HTHSCI 1DT3 Study Guide - Quiz Guide: Yy1, Bulgarian State Railways, Nmda Receptor Antagonist
23 Jun 2018
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that activate microglia.
Activated microglia release cytokines and NO mediating initial attack.
Microglia engulf myelin, present to CD4+ and cause further activation of T-
Cell/microglia.
Myelin activated microglia also release proinflammatory cytokines (IL1, IL6, TNF)
that directly damage oligodendrocytes, myelin sheath and axons.
Parkinson’s
Alcoholic Brain Damage
Evidence shows alcohol can activate microglia by TLR4 stimulation
TLR4 associated with increased ROS production and neuroinflammation
TLR4 KO mice showed a marked reduced microglial response
Conclusion
Importance of microglia
Neuroprotective, but can have neurotoxic activity if above tolerance threshold
Important in understanding the role, to mediate appropriate modulatory therapy that
can improve neurodegenerative disorder progression?
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Compare and contrast development, differentiation and axon myelination in Oligodendrocytes and
Schwann Cells with particular focus on the gene expression and molecular signalling mechanisms.
Introduction
Oligodendrocytes and Schwann Cells are a key part of the nervous system, that are
responsible for ensuring the myelination of axons.
Oligodendrocytes are found primarily in the central nervous system, where they are
capable of myelinating several axons (multiple processes), whilst myelinating Schwann
Cells form a 1:1 relationship with neurones in the peripheral nervous system.
Non-myelinating Schwann cells enwrap several smaller axons in the PNS.
Function of myelin is to protect neurones and increase conductance.
Normal AP – depolarisation of axon, influx of Na+ into cell followed by propagation of
action potential.
Myelination forms distinct Nodes of Ranvier (where Na+ channels become clustered), so
AP ‘jumps’ from node to node via saltatory conduction which greatly increases
conductance speed of AP.
Oligodendrocyte Development, Schwann Cell Development – in red
Occurs in association with development of neurones (e.g. pMN domains), and
development begins after neuralation / formation of the neural tube following reduced
inhibition of proneural inhibitors (inhibition of BMP4 mediated inhibition, by follistatin,
chordin, cerebrus and noggin).
Neural tube is patterned along the dorsoventral axis by Shh Gradient (secreted by the
notochord, below the floor plate)
Shh induces the activation of several different LIM homeodomain transcription factors
that give rise to varying gene expression along the dorsoventral axis, depending on its
concentration. Another concentration gradient exists from roof plate (BMP/Wnt highest
concentration here) – combination of two concentration gradients induces organised
development in correct regions.
E.g. development of motor neurone occurs in presence of high Olig 2, low Pax6 (induced
by Shh/BMP signalling).
Motor neurons arise from the pMN domain, and oligodendrocytes are also believed to
come from here. Oligodendrocytes develop at the SVZ of spinal cord and brain, which
give rise to committed oligodendrocyte precursors.
Experiments with Danforth Short Tail Mouse – show lack of notochord development,
causing failure of both MN and oligodendrocytes to develop (suggesting both develop
along same pathway). Ectopic notochord – shows formation of another pMN domain that
forms MN and oligodendrocytes at the dorsal end.
Proneural (neurogenin) genes (Ngn1&2) are important for neuronal development, along
with overlap of Olig2 (shown through Cre-Lox Fate mapping).
Downregulation of Ngn1/2 in ventral neuroepithelium occurs once neuronal development
occurs, and oligodendrocytes develop in Olig2 domains.
Separation of Ngn1/2 and Olig2 expression required for oligodendrocyte development,
while overlapped expression of Nkx2.2 and Olig2 genes are also required for
development. Shows the precise, controlled nature of oligodendrocyte development.
Development of oligodendrocytes depends on Olig 1 and Olig 2 expression, both
regulated by Shh (indirectly by Nkx6.1, 6.2) – importance demonstrated by KO
experiments (Lu 2002)
Olig1 KO mice viable, but delayed oligodendrocyte maturation. Heterozygous
KO/Olig1 show normal development.
Olig1 KO mice – show no myelination of optic nerve at P14, while heterozygous
and normal mice show 35% - so Olig1 important in maturation later on.
Olig2 KO mice lack oligodendrocytes and motor neurones in SPINAL CORD
(but present in brain stem) – so not the only controlling factor. In spinal cord,
crucial to oligodendrogliogenesis.
Olig1, 2 KO – lack oligodendrocytes anywhere in the CNS.
Cai (2005) – dual origin for oligodendrocytes
Nkx6 KO – lack of ventral OPC (85%), but still produced by dorsal region.
