HTHSCI 1DT3 Study Guide - Midterm Guide: Growth Cone, Synaptogenesis, Actin
23 Jun 2018
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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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stimulates oligodendrocyte production.
Direct stimulation to myelinate by axon (NCAM, L1)
Downregulation of inhibitory molecules (Lingo, Notch)
Myelin assembly can occur distal to cell body (Sherman, Brophy 2005) –
Ribosomes and RNA present in tips of processes.
Myelination programme in Schwann cells:
Radial Sorting (forming 1:1 relationship)
Activation of Myelin Programme (withdrawal from cell cycle,
upregulation of myelin proteins e.g. Pzero)
Downregulation of immature Sch Proteins
Membrane synthesis and wrapping
Conclusion
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Document Summary
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. o. 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) Ablation of one population taken over/replaced by another population, no functional consequences. o. Contact dependent mechanisms: (ecm fibronectin, axon ncam, integrins, 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. Migration involves expression of snail (downregulated when they reach target). o.
