Lecture 29- Glial development II Flashcards
How many cells does a Schwann cell myelinate?
-1
How many cells does an oligodendrocyte myelinate?
-up to 15
What is myelination good for?
-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)
What is the node of Ranvier, the internode, paranode and the juxtaparanode?
- 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
What is the reason for myelinated axons being faster in conducting action potentials?
-clusters of ion channels at the node of Ranvier -this is both in the PNS and CNS
What is the most important function of the Schwann cells and oligodendrocytes?
- 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
What is the mechanism of nodal clustering in the PNS?
- 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
When does myelination in the CNS and PNS happen?
-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
What is the difference between PNS and CNS myelination?
-there is a shorter window for PNS myelination and much longer for CNS myelination
When are Schwann cells generated?
-embryonically but myelination occurs postnatally
What are the 2 types of Schwann cells?
- Myelinating: surround large diameter axons, and surround only one axon 2. Non-myelinating: surround a larger number of small diameter axons= Remak bundles
What are Schwann cells derived from?
-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
What is the Schwann cell lineage development?
- Neural crest cell
- Schwann cell precursor
- 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)
What are 2 transcription factors in Schwann cell development and myelination?
-Sox10 and Krox20 -both Sox10 and Krox20 haev ongoing roles in directly inducing the expression of myelin genes
What does Sox10 do?
- 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)
What does Krox10 do?
- 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
What is the Krox20 specifically for?
-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
What is the Charcot-Marie-Tooth disease?
-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
What is the role of Neuregulin 1 in Schwann cell development?
- 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
What is the role of Neurotrophins and specifically BDNF in PNS myelination?
-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
What is the role of axonal diameter in PNS myelination?
-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
What is the cutoff diameter for myelination in the PNS?
-1 micrometer
What are oligodendrocytes derived from?
-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
Where are oligodendrocytes generated?
- 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+
What is the progression of oligodendrocyte production?
- 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
What is the development of the oligodendrocyte lineage?
- neural precursor cell
- OPC
- Immature pre-myelinating oligodendrocytes (here start expressing myelin protein)
- eventually mature and become myelinating oligodendrocytes
What are the transcription factors involved in oligodendrocyte development?
- 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)
What is the transcription factor Myrf involved in in CNS myelination?
-it is required for CNS myelination -is expressed by oligodendrocytes quite late in their development -controls the maturation of oligodendrocytes
What happens to Myrf knockouts?
-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
What are the extracellular factors involved in myelination of the CNS?
-neurotrophins (e.g.BDNF) -neuregulin-1 a tiny bit but not really -Lingo 1
What is the role of Neurotrophins and specifically BDNF in CNS myelination?
-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 -
What is the role of Neuregulin-1 in CNS myelination?
-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
What is the role of Lingo-1 in CNS myelination?
- 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
How does an oligodendrocyte know which axons to myelinate?
-factors at play: 1. Neuronal activity 2. Experience 3. Axonal diameter
How does neuronal activity influence if an axon is or isn’t myelinated in the CNS?
-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
How does experience influence if an axon will be myelinated or not in the CNS?
-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
How does axonal diameter influence if an axon will be myelinated or not in the CNS?
-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
Summary Schwann cells?
-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
Summary Oligodendrocytes?
-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
Summary myelination?
-most myelination occurs postnatally and is subject to tight controls by transcription factors, extracellular factors, axonal diameter, axonal ligands, axonal activity
Summary table?
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