Myelinating glia: Oligodendrocytes + Schwann Cells

Question 1

How are the speeds of AP conduction increased?

Answer 1

Increased body temperature = faster diffusion

Increased size + diameter = giant axons of invertebrates.
Myelination/insulation + Saltatory conduction…

E.G. primary afferent (sensory) axons = C fibres vs A alpha fibres = A-alpha fibres are wider, with thick myelination and have remarkably increased speed of conduction vs C fibres which are unmyelinated and thin diameter.

Question 2

What cells control myelination in the CNS vs the PNS?

Answer 2

Oligodendrocytes (CNS) myelinate multiple axons within their sphere of influence whereas Schwann cells in the PNS myelinate only single myelin sheaths.

Question 3

Where are Schwann cells and Oligodendrocytes derived from?
What controls their migration?

Answer 3

Schwann cells originate from neural crest cells (few from ventral neural tube)
Schwann cells migrate with and differentiate under control of peripheral axons.

Oligodendrocytes are derived from O2A progenitors in the VENTRAL ventricular proliferative zone of neural tube… O2A progenitor migrates along radial glial cell and in its target, will differentiate into oligodendrocyte progenitor, which when in contact with active axons, will start to myelinate.

Question 4

How is Oligodendrocyte or astrocyte fate controlled?

Answer 4

The O2A progenitor in the ventricular proliferative zone of neural tube is a bipotential cell that arises after birth (V. little myelination at birth!!!)

O2A receives proliferative signalling via PDGF, NT-3, IGF-1 etc from astrocytes…. O2A cell’s intrinsic clock determines when O2A cell withdraws from cell cycle to differentiate into Either:

Type 2 astrocyte - BMP4 signalling + CNTF, plus RA and TH.

Oligodendrocyte - BMP4 signalling inhibits oligodendrocytes… but low serum favours them.

The O2A progenitor follows radial glial cells to its position, where it will differentiate.

Question 5

What are markers of oligodendrocyte precursors and how can their migration be mapped?

Answer 5

olig-2, can show them in VPZ of neural tube.
Sox-10 + PDGFRa… can map the pathway of migration

Oligodendrocyte precursors arise from ventral region of VPZ in the neural tube… closer to the notochord…
Shh signalling gradient up towards the dorsal regions of neural tube…
Shh causes O2A progenitor to differentiate into oligodendrocyte precursors..

Oligodendrocyes arise from stem cells of spinal cord previously gave rise to somatic motor neurones!

Question 6

What signalling affects O2A progenitors, oligodendrocyte precursors?

Answer 6

Shh signalling gradient up towards the dorsal regions of neural tube…
Shh causes O2A progenitor to begin to differentiate into oligodendrocyte precursors..

Oligodendrocyte precursors aren’t very differentiated until they reach the vicinity of axons…

Axons provide mitogenic signals for O2A cells like PDGF and Neuregulin.
Electrical signalling also stimulates O2A proliferation - more mitogens by astrocytes.

Notch signalling provides negative regulation of oligodendrocyte differentiation = Jagged1 on axons, Notch1 on oligodendrocytes…

Surival signals from neurones help maturation of oligodendrocytes and also enhance myelin gene transcription….

Question 7

What oligodendrocytes are migratory?

Answer 7

Mature oligodendrocytes are stationary, whilst oligodendrocytes precursors and O2A progenitors are migratory..

Question 8

What molecules are needed for migration and what guides migration??

Answer 8

Precursors follow radial glia outwards from VPZ and follow developing axon pathways and require integrins, PSA-NCAM for migration

Question 9

What controls oligodendrocyte number?

Answer 9

An excess amount of oligodendrocyte progenitors are produced…. so excess oligodendrocytes die from apoptosis.

Progenitors and newly-matured oligodendrocytes compete for limited amounts of mitogens and survival factors released by astrocytes and neurones…

NRG1-3 bind ErbB receptors on undifferentiated neural crest cells in contact with axons… Setting of Ras/Raf/MAPK pathway acting as potent mitogens to precursors and potent survival factors for mature cells.

Surival signals from neurones help maturation of oligodendrocytes and also enhance myelin gene transcription….

Axons provide mitogenic signals for O2A cells like PDGF and Neuregulin.
Electrical signalling also stimulates O2A proliferation - more mitogens by astrocytes.

Question 10

How do Schwann cell progenitors migrate?

Answer 10

Neural crest cell progenitors migrate to the periphery over the surface of the neural tube and continue along axon pathways to continue their interaction during migration.

Question 11

How do Schwann cells generate myelin sheaths?

Answer 11

The Schwann cell must identify the axon, and then produce myelin sheath through continued migration of the leading glia process to encircle the axon…. Then there is exclusion of contents to allow early formed loops to undergo compaction.

Question 12

Are all Schwann cells myelinating?

Answer 12

No, some Schwann cells develop into non-myelinating cells

Question 13

When is Schwann cell progenitor migration stopped?
What factors promote differentiation, proliferation + survival?

Answer 13

Migration of Neural crest cells stops when they encounter axons.,, expressing Pax3 to inhibit differentiation and myelination…

As they come into contact with axons, downregulation of Pax3 prompts differentiation towards Schwann cell precursors.

