myelination

how to increase speed of action potential conduction

increase in axon diameter-giant axons-invertebrates not in vertebrates because of physical constraints imposed on the CNS by the skull

increased body temperature→faster diffusion

fatty insulation- myelin sheaths- vertebrates

what is myelin

insulates axons from each other, speeds conduction of nervous impulse (saltatory conduction between nodes)

what are node of ranvier

gaps in between myelin. action potential can jump between the nodes and increase the speed

myelination of PNS vs CNS

PNS- schwann cells

CNS- oligodendrocytes active

where are schwann cells derived from

neural crest and migrates and differentiates under control of peripheral axons

where are oligodendrocytes derived from

progenitors that reside in ventricular zone of neural tube

what controls schwann cell migrate and differentiate

peripheral axons

what is the oligodendrocyte precursor cell

a bipotential cell that arises after birth- o2A cell (also NG2)

oligodendrocytes vs schwann cells

a single myelin sheath is formed by schwann cells in the peripheral nervous system (PNS)

multiple myelin sheaths are formed by oligodendrocyte in the central nervous system (CNS)

increase in vertebrate axons

myelin sheath increases the local resistance of the axon and reduces membrane capacitance by several orders of magnitude. Voltage-gated sodium channels are concentrated at nodes of Ranvier and are downregulated along the axon plasma membrane between the nodes, ensuring that current flow is spatially restricted to the nodal region. Paranodal junctions function as an electrical seal that limits current leakage underneath the sheath

what determines whether axons in the PNS are myelinated

if they express threshold levels of neuregulin 1 a membrane-tethered member of the epidermal growth factor.

what determines whether axons in the CNS are myelinated

default pathway for oligodendrocytes

other roles of myelin

also provides a substrate for additional control of the timing of inputs during development and in adult neural circuits. energy conservation, insulation and regulation of ion movement

what does neuronal activity promote

proliferation of oligodendrocyte progenitors and stabilizes axon–oligodendrocyte interactions

the number of oligodendrocytes

excess dies by apoptosis. more progenitors are produced than there are mature oligodendrocytes after myelination

oligodendrocytes and progenitors competing

progenitors and newly-differentiated oligodendrocytes compete for limiting amounts of mitogens and survival factors (from astrocytes and neurons) if they don’t get enough they die

can mature oligodendrocytes migrate

no only the precursors can so they need to move where it’s necessary.

what does oligodendrocytes progenitors need to migrate

require cell adhesion molecules (integrins, PSA-NCAM)

where does the oligodendrocytes precursors go

Follow radial glia (outwards from ventricular zone).

Follow developing axon pathways (dorso-ventral and longitudinal).

what enhances myelin gene transcription

signals from neurons (thicker axons get thicker myelin)

signalling between oligodendrocytes and axons

Axons are not passive in myelination….

They provide mitogenic signals for O2A (NG2) cells - PDGF, neuregulin.

Electrical activity stimulates O2A proliferation (poss. via increasing production of mitogens by astrocytes).

how is myelin sheath generated

CONTINUED MIGRATION OF PROCESS LEADING EDGE AROUND AXON

While the leading glial process continues to encircle the axon, the earlier-formed loops undergo compaction to form the contact myelin sheath

schwann cell development

neural crest cell→schwann cell precursor→immature schwann cell→ myelinating/non-myelinating schwann cell

when does migration of schwann cell progenitors stop

when they encounter axons and their signals tell the cells what to do

neuregulins

eg. Glial growth factor (GGF) expressed by motor neurones and in neurones of peripheral ganglia. Stimulates differentiation and proliferation of Schwann cell precursors.

Neuregulins also contribute to survival of Schwann cell precursors

Krox20

zinc-finger transcription factor. Knockout - no myelinating Schwann cells.

Signals from axons (neuregulins) upregulate Krox20 in Schwann cell precursors that contact them.

not expressed in oligodendrocytes lineage

pax3

paired domain transcription factor.

  Inhibits Schwann cell differentiation.

  Expressed in SC progenitors and downregulated as myelination starts.

  Controls expression of e.g., MBP.

not expressed in oligodendrocyte lineage

L1

NCAM and L1 (another Ig-class cell adhesion molecule) expressed in Schwann cell progenitors, and downregulated after myelination starts. 

L1 is required for initiation of myelination in Schwann cells, but not present in oligodendrocytes.

Oligodendrocytes express a closely related cell adhesion molecule, neurofascin-155, at start of myelination - may ‘replace’ L1.

MAG and periaxin

Myelin-associated Glycoprotein MAG and a cytoskeletal-linking protein, periaxin, are initially located in Schwann cell membranes in contact with axon.  May modulate interaction, but periaxin not in oligodendrocytes.

autocrine survival of mature schwann cells

can schwann cells and oligodendrocytes make myelin on their own

SC only in presence of axons. oligodendrocytes can make in culture on their own

specialised myelin proteins

P₀  (Schwann cells only) A cell adhesion molecule (Ig family).

Proteolipid protein PLP (almost entirely oligodendrocytes only).

Myelin Basic Protein MBP  (both cell types)

Myelin-associated Glycoprotein (MAG) (both cell types)

peripheral myelin protein-22 (PMP-22)

many others.

P₀ and PLP are required in Schwann cells and oligodendrocytes respectively for compaction/stability of myelin - unrelated molecules doing very similar jobs.

the most common protein in CNS myelin

PLP

most common protein in PNS myelin

PO

shiverer mutant

 almost complete absence of myelination, due to a failure of precursor cells to differentiate into oligodendrocytes (MBP)

other mutations

impair myelination are mutations in the major protein components of the myelin sheath

mutation in PLP

causes hypomyelination in CNS

regions of the nodes of ranvier

1.Node - voltage-sensitive Na⁺ channels

2.Paranodal regions – specialized transmembrane proteins that prevents movement of Na⁺ and K⁺ channels in axon plasma membrane

•Contactin

•Caspr (contactin associated protein)

•Schwann cells have nuerexin – thought to interact with contactin–

3.Juxtaparanodal regions – K⁺ channels are highly concentrated

what is the site of tight axon-glial adhesions

paranode

sodium channels in immature notes

Sodium channels cluster early at wide immature nodes.  As nodes narrow and

mature, sodium channel density increases.

potassium channels in nodes

Potassium channels cluster later and shift their position.  They first appear at nodes,

But move to paranode and then juxtaparanode as structure matures.

slides 33-35