Myelination Flashcards
what increases action potential conduction?
larger axon diameter
increased body temp
-> faster diffusion
myelination
what is myelin?
what is its purpose?
a specialised sheath surrounding vertebrate axons
- insulates axons from each other
- speeds up conduction via saltatory conduction between nodes of Ranvier
describe the differences between myelination in the PNS and CNS
PNS
- individual Schwann cells myelinate the axon once
(form a single myelin sheath)
CNS
- Oligodendrocytes can myelinated multiple axons or the same axon in multiple places
Where are Schwann cells derived from?
What is their role?
Neural crest
migrate + differentiate under control of peripheral axon
where are oligodendrocytes derived from?
what are oligodendrocytes 1 of 2 major classes of?
progenitors that reside in ventricular proliferating zone of neural tube
CNS glia
what types of cell can the O2A cell differentiate into?
what factors are required for each cells type?
oligodendrocyte
(low serum)
type-2 astrocyte
(BMP4 + CNTF)
(both require retinoid acid + thyroid hormone)
how to oligodendrocyte precursors migrate?
what molecules are required for migration?
- follow radial glia
(outwards from ventricular zone) - follow developing axon pathways
(dorso-ventral + longitudinal)
cell adhesion molecules
(integrins, PSA-NCAM)
when are mature oligodendrocytes produced?
during myelination
what happens to excess oligodendrocytes?
what do progenitors compete for?
apoptosis
limiting amounts of mitogens + survival factors (from astrocytes + neurones)
which growth factors stimulate oligodendrocyte progenitor survival?
what do these ligands bind to and what does this cause?
neuregulin GF family NRG1-3
e.g. Glial growth factor GGF
receptors (ErbB) on undifferentiated neural crest cells that contact axons
-> sets off Raf-Raf-MAPK pathway
describe the different signalling between oligodendrocytes and axons
axons provide mitogenic signals (PDGF, neuregulin) for O2A cells
electrical activity stimulates O2A proliferation
-ve regulation of oligodendrocyte differentiation via Notch signalling
axons provide survival signals to mature oligodendrocytes
signals from neurones enhance myelin gene transcription
how do neural crest-derived Schwann cell progenitors migrate?
over the surface of the neural tube
-> then through the anterior somites
describe how Schwann cells myelinate axons
- identify axon
- Schwann cell begins to produce the myelin sheath
- wraps sheath around axon
- extrusion of material out of the myelin sheath to allow compaction around axon
describe the stages of Schwann cell development
- neural crest cell migrates to right location e.g. neurones, bones etc
- Schwann cell precursor
- immature Schwann cell
- myelinating Schwann cell
OR
non-myelinating Schwann cell
when does Schwann cell progenitor migration stop?
when they encounter axons
- release neuregulins e.g. GGF expressed by motor neurones
- > differentiation + proliferation of Schwann cell precursors
which 2 TF genes are important for the control of Schwann cell myelination?
Krox20
= zinc-finger TF
- neuregulins from axons up regulate Krox20 in Schwann cell precursors that contact them
Pax3
= paired-domain TF
- inhibits Schwann cell differentiation
-> down regulated as myelination starts
which CAM-type molecules are important for the control of Schwann cell myelination?
what is the role of L1?
NCAM + L1
= expressed in Schwann cell progenitors
- down regulated after myelination starts
Myelin-associated glycoprotein (MAG) + periaxin
= might modulate interaction with axon
initiates myelination
which CAM-type molecules are important for the control of oligodendrocyte myelination?
Neurofascin-155
= expressed at start of myelination
what happens when Schwann cells mature?
why is this important?
lose total dependence on axon + neuregulin
autocrine survival:
NT3 (neurotrophin)
IGF2 (insulin-like GF)
PDGF-BB
enables Schwann cell survival even if axons get damaged/die
-> so can stimulate nerve regrowth
when do Schwann cells and oligodendrocytes make myelin?
SC = only in present of axons
oligo = do it naturally, even in culture on their own
what are the specialised myelin proteins?
P0 (SC only)
= a CAM
PLP (mostly oligo only)
= proteolipid protein
MBP (both cell types)
= myelin basic protein
MAG (both)
= myelin-associated glycoprotein
what is the function of these specialised myelin proteins?
compaction/stability of myelin
PLP + P0 hold membranes together
-> help with extrusion process
which specialised myelin protein is most abundant in the CNS myelin?
what about the PNS?
PLP
P0
what are the 3 regions associated with Nodes of Ranvier?
- node - voltage
- sensitive Na+ channels - paranodal regions
- specialised transmembrane proteins that prevent movement of Na+ and K+ channels in axon plasma membrane - juxtaparanodal regions
- K+ channels are highly concentrated
what are the specialised proteins in the paranodal region?
contactin
caspr
(contactin-associated protein)
neurexin on SC interacts with contactin
describe formation of nodal, paranodal + juxtanodal protein clusters during myelination
Na+ channels cluster at wide immature nodes
-> as nodes narrow + mature, Na+ channel density increases
K+ channels cluster + shift their position
- first appear at nodes
- > then move to paranode and then juxtaparanode as structure matures
how does oligodendrocyte and SC binding to axons regulate Na+ and K+ clustering?
due to specific protein-protein contacts in the paranodal loops
what happens in Shiverer mutant mice?
almost complete loss of myelination as don’t produce MBP
-> precursors cannot differentiate into oligodendrocytes
what do mutations in the PLP gene cause?
hypomyelination in CNS
