L13 - Neuronal Migration in CNS Development

Question 1

Major neuron migrations

Answer 1

Neurons born in ventricular zone migrate out radially

Also migrate tangentially

Question 2

What is interkinetic nuclear migrations in the neuroepithelium?

Answer 2

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

Question 3

Early divisions at the apical/ventricular surface of neuroepithelial cells

Answer 3

Symmetrical

Generate two neuroepithelial daughter cells

Question 4

Later divisions at the apical/ventricular surface of neuroepithelial cells

Answer 4

Asymmetric

Generate radial glia and neuronal precursors

Question 5

The plane of cell division determines?

Answer 5

The localisation of asymmetric localised cytoplasmic components

Question 6

Establishment of layered structures

Answer 6

Mature neurons accumulate in the layers above the ventricular zone by radially migrating
They move into the mantle zone where they differentiate

Question 7

What is birth-dating used for?

Answer 7

Used to follow neurogenesis and migration

Question 8

Birth-dating method

Answer 8

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

Question 9

Neurones born at different times migrate to?

Answer 9

Different layers of the cortex

Question 10

Inside out development of the cortex

Answer 10

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

Question 11

How to test that cortical neuronal fates change over time?

Answer 11

Heterochronic transplants

Question 12

Early precursors - transplanted to an older host

Answer 12

Migrate to and adopt the fate of cell being born at the same time in the host
Fate is still plastic

Question 13

Later precursors - transplanted into a younger host

Answer 13

Migrate to and adopt the fate of the position they would have if not been transplanted
Fates become fixed overtime

Question 14

Mutations affecting migration causes?

Answer 14

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 

Question 15

Lissencephaly genes

Answer 15

TUB1A and TUB2B – alpha and beta tublin

LIS1, DCX – microtubule associated proteins

Question 16

Earliest migration post-mitotic cells

Answer 16

Migrate from ventricular zone from the preplate
Cajal Retzius – cells in marginal zone
Subplate neurones – below

Question 17

Later migrating neurons

Answer 17

Migrate from the cortical plate

Form the major layers of the cortex

Question 18

The cortical plate sits between

Answer 18

The marginal zone and subplate

Question 19

Subplate neurons

Answer 19

Eventually due but its neurons play a role in guiding incoming thalamic axons

Question 20

What are Cajal Retzius cells

Answer 20

First post-mitotic cells to appear

Change shape and die in postnatal period

Question 21

Cajal Retzius cell function

Answer 21

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

Question 22

Loss of Reelin leads to?

Answer 22

Failure of Cajal Retzius cells and subplate cells to separate

• Consequent disruption of layering of cortex
• Due to failure of migrating neurones to stop

Question 23

In humans Reelin mutations lead to?

Answer 23

Lissencephaly

Question 24

Future of radial glia

Answer 24

Increase in number of neurons
Decrease in number of progenitors
A subset however become astrocyte like
- Put aside to become adult stem cells

Question 25

What are the two zones where radial glia are set aside?

Answer 25

Sub-ventricular zone of 4th ventricle | Dentate gyrus of hippocampus

Question 26

Tangential migrations

Answer 26

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

Question 27

Methods to trace neuronal migration

Answer 27

Inject fluorescent dyes Transplantation between chick and quail Inject viruses which infect ventricular zone

Question 28

Cerebellum

Answer 28

Has a cortical region and central nuclei | Cortical layer is made up of multiple layers

Question 29

Where does the cerebellum form?

Answer 29

At the roof of the 4th ventricle from specialised roof plate cells - At boundary of mid and hind brain - Continuous with roof plate

Question 30

What are NCCs?

Answer 30

Highly proliferative but some retained as roof plate

Question 31

What are cells at the hindbrain-midbrain interface called?

Answer 31

Rhombic lip cells

Question 32

Rhombic lip cells

Answer 32

Retain huge proliferative potential | Their daughters migrate but stay in hindbrain becoming neurons of the cerebellum

Question 33

Anterior rhombic lip becomes? | 

Answer 33

Granule neuron precursors

Question 34

Posterior rhombic lip becomes?

Answer 34

Pontine nuclei and inferior olive

Question 35

In developing cerebellum

Answer 35

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

Question 36

Factors controlling cerebellar development

Answer 36

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

Question 37

SHH signalling determines tissue pattern in cerebellum

Answer 37

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

Question 38

Cerebellar disorders and disease

Answer 38

Pontocerebellar hypoplasia Hypoplastic cerebellum Hypoplastic pons Reelin KO mice are ataxic because of failure of layers to form