Glia: Development and Function 2 (Prof Kessaris)

Question 1

Which regions of the brain is supplied w/ new neurons throughout life ?

Answer 1

The olfactory bulb is supplied with new neurons from the adult SVZ.

Question 2

Where do adult neural stem cells in the SVZ come from ?

Answer 2

These are remnants of the embryonic neuroepithelial cells.

Question 3

What types of cells are generated form the adult SVZ ?

Answer 3

Stem cells from different regions of the SVZ generate restricted neuronal subtypes. Neural stem cells in vivo are not plastic and homogenous but rather represent a restricted and diverse population of progenitors.

Question 4

What is the model of stem cell lineage from embryogenesis to adulthood ?

Answer 4

Neuroepithelial stem cell –> RG –> SVZ, subgranular zone (in the hypo campus, SGZ) astrocytes
These SVZ and SGZ astrocytes can potentially amplify and become neuroblasts (committed nerve cell)

Question 5

Where are microglial cells ?

Answer 5

They are cells that originate from blood-derived macrophages (myeloid lineage, or pertaining to the bone marrow) outside the CNS and they are physiologically and embryologically unrelated to the other cell types of the CNS.
They represent the brain defence and immune system, responsible for CNS protection against pathogens. They are mobilised after injury, infection or disease

Question 6

How can we follow the distribution and development of microglia ?

Answer 6

By immunostaining for F4/80, a mouse macrophage-specific membrane marker.

Question 7

Which cells are microglia progenitors ?

When do they enter the neural tube ?

Answer 7

Microglial progenitors are foetal macrophages. These enter the neural tube at early embryonic stages (E8 in rodents) and transform into embryonic microglia.

Question 8

Where are microglia found in the perinatal brain ?

In the adult brain ?

Answer 8

In the perinatal brain amoeboid microglia are found predominantly in the white matter and in close proximity to the blood vessels.
These proliferate extensively and migrate into the overlying cortex.
In the adult brain microglia are distributed everywhere. In the normal brain they are found in a ramified, resting state.

Question 9

How do microglial cells act under normal conditions ?

Answer 9

Microglia are in a ‘resting’ state.
They constantly scan their territories (every microglial cell occupies a distinct territory).
Microglial processes are constantly moving looking for damage signals.

Question 10

How do microglial cells act in the initial stage of brain damage ?

Answer 10

Focal damage causes the transformation of ‘resting’ microglia to an ‘activated’ microglial state.
Initially microglia move their processes towards the site of lesion.
Some of the processes are retracted and others become thicker

Question 11

What are the 3 states the microglial cells can be in ?

Answer 11

• Ramified state: small cell body, many thin and motile processes, multiple branches. Reversible
• Activated state: Process retraction and thickening, enlargement of cell body, movement towards the site of injury, proliferation. Reversible. Activation signals can originate from other microglia, from neurons or from other glia
• Phagocytic state: occurs only under conditions of neuronal and or synaptic/terminal degeneration (cell death). Irreversible. Signals originate from dying or dead neurons or glia.

Question 12

What are schwann cells (SCs) ?

Answer 12

Secs are cells originating from the neural crest. They are the myelinating glia of the PNS. They form a myelin sheath around axons by tightly winding their membranous processes around the axon in a spiral.

Question 13

How are SCs different from oligodendrocytes ?

Answer 13

• SCs act in the PNS whereas oligodendrocytes act in the CNS
• SCs can only myelinated single axon, whereas oligodendrocytes may myelinate many
• the myelin composition is different

Question 14

Where are neural crest cells generated ?

Answer 14

Neural crest cells are generated from the dorsal neural tube.

Question 15

What do neural crest cells give rise to ?

Answer 15

Neural crest cells in the trunk region migrate in different directions to give rise to melanocytes in the skin, neurons and glia in DRG, or neurons of the autonomic NS, glia, and chromaffin cells.

Question 16

How do seemingly similar neural crest cell give rise do such a diversity of differentiated cells ?

Answer 16

This is still heavily investigated.

Question 17

What are the detailed migratory routes that cause neural crest cells to adopts different fates ?

Answer 17

These are not known.

Question 18

When do SC precursors and immature SCs appear ?

Answer 18

SC precursors: E12/13
immature SCs: E15
Both are proliferative.

Question 19

Which of the myelinating and non-mylelinating SCs differentiates first ?

Answer 19

Myelinating SCs differentiate first.

Question 20

How can we distinguish different SC cell differentiation stages ?

Answer 20

By the expression of different marker genes.

Question 21

What is Sox10 ?

Why is it essential ?

Answer 21

Sox10 is a transcription factor that is essential for SC development.
B-FABP (Brain-specific fatty acid binding protein) is a merger for glia. Sox10 mutant lack this marker and thus lack glia (although their neurons still develop).

Question 22

What is the function of unmyelinating SCs ?

Answer 22

• Surround bundles of small diamater unmyelinated axons
• They support and separate unmyelinated axons
• They express markers of immature Schwann cells
• They can myelinate experimentally

Question 23

What is the fct of myelinating SCs ?

