Lecture 29- Glial development II

Question 1

How many cells does a Schwann cell myelinate?

Answer 1

-1

Question 2

How many cells does an oligodendrocyte myelinate?

Answer 2

-up to 15

Question 3

What is myelination good for?

Answer 3

-it increases the rate of action potential conduction -it offers support for the neurons -if neurons are demyelinated they can die -a squid axon: giant and unmyelinated; then it is slow (only 20-25 m/sec) -squid has smaller axons as well= and these are even slower -so larger diameter means faster -rabbit: myelinated axons, much smaller than the squid axons but are faster because they are myelinated (90m/sec)

Question 4

What is the node of Ranvier, the internode, paranode and the juxtaparanode?

Answer 4

• node of Ranvier: the place where ion channels are concentrated and no myelination occurs
• internode: segment between the Nodes of Ranvier
• juxtaparanode: the outermost part of the internode that is in contact with the paranodes
• paranode: region right next to the node
• juxtaparanode: the region near the node of Ranvier between the paranode and internode regions

Question 5

What is the reason for myelinated axons being faster in conducting action potentials?

Answer 5

-clusters of ion channels at the node of Ranvier -this is both in the PNS and CNS

Question 6

What is the most important function of the Schwann cells and oligodendrocytes?

Answer 6

• one of the most important functions of Schwann cells (and oligodendrocytes) is the clustering proteins to the node of Ranvier
• voltage gated Na+ channels need to be confined to the Node of Ranvier
• voltage gated K+ channels confined to the juxtaparanode

Question 7

What is the mechanism of nodal clustering in the PNS?

Answer 7

• nodal clustering occurs through two mechanisms:
  1. Schwann cell microvilli contact the axon and induce clustering of scaffolding proteins and Na+ channels
  2. Tight junctions form at the juxtaparanode and form a barrier to diffusion of the channels

Question 8

When does myelination in the CNS and PNS happen?

Answer 8

-most myelination occurs postnatally both in the CNS and PNS -myelination is an ongoing process, not finished in the nervous system until 28 years of age -in newborns very little myelination -by 4 months much more -myelination is a long process so reasonable to expect more factors at play

Question 9

What is the difference between PNS and CNS myelination?

Answer 9

-there is a shorter window for PNS myelination and much longer for CNS myelination

Question 10

When are Schwann cells generated?

Answer 10

-embryonically but myelination occurs postnatally

Question 11

What are the 2 types of Schwann cells?

Answer 11

1. Myelinating: surround large diameter axons, and surround only one axon 2. Non-myelinating: surround a larger number of small diameter axons= Remak bundles

Question 12

What are Schwann cells derived from?

Answer 12

-derived from the neural crest -neural crest cells are highly migratory and give rise to a variety of cell types: 1. laterla stream gives rise to melanocytes 2. Ventral stream gives rise to neurons and glia in DRG 3. Ventral stream gives rise to glia, autonomic neurons and chromaffin cells

Question 13

What is the Schwann cell lineage development?

Answer 13

1. Neural crest cell
2. Schwann cell precursor
3. Immature Schwann cells -then develop into either non-myelinating Schwann cell or a pro-myelin and eventually Myelinating Schwann cell

(description 2: first commited to schwann precursor= then the immature schwann cell is determined by teh contact to axon, if contact to large axon= myelinating -if small axons= non myelinating Schwann cells)

Question 14

What are 2 transcription factors in Schwann cell development and myelination?

Answer 14

-Sox10 and Krox20 -both Sox10 and Krox20 haev ongoing roles in directly inducing the expression of myelin genes

Question 15

What does Sox10 do?

Answer 15

• controls the lineage commitment in Schwann cells (so Sox 10 determines if cell will become Schwann precursor
• if knockout Sox10 the mice don’t develop any myelination (do have Schwann cells but don’t myelinate)

Question 16

What does Krox10 do?

Answer 16

• controls maturation and differentiation of Schwann cells
• the dash line= means the process is reversible
• a cell can undergo undifferentiation (upon injury) this can happen to both myelinating and non-myelinating
• the reversible part is only to the stage of immature Schwann cells, cannot go further back

Question 17

What is the Krox20 specifically for?

Answer 17

-Krox20 is specifically induced in the myelinating Schwann cells -Schwann cell differentiation into the myelinating stage is blocked in the absence of Krox20 -mice and humans with Krox20 mutations show severe deficits in peripheral myelination -Krox20 knockouts develop Schwann cells but do not myelinate

Question 18

What is the Charcot-Marie-Tooth disease?

