Neural migration in CNS development Flashcards
Where are neurons born?
In the ventricular zone
Which 2 ways do neurons migrate?
1) Radially from the ventricular zone
2) Migrate tangentially
What do tangential migrations allow neurons to do?
Mix neurons up
How do cells initially divide at the ventricular zone?
Later on, how do cells divide?
- Symmetrically, giving rise to 2 daughter cells which are identical to the mother cell
- Asymmetrically, giving rise to a radial glia cell and neural precursors
How do the mature neurons accumulate in the mantle zone over time?
Neural precursors migrate outwards along the process of the radial glia
What is birth-dating and what did this show?
- Inject tritiated thymidine into pregnant females - incorporated into newly synthesised DNA at S phase
- When the cells divide, the tritiated thymidine is diluted out (cells with a more dilute TT are older)
- Can follow where cells are born and can trace what happens to theses cells overtime
(can trace their migration to their final destination overtime) - Showed that neurons born at different times migrate to different layers of the cortex, from the VZ to the MZ
What is more widely used to birth-date cells, other than tritiated thymidine?
BrdU
Bromodeoxyuridne
What is each layer of the cortex characterised by?
What does this indicate?
Different neurons which are expressing a different set of transcription factors
Indicates that neurons born at different times have different fates
How does the cortex develop from the migrating layers of the cortex?
Inside-out:
So that the neurons born first occupy the deepest layer and the neurons born last occupy the highest layer
How many layers of the cortex are there?
6
What must happen to the radial glial cells to produce neuronal precursors with different fates?
They must undergo changes
What do herrochronic transplant show about the fates of the neuronal precursors?
How was this shown?
Precursors have the ability to adopt many fates, but this is lost in older precursors
- Earlier precursors were transplanted in to an older host at the VZ - migrated to adopt the cells born at the same time in the host (their fate is plastic)
- Late born precursors, when transplanted into a younger host, migrated and adopted the fate of the position they would have done if weren’t transplanted
What is Lissencephaly what does it cause?
A brain which is agyria (sulci and gyri are deminished or absent)
Failure or abnormal neuronal migration
In Lissencephaly, where are most of the neurons found and why?
In the deeper layers
Mutations in the genes associated with microtubule function, meaning that the neuronal precursors cannot migrate up the radial glial cell
What causes Lissencephaly?
Mutations in the genes of proteins associated with microtubule function
- Alpha tubulin (TUBA1A)
- Beta-tubulin (TUBB2B)
- Microtubule associate proteins (LIS1, DCX)
Why are mutations in proteins associated with microtubule function detrimental?
Microtubules are critical for the migration of the neuronal precursors up the radial glia
Before the 6 layers of the cortex can form, what must happen?
2 layers must form the PREPLATE
Which cells form the preplate and where are they located?
Cajal Retzius cells (in the marginal zone) Subpplate neurons (below)
What is the cortical plate and where does it form?
Made of the 6 layers of the cortex
Lies between the cajal retzius cells at the marginal zone, and the subplate
Once the cortical plate has formed, what happens to the subplate neurons?
They die
What is the role of the subplate neurons?
To guide incoming thalamic axons
When were cajal retzius cells discovered?
In 1890
Which are the first post-mitotic cells to appear in the brain?
Cajal Retzius cells
What happens to Cajal Retzius cells post natally?
They change shape and die
How was is discovered that CR cells tell migrating cells when to stop? (in mice)
Studies of a reeler mouse:
- Mutation in reelin gene encoding a large ECM protein expressed specifically by CR cells
- Caused the failure of CR cells and subplate cells to separate
- Therefore disruption of the layering of the cortex
What do Cajal Retzius cells do?
Stop newly born cortical plate cells from migrating anc cause them to differentiate
In humans, what do reelin mutations cause?
Lissencephaly
What happens to the radial glia cell progenitor pool at the ventricular zone over time?
It becomes depleted as the cells divide symmetrically to give 2 neuronal precursors
What happens to a subset of radial glia cells at the VZ as the radial glial progenitor pool becomes depleted and why?