Answer 23

• Schwann cells form a myelin sheath around axons by tightly winding their membranous processes around the axon in a spiral
• Myelinating Schwann cells myelinate axons larger than 1 μm in diameter
• Each Schwann cell myelinates only 1 axon

Question 24

How do SCs respond to injury ?

Answer 24

During Wallerian degeneration, SCs distal to the site of injury dedifferentiate and participate in the phagocytosis of their own myelin sheaths, and recruit macrophages to aid in the clearance of myelin debris.

Question 25

How to SCs react after successful axonal regeneration ?

Answer 25

SCs demyelinate the axon but w/ a thiner layer then before.

Question 26

What are satellite cells ?

Answer 26

These are flattened sheet-like cells that cover neuronal cell bodies in DRG and in sympathetic and parasympathetic ganglia.

Question 27

What are olfactory ensheathing cells ?

Answer 27

These cells envelop the axons of the olfactory nerve.

Question 28

What are terminal glia (teloglia or presynaptic SCs) ?

Answer 28

These glial cells cover axon terminals at the skeletal neuromuscular junction.

Question 29

What are enteric glia ?

Answer 29

Enteric glia are found in the enteric NS. They are similar to astrocytes.

Question 30

What are Müller glia ?

Answer 30

Müller glia originate from retinal neuroepithelial cells. They are the last cells to differentiate in the retina. They are situated in the Inner Nuclear Layer (INL, layer w/ bipolar cells).

Question 31

What is the proportion of Müller glia in the mature murine (mouse) retina ?

Answer 31

4-5%.

Question 32

Are Müller glia involved in generating new cells in the retina or guiding existing cells ?

Answer 32

No, müller glia are not the progenitor cells for retinal neurons and do not serve as guides/scaffolds for the migration of early born retinal neurons.

Question 33

What do progenitor cells and Müller glia have in common?

Answer 33

Both retinal progenitor cells and Müller glia share a radial morphology but differ in many ways.

Question 34

What are the fcts of Müller glia ?

Answer 34

• directly contribute to vision by acting as optical fibres to guide light to photoreceptors
• monitor retinal homeostasis and contribute to retinal - structure and function
• support neurons by releasing trophic factors, recycling neurotransmitters and controlling ionic balance in the extracellular space
• phagocytose cone outer segments, contribute to outer segment assembly and participate in a cone-specific visual cycle that helps to recycle the retinal chromophore for photodetection
• express progenitor-like genes, have proliferative responses and the ability to generate neurons under special conditions

Question 35

How do Müller glia respond to injury ?

Answer 35

By changing their morphology, biochemistry and physiology = reactive gliosis.
Depending on the severity of damage, this response may include proliferation of Müller glia.
Both proliferative and non-proliferative responses to injury are accompanied by changes in gene and protein expression and are often associated with Müller glial cell hypertrophy.

Question 36

What can happen to Müller glia in injured in injured mammals ?

Answer 36

Mammalian Müller glia can respond to injury, proliferate and express genes that are associated with retinal stem cells but they do not function as retinal progenitors in vivo. However, under the right circumstances Müller glia might be persuaded to adopt characteristics of a retinal progenitor that can be used for repair.

Question 37

How can teleport fish (such as zebrafish) regenerate a damaged retina ?

Answer 37

Unlike birds and mammals, Müller glia in the zebrafish retina have been identified as the source progenitors that regenerate cells in the zebrafish retina.

Question 38

Where are Bergmann glial cells (BGC) of the cerebellum localized ?

Answer 38

BGCs are localized in the Purkinje cell layer (PCL). BGCs associate closely w/ PC dendrites.

Question 39

Where are cerebellar astrocytes present ?

Answer 39

In the granule cell layer (gal) and white matter (wm).

Question 40

How have researchers observed the relationships between PCs and BGCs ?

Answer 40

(Glial fibrillary acidic protein) GFAP-positive BGC processes show intimate structural relationships with calbindin (calcium binding proteins)-positive PC dendrites in the molecular layer.

Question 41

What is the structure and physiology of BGCs in the mature cerebellum ?

Answer 41

• Mature BGCs are unipolar astrocytes that extend long processes across the molecular layer of the cerebellum
• Their processes form intimate structural relationships with the dendrites of PCs, which are inhibitory neurons that act as the sole source of output from the cerebellar cortex
• They express GABA and glutamate transporters, which in turn are involved in their clearance from the synapses
• Photoactivation of BG can modulate the neuronal activity of Purkinje cells by releasing glutamate

Question 42

What is the structure and physiology of BGCs in the developing cerebellum ?

Answer 42

• BG have similar morphology to radial glia cells: long radial fibres that extend toward the pial (basal) surface and guide the radial migration of immature neurons
• They are amongst the earlier cells to develop in the cerebellum.
• BG arise from neuroepithelial cells in the fourth ventricle and migrate from the ventricular zone through the mantle zone in synchrony with the migration of Purkinje cells.
• Bergmann glia play an important role in guiding the migration of granule neurons to their final position during cerebellum development.