AF - Neuronal migration in CNS development

Question 1

Neuronal migration stages in CNS development

Answer 1

Radial migrations part 1: Interkinetic Nuclear migrations in neuroepithelium
Radial migrations part 2: establishment of layered structures (cortex and cerebellum)
Tangential migrations

Question 2

RM Pt1: Early divisions of neuroepithelial cells are?

Answer 2

symmetrical division - two daughter neuroepithelia - size of neuroepithelium increases

Question 3

RM Pt 1: Early neuroepithelium are? why?

Answer 3

Pseudostratified
single celled but Interkinetic nuclear migration occuring
Nuclei moves up (G1) and down (G2) as go through diff stages of cell cycle

Question 4

RM Pt1: Later divisions of neuroepithelial cells are?

Answer 4

Asymmetric

Change shape generating radial glia and neuron precursors

Question 5

RM Pt2: Mature neurons accumulate over time

Answer 5

In the layers above the ventricular zone by radially migrating - happens in many structures in CNS

Question 6

Birth-dating - what is is used for? and the stages?

Answer 6

To follow neurogenesis and migration

• 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)

Question 7

How do first and later born neurons differ? - how is each layer characterized?

Answer 7

First born neurons occupy the deepest layers,
Latest born occupy the uppermost (superficial) layers
Each layer is characterized by the expression of a specific set of transcription factors - neurons born at different times have different fates.

Question 8

What do heterochronic transplants test? what does it suggest?

Answer 8

Test whether the fates of neuronal precursors at different ages is fixed or plastic

Strongly suggests early precursors have the ability to adopt many fates, but that this is lost in older precursors

Question 9

Mutations affecting migration cause?

Answer 9

‘lissencephaly’
Sulci and gyri are diminished or absent
Majority of neurons are found in the deeper layers
Failure/abnormality neuronal migration
Causative mutations in genes of proteins associated with microtubule function:
TUBA1A (α tubulin), TUBB2B (β tubulin),
LIS1, DCX (microtubule associated proteins)

Question 10

what are microtubules critical for?

Answer 10

Microtubules are critical for migration:

Question 11

Earliest post-mitotic cells migrating from the ventricular zone form?

Later migrating neurons form?

Answer 11

Earliest post-mitotic cells form
- the preplate (PP):
- Cajal Retzius* cells in the marginal zone (Cajal cells)
- Subplate neurons below - eventually die
Later migrating neurons form the cortical plate (in which major layers of the cortex form)

Question 12

Cajal-Retzius Cells

Answer 12

First post-mitotic cells to appear
Characteristic morphology
Change shape and die in postnatal period

Question 13

What does Loss of reelin lead to? and why?

Answer 13

Loss of Reelin leads to failure of CR cells and subplate cells to separate and consequent disruption of layering of cortex
Thought to be because migrating neurons fail to stop.
In humans, Reelin mutations -> Lissencephaly

Question 14

What happens to Radial glia and intermediate progentiors over time?

Answer 14

Radial glia become depleted over time

But intermediate progenitors accumulate in the Subventricular Zone (SVZ) and continue producing upper layer neurons

Question 15

What do a subset of Radial Glia cells become? what they put aside for?

Answer 15

Astrocyte-like

These are put aside to become adult neural stem cells that can produce new neurons

Question 16

Two major zones of adult SCs:

Answer 16

Subventricular Zone (SVZ) of 4th ventricle 
Dentate gyrus of hippocampus

Question 17

Where are tangential migrations occuring?

Answer 17

Tangential migration occurring in both spinal cord and brain, with key neuronal subpopulations migrating in from other regions

Question 18

Inhibitory interneurons of the cortex migrate in from? give examples

Answer 18

Migrate in from the subpallium

a) GABA-ergic inhibitory interneurons go to cortex
b) Dopaminergic inhibitory interneurons go to the olfactory bulb
c) Cholinergic inhibitory interneurons go to the striatum

Question 19

Where do Anterior RL daughters and Posterior Rhombic lip cells migrate?

Answer 19

Rhombic lip cells are, like NCCs, also highly proliferative and have migratory, proliferating daughters.
Anterior (Superior) RL daughters migrate tangentially across the surface of the anterior HB to form the External Germinal Layer (EGL) of the cerebellum which later differentiate into granule neurons.
Posterior (Inferior) RL cells migrate tangentially to the ventral hindbrain -> pontine nuclei and inferior olive

Question 20

Granule neuron precursors

Answer 20

Proliferative zone on the outside (pial not ventricular)

Tangential, then radial migration

Question 21

Factors controlling cerebellar development

Answer 21

Production of rhombic lip cells is regulated by AT0H1 (Atonal-like transcription factor; aka Math1)

Sonic HH released from Purkinje cells stimulates mitosis in EGL

Question 22

What do mutations in human RELN display?

What do mutations in Reelin receptor lead to?

Answer 22

Mutations in human RELN often also display cerebellar hypoplasia.

Mutations in Reelin receptor (VLDLR) also lead to cortical and cerebellar disruptions