Glia: Development and Function 1 (Prof Kessaris)

Question 1

Where does the world “glia” come from ?

Is this rigorously accurate ?

Answer 1

“Glia” derives from the Greek word for glue
This name suggests that they function to hold nerve cells together, which is not quite the case.
Glia support neurons and their communication. Without glia, the nervous system would not function properly.

Question 2

How much glia is there in the NS w/ report to neurons ?

Answer 2

10‐50 times more glia than neurons in the CNS.

Considered by some to be the “sleeping giants” of neuroscience.

Question 3

Which glial cells are present in the CNS ?

Answer 3

• Macroglia: oligodendrocytes + astrocytes
• Microglia
• Adult neural stem cells: sub-ventricular zone (SVZ) astrocytes
• Glia in the retina: Müller glia
• Glia in the cerubellum: Bergmann glia

Question 4

Which glial cells are present in the PNS ?

Answer 4

• Schwann cells
• Satellite cells in the DRG and other ganglia
• Enteric glial cells
• Other PNS glia

Question 5

What is the function of oligodendrocytes ?

Answer 5

They are the myelinating cells of the CNS.

Question 6

Give 3 examples of animal model that are useful to study the development and fct of the NS.

Answer 6

• the chicken: its egg can be easily manipulated
• the mouse: it is a mammal
• the zebrafish: short life cycle

Question 7

What are neuroepithelial cells and where are they found ?

Answer 7

Neuroepithelial cells are the early precursors of neurons and glia in the CNS. They line the ventricles throughout the CNS and form the ventricular zone.

Question 8

Wha are radial glia ?

Where are they found ?

Answer 8

At later stages neuroepithelial cells give rise to radial glia (RG). RG cell bodies remain within the ventricular zone (VZ) but their processes extend to the pial (or basal) surface. They divide and differentiate to become neurons and glia.

Question 9

Do neuroepithelial cells and RG generated neurons at the same time during development ?

Answer 9

No, neuroepithelial cells and radial glia generate neurons at different times during development.
Some neurons generated from radial glial cells migrate along radial glia.

Question 10

How is the neuroepithelium divided ?

Answer 10

The neuroepithelium can be subdivided into several progenitor domains which are specialized with respect to the neurons they give rise to: FP (floor plate), p3, pMN (motoneurons), p2, p1, p0.

Question 11

How can progenitor domains be identified ?

Answer 11

Progenitor domains can be identified by expression of specific marker genes:

• Msx3 for the dorsal part of the neuroepithelium
• Dbx1 for the medial part
• Nkx2.2 for the ventral part (floor plate)

Question 12

How can we follow the development of progenitor domains ?

Answer 12

Progenitor domains can be labelled in transgenic mice and their fate can be followed throughout development.

Question 13

Where do oligodendrocytes originate from ?

Answer 13

The first oligodendrocytes originate from the pMN domain in the spinal cord which generates first motor neurons and then switches to generate oligodendrocytes.

Question 14

From which cells do oligodendrocytes originate from ?

Which genetic markers (mRNA) do they express ?

Answer 14

Oligodendrocytes originate from VZ precursor cells in the ventral spinal cord that express Olig2, Sox10 and Pdgfra.

Question 15

How do oligodendrocytes migrate in the spinal chord ?

Answer 15

The first oligodendrocyte progenitors are generated in the ventral spinal cord. They migrate away from the VZ and proliferate to populate the entire spinal cord

Question 16

How does oligodendrocyte generation vary w/ embryonic development in the dorsal spinal chord ?

Answer 16

The dorsal spinal cord generates small number of oligodendrocytes at late embryonic stages.

Question 17

Where do the first oligodendrocyte progenitors appear in the telencephalon and the spinal chord ?

Answer 17

In ventral territories.

Question 18

What are the 3 stages of oligodendrocyte development ?