Answer 18

-a disease in humans when have a problem with myelination -deletion in the Krox20 gene -comes on a spectrum, depends how much of the gene is damaged or mutated

Question 19

What is the role of Neuregulin 1 in Schwann cell development?

Answer 19

• determines the ensheathment fate of peripheral axons
• neuregulin= protein that is expressed by axons
• Schwann cells have a receptor for it
• the large axons express high levels of neuregulin 1
• the small diameter axons= have low levels oof neuregelin 1
• there is a minimum requirement for the axons to express neuregulin 1
• the role of neuregulin has been proven: genetically, if knockout one allele for neuregulin 1= has thinner myelination, if knockout completely= no myelination occurs
• if overexpress neuregulin 1= then have thicker myelination
• the level neuregulin 1 type III= can switch axons from nonmyelinated to myelinated in the SCG (there are usually non myelinated) and if you overexpress neuregulin I type III= then become myelinated (eventough not normally so

Question 20

What is the role of Neurotrophins and specifically BDNF in PNS myelination?

Answer 20

-the brain-derived neurotrophic factor (BDNF) regulates peripheral myelination via acting on neurons -another factpr controlling axonal myelination in PNS -extracellular factors that act on neurons or on the Schwann cells (depends which one has the receptor) -BDNF= is important factor -if overexpressed= have normal size of axons but their myelin sheath= much thicker -proven in vitro as well -so BDNF acts on the neuronal receptors (p 75 receptor. if delete it= then BDNF has no effect) -if remove p75 removed from Schwann cells= no difference -it is the neuronal receptor p75

Question 21

What is the role of axonal diameter in PNS myelination?

Answer 21

-the axons that are non myelinated= usually smaller than 1 micrometer, so must be larger than that to have myelination =probably regulated by neuregulin I type III expression (larger axons have more -the thicker the myelin, the larger the diameter= the faster the conduction -the larger the diameter= the thicker the myelin= the faster the conduction • Well known as a general rule, larger diameter axons are more likely to be myelinated (axonal diameter below 1 micrometer are not myelinated) -axonal caliber sizes correlated their myelin thickness and the speed of signal transduction along axons

Question 22

What is the cutoff diameter for myelination in the PNS?

Answer 22

-1 micrometer

Question 23

What are oligodendrocytes derived from?

Answer 23

-derived from the Neural tube -both oligodendrocytes and astrocytes are generated from radial glial cells -oligodendrocyte generation is embryonic, at birth and into adulthood= again an ongoing process

Question 24

Where are oligodendrocytes generated?

Answer 24

• this tells you where oligodendrocytes are generated
• both dorsally and ventrally, all the way thorugh
• majority are generated early in the ventral domain, = 85% are generated in the pMN domain and they express Olig2
• pMN gives rise to motor neurons and oligodendrocytes
• small proportion is generated later and they are more dorsal
• the majority of oligodendrocytes are generated from ventral progenitor cell domains and the remainder form other progenitor domains
• early in development oligodendrocyte progenitors (and motor neurons) are specified from the pMN (venral) domain by Olig2+

Question 25

What is the progression of oligodendrocyte production?

Answer 25

• within the spinal cord and the brain there is an initial wave of ventrally derived oligodendrocytes from Olig2+ cells, followed by waves of more dorsally derived oligodendrocytes
• over time dorsally derived oligodendrocytes replace ventrally derived oligodendrocytes (unclear why and what is the difference between the two groups)
• 2 waves: 1. ventral, 2. dorsal

Question 26

What is the development of the oligodendrocyte lineage?

Answer 26

1. neural precursor cell
2. OPC
3. Immature pre-myelinating oligodendrocytes (here start expressing myelin protein)
4. eventually mature and become myelinating oligodendrocytes

Question 27

What are the transcription factors involved in oligodendrocyte development?

Answer 27

• maturation is controlled by transcription factors
• different stages of lineage express different sets of transcription factors
• Olig2 is expressed throughout the oligodendrocyte lineage (not in Schwann cells)
• NG2
• PDGF= OPC’s proliferate in response to platelet derived factor (PDGF), its levels control OPC numbers
• MBP (myelin basic protein)

Question 28

What is the transcription factor Myrf involved in in CNS myelination?