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Nkx6 KO – lack of ventral OPC (85%), but still produced by dorsal region.
Dorsal OPCs arise from Pax7, Msx-3 expression region.
So two regions mediate oligodendrocyte development in spinal cord.
Cre-Lox Fate mapping showed multiple origins of oligodendrocytes in forebrain
Ventral domain – Nkx2.1 (populates all of cortex, then disappears after birth –
replaced by OPC from other two waves)
Medial domain – Gsh2 (follows ventral domain)
Third domain – Emx1
Ablation of one population – taken over/replaced by another population, no
functional consequences.
Oligodendrocyte migration determined by:
Secreted molecules:
Growth Factors (PDGFa, FGF)
Chemotrophic molecules (netrins, semaphorins)
Chemokines (CXCL1)
Contact dependent mechanisms: (ECM – fibronectin, Axon – NCAM, integrins,
Blood vessels)
Schwann Cell Development and Migration
Schwann Cells develop from the neural crest region adjacent to the newly formed
neural tube. Migration from neural crest to various regions in the embryo via
EMT (epithelial-to-mesenchymal transition) with loss of E-Cadherin, cell polarity
and cytoskeletal rearrangement.
Two key pathways taken: Ventromedial Pathway or Dorsolateral Pathway.
Neural crest cells differentiate as they migrate (including into Schwann Cells) via
GGF inductive factor. Migration involves expression of Snail (downregulated
when they reach target).
Proliferation of Oligodendrocytes
Perinatal progenitors – responsive to PDGF mitogen to proliferate, expand and
migrate away
OPCs become unresponsive to PDGF, become responsive to FGF (causes
division, but not migration). Proliferation stops at premyelinating state.
Calver (1998) – Dose relationship between PDGFa and OPC number, but
number of mature oligodendrocytes remain same (even if more produced by
increased PDGFa, rest die by apoptosis) – correct number maintained.
Differentiation – Key factors:
Yingyang 1 – regulates oligodendrocyte differentiation (inhibits inhibitors of
myelin genes e.g. Tcf4, Id2,4), permitting myelination.
He (2007) – YY1 KO caused defective myelination.
Myelin Gene Regulatory Factor (MRF) also important. KO (Emery 2009) causes
severe loss of myelin, tremor and ataxia in mice.
c.f. similar role of Krox20 in inducing the myelination of PNS axons via
Schwann Cells – binary switch gene.
Krox20 KO – no myelination at all in PNS.
Oligodendrocyte contact/survival
Contact with axon important, oligodendrocytes make several contacts with axons
and then these are pruned down (Trapp 1997)
NCAM on axon thought to be important in oligodendrocyte-axon contact/survival
– shown by Palser (2010) in experiment with IGF vs. no IGF (reduced
oligodendrocytes) – NCAM restored oligodendrocyte number.
Schwann Cells die under normal culture conditions, unless rescued by neurone-
conditioned medium.
Neuregulin 1ß (NRG1ß) – on axon surface, acts as key survival signal for
Schwann Cells. Binds to ErbB2/3 receptors on Schwann Cells.
ErbB2/3 KO – death of Schwann cells, but peripheral nerves still formed.
However, nerves found to die later – suggesting how Schwann cells and
peripheral neurones have an intimate relationship in ensuring survival of each
other.
Initiation of Myelination
Target innervation and electrical activity in axon – release of ATP
ATP stimulates astrocytes to produce Leukaemia Inhibitory Factor (LIF),
stimulates oligodendrocyte production.
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Document Summary
Activated microglia release cytokines and no mediating initial attack. Microglia engulf myelin, present to cd4+ and cause further activation of t- Myelin activated microglia also release proinflammatory cytokines (il1, il6, tnf) that directly damage oligodendrocytes, myelin sheath and axons. o o. Evidence shows alcohol can activate microglia by tlr4 stimulation. Tlr4 associated with increased ros production and neuroinflammation. Tlr4 ko mice showed a marked reduced microglial response o. Neuroprotective, but can have neurotoxic activity if above tolerance threshold. Compare and contrast development, differentiation and axon myelination in oligodendrocytes and. Schwann cells with particular focus on the gene expression and molecular signalling mechanisms. Oligodendrocytes and schwann cells are a key part of the nervous system, that are responsible for ensuring the myelination of axons. Oligodendrocytes are found primarily in the central nervous system, where they are capable of myelinating several axons (multiple processes), whilst myelinating schwann. Cells form a 1:1 relationship with neurones in the peripheral nervous system.