They become astrocyte-like and remain at the VZ as adult stem cells
What are the 2 major zones of adult stem cells?
Sub ventricular zone of the 4th ventricle
Dentate gyrus of the hippocampus
Where do the inhibitory interneurons of the cortex migrate in from and how do they migrate?
The subpallium
Migrate tangenitally over large distances as neuronal precursors
Which neurons are not generated in the cortex?
Inhibitory interneurons
Where do different types of inhibitory interneuron precursors migrate to?
Olfactory bulb (dopaminergic inhibitory interneurons)
Striatum (Cholinergic inhibitory interneurons)
What 3 methods can be used to trace neuronal migration?
1) Injection of lipophilic dyes (birth-dating)
2) Transplantation experiments
3) Virus injection
How does injecting a virus allow to trace neuronal migration?
They infect the VZ and may carry a GFP - can trace the cells which have become infected
Where is the cerebellum located?
Over the 4th ventricle, above the medulla
What is the cerebellum important in?
Motor learning
What is the structure of the cerebellum?
Highly folded
Has a cortical region (made of many layers) and a central nuclei
Where does the cerebellum arise from and in what shape?
As a open structure rhombus shaped, from the specialised roof-plate cells at the boundary of the mid and hind-brain
What are rhombic lip cells?
Highly proliferative roof-plate cells at the midbrain-hindbrain interface
Formed by the joining of the roof plate
What do the daughters of the rhombic lip cells do?
Migrate, but stay in the hindbrain and become the neurons of the cerebellum
Proliferate as they move over the surface of the anterior medulla
What do the cells of the anterior rhombic lip become?
Granule neuron precursors
What do the cells of the posterior rhombic lip become?
Pontine nuclei and inferior olive
What happens during development of the cerebellum?
- EGL cells proliferate and at the same time, cells start to differentiate
- At the same time as differentiating, they migrate tangentially, extending their axons
- Eventually (once differentiated) their cell body ‘absails’ into the IGL past the PCL and into the IGL
- Leaving their axons behind
After the EGL cell bodies have migrated into the IGL, what happens to the axons they have left behind?
They make synapses with purkinje cell dendrites
Where are granule cells born?
At the OUTSIDE of the cerebellum
Where are purkinje cells born?
At the ventricular zone
What regulates rhombic lip cell production?
MATH-1 transcription factor
What happens if MATH-1 is inhibited?
- No layering
- No IGL
- No pontine nuclei
What stimulates mitosis (cell proliferation) in the EGL?
Shh release from the Purkinje cells
In Reeler mice, what happens in the cerebellum?
Disordered layers
What does the level of Shh effect?
The amount of lobulation in the brain, which differes between species
What do mutations in Shh cause?
Medulloblastoma (bulging of the brain in children - tumor)
How can tridiated thymidine be seen in the cells and why?
Using an antibody - tridiated thymidine has an epitope
Using tridiated thymidine, how was it possible to see the neurons born at different times migrated to different layers of the cortex?
Inject into mice at different stages of pregnancy
What do subplate neurons play an important role in?
Guiding thalamic neurons
Along with inhibitory interneurons for the cortex, what other neurons migrate from the subpallium? (3)
1) GABA-ergic interneurons
2) Dopaminergic inhibitory interneurons
3) Cholinergic inhibitory interneurons
In the cerebellum, where do the cell bodies of the granular cells lie?
In the inner granular layer
In the cerebellum, where do the axons of the granular cells lie?
What do they synapse with?
In the molecular layer, above the purkinje cells
Synapse with the purkinje cell dendrites
In the cerebellum, what are the main output neurons?
The purkinje
What is the developing cerebellum continuous with and what does this form?
The roof plate of the lower spinal cord, forming a rhombic lip (as the developing cerebellum is an open structure- roof plate slightly hangs over)
How do anterior rhombic lip cells migrate?
Initially anteriorwards and then tangenitally
Why in mice with a reeler mutation, do the mice become ataxic?
Due to disordered layers in the cerebellum, which is involved in motor learning
What is ataxia?
Lack of voluntary coordination of muscle movements