Answer 28

-it is required for CNS myelination -is expressed by oligodendrocytes quite late in their development -controls the maturation of oligodendrocytes

Question 29

What happens to Myrf knockouts?

Answer 29

-if knockout MYRF then no myelination in CNS, specific to CNS, no myelin proteins or myelin -but doesn’t affect the PNS, those still myelinate normally

Question 30

What are the extracellular factors involved in myelination of the CNS?

Answer 30

-neurotrophins (e.g.BDNF) -neuregulin-1 a tiny bit but not really -Lingo 1

Question 31

What is the role of Neurotrophins and specifically BDNF in CNS myelination?

Answer 31

-BDNF promotes CNS myelination via acting on oligodendrocytes -BDNF is the most common neurotrophin in the brain, (knockouts died after birth= very important to have it) -try to overexpress= then less myelination and the sheath is thinner than in the wildtype -the condition knockout mice: (BDNF receptors are on both the axons and on the oligo) and through experiments= direct role on acting on oligodenrocytes receptors in the CNS!! the TrkB is knockout= the receptor, then myelination thinner -difference in how myelination is regulated by BDNF in PNS and CNS -

Question 32

What is the role of Neuregulin-1 in CNS myelination?

Answer 32

-axonal ligand -Neuregulin-1 is not required for CNS myelination, unlike in PNS, myelination in CNS proceeds fairly normally in the absence of neuregulin though overexpression doe increase myelin thickness neuregulin 1 is not required for CNS myelination -but overexpression= thicker myelin sheaths in the CNS! -but compared to PNS not that big an effect

Question 33

What is the role of Lingo-1 in CNS myelination?

Answer 33

• inhibitory axonal ligand -Lingo 1= axonal ligand (protein expressed by the axons)
• inhibits myelination
• if knockouts= have more myelination (so the presence inhibits it)
• if express lingo1 specifically in axons= then less myelination = negative role in myelination

Question 34

How does an oligodendrocyte know which axons to myelinate?

Answer 34

-factors at play: 1. Neuronal activity 2. Experience 3. Axonal diameter

Question 35

How does neuronal activity influence if an axon is or isn’t myelinated in the CNS?

Answer 35

-experiment 1 :-inject toxin into a mouse eye, this blocks action potential= reduction of myelinated axons but not in number of axons -so positive role= the action potential = neuronal activity promotes myelination -experiment 2: OPCs receive direct input from the adjacent axons and can depolarize in response, activate cells in C1 hippocampus using glutamate (get action potentias spreading)= can see that OPCs activate too -so they can communicate directly

Question 36

How does experience influence if an axon will be myelinated or not in the CNS?

Answer 36

-experience driven myelination occurs both in development and adulthood -experience, exercise can influence myelination in adults -normally get reduction in myelination as you age -young adults levels before and after juggling = increase in myelination! -exercise, experience driven activity = higher myelin -if you learn to play the piano increases the myelination

Question 37

How does axonal diameter influence if an axon will be myelinated or not in the CNS?

Answer 37

-general rule: larger diameter axons are more likely to be myelinated -axonal caliber sizes correlated their myelin thickness and the speed of signal transduction along axons -found out in vitro: in some situation axonal caliber can be experimentally manipulates, a new in vitro myelination system of artificial fibres of different diameter shows that oligodendrocytes preferentially ensheath larger diameter fibre -in vitro: can put oligo on fibres and 0.4 micrometer seems to be the cutoff= bigger than 0.4=myelinated smaller= non myelinated -but unclear if this would be functinally as well

Question 38

Summary Schwann cells?

Answer 38

-Precursors derived from the neural crest and specified through Sox10 -Nrg1 promotes both survival and proliferation of Schwann cell precursors as well as the differentiation into myelinating Schwann cells -Krox20 expression is required to stimulate myelination

Question 39

Summary Oligodendrocytes?

Answer 39

-progenitors specified by radial glial cells -first arise from Olig2+ neural stem cells in the ventral neural tube, later also from dorsal regions -OPCs proliferate and migrate throughout the CNS before differentiating into myelinating oligodendrocytes

Question 40

Summary myelination?

Answer 40

-most myelination occurs postnatally and is subject to tight controls by transcription factors, extracellular factors, axonal diameter, axonal ligands, axonal activity

Question 41

Summary table?

Answer 41

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