Answer 18

• Oligodendrocyte precursora: Pdgfra+ve or NG2+ve precursor cells proliferate rapidly. They have simple morphologies.
• Immature oligodendrocytes have a more elaborate morphology. They express O4 and other markers. They have limited proliferative capacity.
• Mature oligodendrocytes express markers such as galactocerebroside (GC). They ensheath and myelinate axons.

Question 19

What are the 4 stages of axon myelination by oligodendrocytes ?

Answer 19

1. Axon contact: Contact with axon stimulates differentiation. Reciprocal interactions with axons take place to promote differentiation.
2. Axon ensheathment: Initiator process extends and begins to spiral along the axon. Most oligodendrocytes ensheath multiple axons within the proximity of their cell body.
3. Remodeling: Non-ensheathing processes are lost.
   The initial ensheathments are uncompacted.
4. Maturation: Oligodendrocyte sheath wraps interact and fuse to each other to produce compact myelin.
   The myelin sheath grows longitudinally. Nodes of Ranvier develop.

Question 20

What are nodes of Ranvier ?

What can be found in these nodes and why ?

Answer 20

Nodes of Ranvier are small unmyelinated regions on axons. They are gaps in the myelin sheath.
Sodium channels are clustered at the Nodes of Ranvier. These are necessary for action potential propagation.

Question 21

How does the myelin sheet allow saltatory conduction along nerve fibers ?

Answer 21

Local current in response to action potential initiation flows locally. The presence of myelin prevents the local current from leaking across the internodal membrane; it therefore flows farther along the axon than it would in the absence of myelin. The result is a greatly enhanced velocity of AP conduction.

Question 22

How are astrocytes distributed in the CNS ?

How can observe this ?

Answer 22

Astrocytes are distributed everywhere in the adult CNS. This can be observed though in situ hybridization for Fgfr3, a marker for astrocytes at all stages of their development and differentiation.

Question 23

What are the 2 main types of astrocyte morphologies ?

Answer 23

Astrocyte morphologies vary according to the region they are in:

• “Fibrous” astrocytes are found in the white matter of the CNS. They have long sparsely-branched processes.
• “Protoplasmic” astrocytes are found mainly in the gray matter. They have numerous short and highly-branched processes.

Question 24

How do the appearances of “fibrous” and “protoplasmic” astrocytes differ ?

Answer 24

Fibrous astrocytes have a “radial” appearance.

Protoplasmic astrocytes have a “bushy” appearance.

Question 25

From which cells are astrocytes generated ?

Answer 25

Astrocytes are generated from radial glial cells during embryogenesis. Some astrocytes are generated by transformation of radial glia at the end of neurogenesis.

Question 26

How do astrocytes migrate in the cortex ?

Answer 26

Unlike oligodendrocyte precursors, astrocyte precursors do not spread extensively. Astrocytes generated from cortical precursors remain in the cortex

Question 27

What are the fcts of astrocytes in the adult CNS ?

Answer 27

- Structural support. Interspersed amongst neurons providing architecture. Formation and regulation of the blood-brain barrier (BBB). - Metabolic support: they provide energy substrates for neurons. Regulation of extracellular ion concentrations and pH. - Removal of neurotransmitters from the extracellular space. - They participate in synapse formation and possibly synapse elimination by secreting factors required for these processes.

Question 28

What is the role of the BBB ?

Answer 28

The BBB allows selective nutrients to enter the CNS from the blood and restricts the passage of larger objects such as bacteria. Vascular endothelial cells form the barrier. Astrocyte endfeet have receptors, transporters, channels and regulate the interface between blood and the brain.

Question 29

How do astrocytes remove neurotransmitters the extracellular space ?

Answer 29

Astrocytes have neurotransmitter receptors, like postsynaptic cells. They represent the main sink of Glutamate in the brain. Glutamate is converted to Glutamine by astrocytes and then released back for uptake by pre- synaptic neurons. Other active substances such as ATP are also released by astrocytes and can modulate synaptic transmission..