Lecture 10 Neuronal migration Flashcards
What determines the fate of neurones
The TF of neurones along the DV and AP axis
What are the two types of neuronal migration?
- radial - move to outer layers
- tangential - sideways movement
Where does neuronal migration occur
Throughout the developing brain
What happens in the first part of radial migration?
Interkinetic Nuclear Migrations in the neuroepithelium
Here the nuclei are moving, not the cells
Describe Interkinetic Nuclear Migrations in the neuroepithelium
One cell thick neuroepithelium undergoes interkinetic nuclear migration
The nuclei move up and down to give the appearance of multiple layers = pseudostratified
Describe position of nuclei at different stages of cell cycle
Up G1 (towards pial outer layer)
Down G2
Basal S (pial layer)
Apical M
Define apical in neuroscience
This means inside i.e. ventricular surface
what type of division occurs early on?
symmetrical - two daughter cells have equal potential to act as progenitors and expand neuroepithelium
what type of division occurs later on?
asymmetrical - one neuronal progenitor and one radial glial cell (shape change)
What is important to remember about radial glial cell division
In late stages they can still undergo symmetrical divisions
What does the plane of division determine
The localisation of assymetric localised cytoplasmic components in daughter cells
What happens in the part 2 of radial migration?
Mature neurons accumulate over time in the layers above the ventricular zone by radially migrating
What does part 2 form
Layered structures e.g. cortex and cerebellum
Describe layers formed from part 2 inside to out
Ventricular surface
VZ
Mantle zone
Pial surface
How do we know this?
Birth dating to follow neurogenesis/migration
Describe process of birth dating
•Tritiated (3H) thymidine incorporates into newly synthesized DNA
•Injected into pregnant females it incorporates into cells in S phase
•However, only those cells in their final division retain the label over time (so are often called label-retaining cells)
-> This ‘birth-dates’ these cells, allowing us to trace their migration to their final destination over time
Birth dating results
Neurones born at different times migrated to different areas
What can be used instead of 3H
BrdU
What layers do cells born early go to?
lower layers of the cortex
What layers do cells born later go to?
upper layers of the cortex
What does each layer express
A specific set of TF so neurons born at different times have different fates
Do cortical neuronal fates change?
Yes
How do we know fates change?
Classical ‘heterochronic’ transplants test whether the fates of neuronal precursors at different ages is fixed or plastic
- > found that early precursors can change fate
- > this ability is lost as they age
How do we know early precursors change fate
When transplanted into an older host they adopt the fate of the cells born at that time
How do we know late precursors are fixed
When transplanted into an early host they adopt position that they would have been
What do mutations affecting migration cause?
Lissencephaly
Smooth brain - agyria
No sulci or gyri
Affects neuronal migration of deeper layers
What is Lissencephaly associated with
Mutations in MT genes
= TBA1a - alpha tubulin
= TUBB2B - beta tubulin
LIS1, DCX MT assoc proteins
What occurs in the 1st migrations
Cells delineate form the boundaries of the cortical layers
The cells that first leave the ventricular zone form what?
Preplate
What cells make up the preplate?
- Cajal Retzius (CR) cells in marginal zone
- Subplate neurons
The cells leaving the ventricular zone later form?
Cortical plate which forms the many layers of the cortex
What are subplate neurons important for?
Play an important part in guiding incoming thalamic axons
They eventually die
What are Cajal-Retzius cells?
first post-mitotic cells to appear in cortex
Loss of what protein in CR cells disrupt layering?
Reelin
How visualise CR cells
GFP - can see change shape and die in post-natal period
What did Reeler mouse mutants show
Mutation in Reelin gene which encodes ECM protein in CR cells
KO led to failure of CR and Subplate cells to separate –> migrating cells didn’t stop but continued to migrate –> Lissencephaly
Over time what happens to radial glia
Depleted
However, what do some radial glial cells become?
Adult neural stem cells
What are adult neural stem cells?
Astrocyte-like cells that can produce new neurons in adults
What are the two major zones of radial glia stem cells? What neurons are produced in these zones?
- subventricular zone of 4th ventricle –> olfactory neurons that migrate to rostral migratory system in olfactory bulb
- dentate gyrus of hippocampus –> granule neurons
Where to intermediate progenitors accumulate and produce
Subventricular zone
Upper layer neurons
= VZ, SVZ, CP, MZ
What are granule neurons for
Spatial memory
What happens in part 3 of neuronal migration?
Tangential migration
What is tangential migration?
mixing it up - occurs at a right angle to radial migration
Key neuronal subpopulations migrate in from other regions
Where do inhibitory interneurons of cortex come from?
they tangentially migrate from the subpallium and migrate tangentially over large distances
Three examples of inhibitory interneurones and where they migrate to
GABAergic –> cortex
Dopaminergic –> olfactory bulb
Cholinergic –> striatum
Other methods used to trace migration
Quail into chick as bright nucelus
Inject DNA label and follow fate
Genetic editing to turn on and off marker at diff stages
What are the 3 layers of the cerebellum?
Granule layer (axons) –> Purkinje cell layer (output neurons) –> molecular layer
Which part of brain has unusual migrations
Cerebellum
= root of rhombencephalon = hindbrain = deeply folded, many neurones
What is the equivalent of neural crest cells in the hindbrain?
Rhombic lip
What is important about neural folds of rhombic lip
Never fully fuse to give rhombus shape of rhombencephalon
What are the two daughter cells of rhombic lip cells?
- anterior rhombic lip cells (superior)
- posterior rhombic lip cells (inferior)
Where do anterior rhombic lip cells migrate? What will they become?
- migrate tangentially across anterior HB to form the External Germinal Layer (EGL) of the cerebellum
- EGL differentiate into granule neurons
Where do posterior rhombic lip cells migrate? What will they become?
migrate tangentially to the ventral hindbrain
-> pontine nuclei and inferior olive
Why is migration unusual in hindbrain?
Granule neuron precursors do it backwards
- there is early tangential migration of rhombic lip cells before radial migration
- proliferation zone on outside of cell (pial not VZ)
Describe the layers formed from rhombic lip
Ext germinal layer –> ML –> PCL –> Int germinal layer
What is important about EGL
Disappears as pool of progenitors deplete and differentiate into neurons that abseil into inner GL
What is the production of rhombic lip cells regulated by?
ATOH1 (atonal-like TF)
What would happen if there was no ATOH1?
- no foliation
- no internal granular layer
- no pontine nuclei
ATOH1 mutations can cause what?
Human hypoplasia = small cerebellar
May affect pons too showing role in A and P dorsal lip
What fibres release sonic Hh?
Purkinje fibres
What does sonic Hh in the external granular layer stimulate?
Mitosis
Increased sonic Hh in external granular layer leads to?
Increased lobulation - child tumour
Reelin gene in humans mutation causes
RELN –> lissencephaly in cerebral cortex + cerebellar hypoplasia
KO disrupts PCL i.e. more dispersed –> ataxia
Where is Reelin expressed
Granule neurons and above/below Purkinje cell layer