Neuregulins, like GGF, expressed by motor neurones + peripheral neurones activate ErbB receptors on Schwann cell precursors..
= Stimulates the differentiation into and proliferation of Schwann cell precursors… aswell as promote their survival.
= Schwann cell starts upregulating Krox20 and P0….

Start to express CAMs like NCAM, GFAP to begin adhesion to axons and starts to begin myelination with MBP, NCAM, GFAP, L1, P0 etc.

Here there is Axon-dependent survival via Neuregulins like GGF…. but unlike oligodendrocytes, which have axon dependency forever!!, Schwann cells switch dependency to autocrine/ self-survival mechanisms…

Question 14

What transcription factors control Schwann cell myelination?

Answer 14

Krox20 = required for myelination…. Axon neuregulins upregulates Krox20 in Schwann cell precursors… Starts expressing myelin proteins…

Pax3 = inhibits Schwann cell differentiation so expressed in progenitors, but is downregulated as myelination starts when in contact with axons…

These TFs are unique to Schwann cells

Question 15

What CAMs are different between oligodendrocytes and Schwann Cells?

Answer 15

L1 is required for the initiation of myelination in Schwann cells = a CAM… and allows adhesion of myelin sheath to the axon
Whereas, Neurofascin-155 is expressed in oligodendrocytes…

Periaxins are located in SC membranes in contact with axons, but not in oligodendrocytes

Question 16

What other proteins are central to myelination?

Answer 16

NCAM expressed in Schwann cells and oligodendrocytes…
Myelin-associated glycoprotein = MAG, are located in Schwann cell membranes in contact with axons… as well as periaxin..

Question 17

After axon dependent survival, what keeps Schwann cells alive?

Answer 17

Schwann cells lose complete dependence on neuregulin (NRG3) released by axons and astrocytes…

Survival is promoted by neurotrophin-3 (NT3), IGF2 and PDGF-BB released via autocrine survival…

Question 18

What does this mean in terms of Schwann cell survival without axons?

Answer 18

Schwann cells, due to switching to autocrine survival with NT-3, IGF2, PDGF-BB, can survive the death of axons, and retain the ability to stimule nerve regrowth!!!

Question 19

Can schwann cells make myelin without axons?

Answer 19

No!
Schwann cells ONLY make myelin in the presence of axons, whereas oligodendrocytes will produce myelin in culture on their own.

Question 20

Why is myelin compaction so important?

How is exclusion achieved?

Answer 20

Myelin compaction occurs in both oligodendrocytes and Schwann cells.
Compaction required for effictivity of the myelin sheath… needs compaction to be fully formed.

Need exclusion of other cellular material out of the membrane that wraps around the axon.
MBP is basic and involved in exclusion of proteins unrelated to myelin sheath.

Question 21

What are the specialised myelin proteins in both cell types?

What proteins are unique to each cell type?

How abundant are each proteins?

Answer 21

Schwann cells and oligodendrocytes both require MBP for exclusion of cellular material during compaction..

Po = SChwann cells only = an Ig-CAM.
PLP = oligodendrocytes!!
Both Po and PLP are required for organising myelin repeat periods by linking the layers together.

MBP for both.

Both Po (SChwann) and PLP (Oligo) are required for compaction/stability of myelin…

AS Po is Schwann cell only = most abundant protein in PNS myelin.
As PLP is OligoD only = most abundant protein in CNS myelin

Question 22

What are the regions of the Nodes of Ranvier?

Answer 22

Node = VG Na+ channels.
Paranode = TM proteins prevent movement of Na+ and K+ channels in axon PM.. Contactin, Caspr, and Nuerexin in Schwann cells…
Juxtaparanode = High conc. of VG K+ channels. Kv1.1

Question 23

What is found in the paranode?

Answer 23

TM proteins prvent movement/maintain separation of Na+ and K+ channels to their respective regions.

Caspr, Contactin, Nuerexin in Schwann cells…

Question 24

Why is the myelin sheath so important?

Answer 24

The myelin sheath creates region of high resistance, due to its insulation properties,.

The node itself, in absence of myelin, has low resistance to facilitate the flow of ions.

This charge separation makes APs more likely to occur at the nodes themselves rather than elsewhere.

Question 25

How do the Nodes of Ranvier mature?

Answer 25

First point of contact with axon occurs at the node with expression of Ezrin and others asspioated with initial adhesion.

Clustering of Sodium channels widely in early node - but as node matures, clustering narrows and sodium channel density increases within narrowing node.

Potassium channels cluster later on, initially in the node but shift towards the juxtaparanode as maturation of structure.

Question 26

How do oligodendrocytes/Schwann cells regulate channel clustering in Nodes of Ranvier?

Answer 26

When the cells bind to the axon, causing regulation of clustering of Na+ and K+ channels to node and juxtaparanode respectively.
Thought to be a consequence of specific protein-protein contacts in paranodal loops.
Paranodal loops are strongly adhered at the paranode, help with the segregation of channels…

Question 27

What mutations affect myelination?

Answer 27

SHIVERER mutant mice have nearly no myelin = oligodendrocytes fail to produce MBP..

PLP associated with linkage between sheets in the sheeth (oligodendrocytes) or Po in Schwann cells.