Terms in this set (38)
What are the different types of glia?
How many glial cells are there in the body?
There are several times more glia than neurons (about 100 billion neurons)
Half of the brain is glia by volume
In the PNS, the relative number of glia is even greater
At what level of the neural tube do early glia appear?
Ventral third of the neural tube
What are the different cells that form the rodent schwann cell lineage?
Neural crest -> Schwann cell precursor (SCP) -> Immature Schwann cell
Immature Schwann cell -> Pro-myelin cell -> Myelin Schwann cell
Immature Schwann cell -> Remak cell
When do Schwann cell precursors form?
Embryo day 12/13
When do immature Schwann cells form?
Embryo day 15/117
When do myelin Schwann and Remak cells form?
What do Schwann cell precursors give rise to?
More Schwann cell precursors (needed for neuronal survival)
Immature Schwann cells
What is the role of Bungner cells?
Serve as repair cells in injured nerves
What does the survival of Schwann cell precursors depend on?
Schwann cell precursors (SCPs) survive for less than 12 hrs when removed from axonal contact.
Inactivation of neuregulin signals in vivo
results in nerves without Schwann cell precursors or Schwann cells
They are rescued by neuron-derived neuregulin.
What is the significance of ErbB2/ErbB3?
Neuregulin -> ErbB2/ErbB3 signalling is a key cell-cell signalling system in Schwann cell development.
ErbB2/ErbB3 neuregulin receptors are expressed on Schwann cell precursors.
What happens to motor neurons and DRG sensory neurons without Schwann cell precursors?
What is the relationship between neurons and Schwann cell precursors during development?
Neurons and Schwann cell precursors rescue each other during development
What percentage of neurons and glial cells die during development?
About 50% of neurons and a large percentage (~50%?) of glial cells die during development
What do Schwann cells do around birth?
Around birth, Schwann cells randomly associate either with large or small axons.
The process by which Schwann cells associate with large axons is termed Radial sorting.
• Radial sorting is a necessary for myelination to occur
• It generates so called "pro-myelin" cells
• But it is not myelination: in humans, many axons sort, but do not myelinate
What drives the generation of myelin- and non-myelin (Remak) cells?
Signals from the axon and the basal lamina
drive the association of axons with Schwann cells and subsequent generation of myelin- and non-myelin (Remak) cells
What does myelination depend on?
Myelination is not an unfolding of an intrinsic developmental program
-but depends completely on extrinsic signals.
The most important of them come from:
(2) extracellular matrix (basal lamina)
Each Schwann cell makes only one myelin sheath
Myelin is formed by wrapping movements that are poorly understood.
A myelin cell can be imagined as an extremely flattened cell.
Myelination involves a combination of
up-regulation and down-regulation of key genes.
What are some markers of immature Schwann cells?
What are some markers of Myelin Schwann cells?
What are some markers of Non-myelin (Remak) cells?
What are the myelination signals from
axons and the basal lamina?
1) Neuregulin- promotes myelin thickness
2) A signal (basal lamina) that activates
gpr126 receptors on Schwann cells
and elevates cAMP
What is transcriptional machinery in Schwann cells that organizes myelin differentiation?
Krox 20 (Egr2)
Krox-20 is essential for
The Schwann cell transcription factor Krox-20 is a global regulator ("masterswitch") of myelination.
What is the Myelin Programme?
Withdrawal from the cell cycle
Cessation of developmental death
Increase in myelin proteins
Decrease in I-Sch markers
Which are the positive transcriptional regulators of myelination?
Which are the negative transcriptional regulators of myelination?
Pax3 , Sox2, Id2
What are the features of negative transcriptional regulators?
Counteract pro-myelin signals
( axonal signals, Krox20 , cAMP)
Suppress myelin genes
Active in immature Schwann cells
Down-regulated in adult nerves
Enforced expression causes demyelination
What are some factors involved in MAP kinase pathways?
Jun kinase (JNK)
What are the functions of negative transcriptional regulators ?
1. Control timing of myelination (Notch)
2. Control rate of myelination ?
3. Function in demyelinating disease?
4. Function in nerve injury (c-Jun, Notch)
How does the response of the CNS differ from that of the PNS after injury?
CNS fibre tracts don't regenerate (e.g spinal cord cannot regenerate)
PNS fibre tracts regenerate (e.g Sciatic nerve can regenerate)
What does axon regeneration depend on?
1) Intrinsic capacity of the neuron to build a new axon
2 )The growth-permissiveness of the axonal environment
Do myelin Schwann and non-myelin (Remak) cells support axon growth?
Normal Schwann cells do not support axon-regeneration
What is the Schwann cell injury response?
Injury triggers the generation of a Schwann cell specialized to support repair (Repair Schwann cell) in the distal stump of injured nerves
Repair Schwann cell-> A dedicated repair cell
The response gives rise to a permissive environment.
Initiation of a repair and dedifferentiation programs
What does the repair program involve?
Trophic support for injured neurons and substrate for growth cones: Activation of trophic factors and surface proteins providing support for injured neurons and substrate for growth cones
Axon guidance by formation of regeneration tracks (Bands of Bungner)
Myelin breakdown directly and by organising macrophage activity: Activation of cytokines and autophagy
What does the dedifferentiation program involve?
Suppression of myelin differentiation:
Downregulation of myelin genes
Upregulation of iSch markers
What are the roles of c-Jun?
The transcription factor c-Jun is a global regulator of the generation of the Repair cell.
Functional nerve repair depends on activation of Schwann cell c-Jun
Functional recovery after nerve injury is strikingly compromised or absent when Schwann cell c-Jun is inactivated
c-Jun controls direct interactions between Schwann cells and growing axons
Mice with conditional inactivation of c-Jub in Schwann cells exhibit very poor regeneration.
172 genes are disregulated in c-Jun -/- (GDNF, BDNF, artemin, cadherin1, Shh, Olig1,
c-Jun determines the typical bipolar morphology of Schwann cells
c-Jun controls the generation of regeneration tracks (Bungner bands)
Without Schwann cell c-Jun, many injured neurons die
c-Jun dependent signals from Schwann cells keep neurons alive during nerve regeneration
What is the paradox of PNS repair?
On the one hand -
"In higher vertebrates, PNS axons regenerate after injury while CNS axons do not" (Lutz and Barres 2014)
"Following injury to peripheral nerves - axons regenerate vigorously and successfully reinnervate their targets" (Stam et al 2007).
But on the other -
"Only 10% of adults regain normal function
after transection and suture of a major
peripheral nerve " (Brushart 1998)
"sensory outcome ... remains so poor that even reasonable restoration of function is unattainable" (Welin et al 2008)
"the outcome [after PNS injury]has improved little since the 1940s" (Hart et al 2008)
What are some limitations of the repair process?
Axon growth is slow (1-2mm/day)
Long-term denervation: Schwann cells remain denervated for months
This phenotype (Repair Schwann cells) is not stable
The distal stump deteriorates and growth support decreases over time.
Capacity of distal stumps to support regeneration gradually decreases
Levels of GDNF in distal stumps gradually decrease
c-Jun levels in distal stumps gradually decrease
A) The deterioration of the distal stump
is a major reason for poor outcomes of PNS injuries
B) The deterioration of the distal stump occurs in two phases:
First, fading of the repair phenotype in surviving cells.
Followed by death of faded (non/poorly-functional) repair cells
C) The fading of the repair phenotype is caused by gradual reduction in c-Jun levels
Is there a pharmacological way of elevating c-Jun levels in Schwann cells?
The c-Jun Jun kinase pathway is a pharmacological target for promoting Peripheral nerve repair (- would it work in the CNS?)
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