem cells?
They are self-renewing (divide to generate more stem cells) and they are multipotent (exposure to different signals can stimulate differentiation into multiple cell types).
What are neurospheres?
Culturing of stem cells in the brain tissue.
What can neurospheres differentiate into?
Neurons, astrocytes and oligodendrocytes.
How can neurospheres be induced to produce different cell types?
Applying different growth factors.
How is the differentiation of neurospheres important?
Neurospheres could be cultured and have different growth factors applied to them to induce neurons/astrocytes/oligodendrocytes that can replace damaged structures.
What happens if human neural stem cells are transplanted into a rat brain?
Some of the cells will differentiate into neurons and migrate into the particular brain regions - the morphology is appropriate for this region of the brain.
What does the neural tube generate?
Many different neuronal and glial cell types.
Where do neurons and glial cells arise from?
The ventricular proliferative zone (VPZ), which is a layer of epithelial cells lining the lumen of the neural tube.
What happens to a neuron once it has formed?
It does not divide again.
How many layers does the mammalian cerebral cortex have?
6 - each with distinctive cells.
Where do the layers of the cerebral cortex originate?
In the VPZ and then migrate out to their final position along the elongated radial glial cells.
When is a cortical neuron specified?
Before migration starts - specification is dictated by the time when it is born - the time of its last mitotic division.
What is the difference in migration between early neurons and later ones?
Early neurons migrate to close sites whereas later ones travel past the early neurons to far locations.
What sort of distances do cortical neurons migrate?
Long distances.
What are the layers in the cerebral cortex?
5 layer structure: Incoming axons, pyramidal cell layers (projecting to the neighbouring cortex), stellate cells (local projections), pyramidal cells (projection out of the cortex)
What controls the pathways that allow the migration of neurons?
Radial glia - long, thin glial cells that span the neural tube from the central ventricular proliferating zone to the outside area.
How do the radial glia allow migration of neurons?
The migrating neurons climb the scaffold of the glia in culture.
How can the birth date of neurons be determined?
Radioactive thymidine can be injected in a short pulse. Only cells in the S phase will incorporate this into the DNA. Cells that make terminal division are heavily labeled, and cells that continue through the cycle will be dilutely labelled. This information can be collected at various times during development, collected and sectioned after birth.
Where are gradients of molecules or receptors present?
In the anterior-posterior and dorsal-ventral regions.
What are some of the molecular/receptor gradients in the anterior-posterior axis?
Proteins such as noggin and chordin are essential for formation of anterior parts of the brain, FGF3, FGF8, Wnt3a and retinoic acid and Hox genes influence posterior aspects of the brain.
What are some of the molecular/receptor gradients in the dorsal-ventral regions?
Secretion of Sonic hedgehog from the notochord (ventral). Ectodermal molecules from the dorsal area into the neural tube - Wnt and BMP (ectoderm).
Why is drosophila often used as a model?
It is a simple model that is easy to study.
Why are some names of proteins strange?
Mutations in the drosophila caused effects that looked like the name - e.g. hedgehog.
What growth factors are released near the caudal part of the neural tube?
Wnts, FGFs and retinoic acid.
What growth factors are released near the anterior end of the developing neural tube?
Cereberus, Dickkopf.
How do gradients arise in development?
Asymmetrical release of factors - stronger influence close to release. This influence how cells differentiate and what they differentiate into.
Where is sonic hedgehog released?
The notochord - it moves by diffusion into the neural tube. the further away from the source the protein is, the lower density it has. Closer to the source/notochord will receive more of that molecule. This may have no influence if there are no receptors, but if there is an even distribution, those closer to the notochord will have a greater influence.
How are gradients important in development?
The gradients released will mean different receptors along the pathway will receive differing amounts of ligand. This will result in differentially triggering of the receptors.
What is sonic hedgehog important in?
Controlling ventral patterns - it can enter the neural tube
What is the receptor for sonic hedgehog composed of?
Two components that are smoothened and patch that signal into the cell to alter gene expression.
What are Notch and sevenless?
Two mutations in the fly due to key proteins that lose their function as a result of these mutations.
What happens in the Notch mutation?
Too many neuroblasts develop due to failure of information exchange between cells.
What is lateral inhibition?
Protein expressed on one cell type and a protein it interacts with is expressed on another cell type - this interaction creates an inhibitory signal which then influences what happens, so this will prevent differentiation into neuroblasts. (delta on one cell and notch on another cell)
What type of environments must neurons be present in in order to differentiate?
Areas where there is no delta-notch signalling - areas of no lateral inhibition.
