L13 - Neuronal Migration in CNS Development Flashcards
Major neuron migrations
Neurons born in ventricular zone migrate out radially
Also migrate tangentially
What is interkinetic nuclear migrations in the neuroepithelium?
Early neuroepithelium is pseudostratified due to nuclear migration
Because their nuclei move up and down it has the appearance of multiple layers – pseudostratified
Neuroepithelial cells go through different phases of the cell cycle as their nuclei move
Early divisions at the apical/ventricular surface of neuroepithelial cells
Symmetrical
Generate two neuroepithelial daughter cells
Later divisions at the apical/ventricular surface of neuroepithelial cells
Asymmetric
Generate radial glia and neuronal precursors
The plane of cell division determines?
The localisation of asymmetric localised cytoplasmic components
Establishment of layered structures
Mature neurons accumulate in the layers above the ventricular zone by radially migrating
They move into the mantle zone where they differentiate
What is birth-dating used for?
Used to follow neurogenesis and migration
Birth-dating method
Tritiated thymidine incorporated into newly synthesised DNA
- Bromodeoxyuridine now more commonly used
Injected into pregnant females it incorporates into cells in S phase
Only cells in their final division retain the label over time
- This allows tracing of their migration to their final destination
Neurones born at different times migrate to?
Different layers of the cortex
Inside out development of the cortex
Cells born first, occupy the deepest layers
Eventually build up the 6 layers of the cortex
Each layer characterised by the expression of a specific set of transcription factors
How to test that cortical neuronal fates change over time?
Heterochronic transplants
Early precursors - transplanted to an older host
Migrate to and adopt the fate of cell being born at the same time in the host
Fate is still plastic
Later precursors - transplanted into a younger host
Migrate to and adopt the fate of the position they would have if not been transplanted
Fates become fixed overtime
Mutations affecting migration causes?
Lissencephaly
Sulci and gyru are diminished or absent
Majority of neurons are found in the deep layers
Failure of neurones to migrate
Causative mutations in genes of proteins associated with microtubule function
Lissencephaly genes
TUB1A and TUB2B – alpha and beta tublin
LIS1, DCX – microtubule associated proteins
Earliest migration post-mitotic cells
Migrate from ventricular zone from the preplate
Cajal Retzius – cells in marginal zone
Subplate neurones – below
Later migrating neurons
Migrate from the cortical plate
Form the major layers of the cortex
The cortical plate sits between
The marginal zone and subplate
Subplate neurons
Eventually due but its neurons play a role in guiding incoming thalamic axons
What are Cajal Retzius cells
First post-mitotic cells to appear
Change shape and die in postnatal period
Cajal Retzius cell function
Required for orderly layering
From analysis of the reeler mouse mutant
Mutation in Reelin gene encoding protein expressed by Cajal Retzius cells
Reelin acts as a stop signal for migrating neuronal precursors
Loss of Reelin leads to?
Failure of Cajal Retzius cells and subplate cells to separate
- Consequent disruption of layering of cortex
- Due to failure of migrating neurones to stop
In humans Reelin mutations lead to?
Lissencephaly
Future of radial glia
Increase in number of neurons
Decrease in number of progenitors
A subset however become astrocyte like
- Put aside to become adult stem cells
What are the two zones where radial glia are set aside?
Sub-ventricular zone of 4th ventricle
Dentate gyrus of hippocampus
Tangential migrations
Help inhibitory interneurons of the cortex migrate in from subpallium
Subpallium is the source of many interneurons for the cortex and other regions of developing brain
Precursors migrate tangentially over large distances
Methods to trace neuronal migration
Inject fluorescent dyes
Transplantation between chick and quail
Inject viruses which infect ventricular zone
Cerebellum
Has a cortical region and central nuclei
Cortical layer is made up of multiple layers
Where does the cerebellum form?
At the roof of the 4th ventricle from specialised roof plate cells
- At boundary of mid and hind brain
- Continuous with roof plate
What are NCCs?
Highly proliferative but some retained as roof plate
What are cells at the hindbrain-midbrain interface called?
Rhombic lip cells
Rhombic lip cells
Retain huge proliferative potential
Their daughters migrate but stay in hindbrain becoming neurons of the cerebellum
Anterior rhombic lip becomes?
Granule neuron precursors
Posterior rhombic lip becomes?
Pontine nuclei and inferior olive
In developing cerebellum
The external germinal layer (highly proliferative) disappears as pool of progenitors is depleted
- Begin to send axons out tangentially
- Begin to differentiate on outside of neural tube
- Move down past Purkinje cell layer to their final location on internal granular layer
Factors controlling cerebellar development
Production of rhombic lip cells is regulated by MATH-1
No MATH-1 – no foliation, no GL, no pontine nuclei
SHH is released from Purkinje cells stimulates mitosis in external germinal layer
Reeler mice – disordered layers
SHH signalling determines tissue pattern in cerebellum
In development SHH from Purkinje cells drive granule neuron precursor proliferation
Levels of SHH signal affect amount of lobulation in adult mouse
Mutations in SHH cause medulloblastoma
Cerebellar disorders and disease
Pontocerebellar hypoplasia
Hypoplastic cerebellum
Hypoplastic pons
Reelin KO mice are ataxic because of failure of layers to form
