Cell Lineage of Neurons and Glia

Question 1

In what region is found the progenitor cells with the ability of becoming neural precursors? How is this specific region called? Via which model organism was the region identified?

Answer 1

Genetic screens in the Drosophila allowed to identify the proneural region, which is part of the ventral ectoderm.

Question 2

How can be identified potential neuroblasts?

Answer 2

They express proneural genes (achaete-scute TFs).

Question 3

The proneural region contains clusters of potential neuroblasts. Usually, only one potential neuroblast per cluster actually becomes a neuroblast. Which mechanism is at the root of this process? What experiment demonstrated the relevancy of this model?

Answer 3

In a cluster, potential neuroblasts mutually inhibit and only one (random) cell can become a neuroblast. Ablating one neuroblast leads to its replacement by another neuroblast, suggesting that potential neuroblasts generates surround inhibition.

Question 4

What signaling system would underlie the surround inhibition mechanism of potential neuroblasts?

Answer 4

Delta-Notch signaling.

Question 5

What is happening if either Delta or Notch are KO?

Answer 5

Overproduction of neuroblasts and underproduction of epidermal cells.

Question 6

Is Delta-Notch a cell-to-cell interaction signal or is it a secreted signal?

Answer 6

Cell-to-cell interaction signal.

Question 7

Delta is the _____, whereas Notch is the _____.

Answer 7

Delta is the ligand, whereas Notch is the receptor.

Question 8

What is happening downstream of Notch?

Answer 8

Notch activation via Delta binding ->protease activation ->intracell. domain of Notch cleaved -> enters nucleus and interacts with TFs that block proneural transcription.

Question 9

What is determining which cell becomes the neuroblast in a cluster of potential neuroblasts?

Answer 9

The cell that happens to have the highest Delta expression (random).

Question 10

Explain in detail the surround inhibition mechanism of Delta-Notch signaling.

Answer 10

The cell with higher Delta expression causes the Notch signaling of its neighbouring cell to increase. The increasing Notch signal inhibits the expression of achaete-scute proteins. Downregulation of achaete-scute proteins decreases expression of Delta. Decrease in delta expression causes the initial neighbouring cell to have lower Notch signaling, which allows more Delta to be expressed (and the cycle repeats). Less Notch signaling = neural fate.

Question 11

What could be one TF that is downregulated by Notch signaling?

Answer 11

BHLH.

Question 12

Which signal can control Notch activity? In what documented process is it involved?

Answer 12

Numb. Involved in the differentiation of sensory organ precursors in Drosophila (SOP).

Question 13

What is the consequence of the asymmetric distribution of Numb in SOPs daughter cells?

Answer 13

Some daughter cells acquire Numb and other don’t. Therefore, some cells can acquire a neural fate (acquire Numb) and the others become epidermal.

Question 14

True or false: neural fate determination is always random.

Answer 14

False. Yes it is random if determined by Delta-Notch signaling, but can also be pre-determined by acquisition of Numb (inhibiting Notch).

Question 15

True or false: humans have one more ventricular zone than mice.

Answer 15

True, the outer subventricular zone.

Question 16

From what progenitors do arise radial glial cells? Provide two essential functions of RGCs.

Answer 16

Originate from neuroepithelial cells in the ventricular zone. They are the progenitors of neurons and glia during development. They also provide a scaffold for neuronal migration into cortical layers.

Question 17

At different time points during development, radial glial cells divide into different cellular identities. State in what cellular identities they divide 1) early in dev. 2) mid. dev. and 3) end of development.

Answer 17

1. Amplification stage: neuroepithelial cells divide symmetrically.
2. Middle stages: RGCs divide asymmetrically to give rise to both neurons and RGCs.
3. Late stages: RGCs give rise to oligo. and become astrocytes.

Question 18

Explain how oblique division in RGCs leads to the generation of neurons.

Answer 18

Oblique divisions of RGCs asymmetrically distribute apically localized proteins (Par3) in the two daughter cells. The daughter cells with high Par3 concentration conserves its RGC phenotype because Par3 inhibits Numb, relieving its inhibition on Notch signaling (binding to its intracellular domain). The other daughter cell still has active Numb signaling, therefore acquiring a neural fate.

Question 19

Neurons and glia of the PNS originate from which progenitor cells.

Answer 19

Neural crest cells.

Question 20

Which signal imposes neuronal identity for PNS cells? Which signal for Schwann cell identity?

Answer 20

BMP signaling.
Glial growth factor (GGF).

Question 21

How are PNS cells differentiated in their specific neural or glial identities?

Answer 21

By the environmental cues they encounter while migrating.

Question 22

In the CNS, from what region are originating the cells migrating to different cortical layers?

Answer 22

The ventricular zone.

Question 23

The superficial layers of the cortex are most likely composed of old or new neurons/glia?

Answer 23

New (young, later born).

Question 24

What can be experimentally done to demonstrate that the positioning of cortical neurons is age-dependent?

Answer 24

Injecting the cortex at different time intervals with a dye that stains specific cortical neurons.

Question 25

Why is regulation of movement and adhesive properties critical for proper radial migration?

Answer 25

The cells need to know when to stick, when to detach, when to move, when to stop moving.

Question 26

What are the cues regulating movement of neurons in radial migration?

Answer 26

Environmental: BDNF + NT-4.
Intracellular: Lis-1.

Question 27

What are the cues regulating adhesion of neurons in radial migration?

Answer 27

Specific to the neuron: Astn1 (adhesion protein).
Specific to the environment: Reelin (ECM protein regulating layer formation).

Question 28

What causes lissencephaly?

Answer 28

Migration arrest of cortical neurons before reaching their target = inverted cortex. Linked to mutation in Reelin gene.

Question 29

How do relate, reeler, scrambler, reelin and Dab1?

Answer 29

Reeler and scrambler are very similar lissencephaly phenotypes respectively caused by the mutations in Reelin and Dab1. Dab1 is downstream of Reelin’s receptor.

Question 30

Does non-radial migration exist in the CNS?

Answer 30

Yes, tangential migration.

Question 31

What specific type of neuron uses tangential migration to translocate itself across the cortex?

Answer 31

Cortical interneurons.

Question 32

SUMMARY CARD:

What is controlling the differentiation of neural precursor cells into neurons or glia?

How do radial glial cells give rise to different neural cellular identities?

From what regions of the neural tube are precursor cells for CNS and PNS neural cells respectively originating?

How do neural crest cells give rise to different neural cellular identities?

How do cells form different layers in the cortex?

Answer 32

What is controlling the differentiation of neural precursor cells into neurons or glia?

-Delta-Notch signaling.
- ^^ can be modulated by Numb proteins.

How do radial glial cells give rise to different neural cellular identities?

-Asymmetric division: Par3 - Numb - Notch pathway.

From what regions of the neural tube are precursor cells for CNS and PNS neural cells respectively originating?

-CNS: proneural region (ventral ectoderm).
-PNS: neural crest cells from the dorsal part of the neural tube.

How do neural crest cells give rise to different neural cellular identities?

-BMP imposing neuronal fate and GGF imposing glia fate (Schwann cell).

How do cells form different layers in the cortex?

-Radial migration.

Question 33

How d