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Axonal Growth: Understanding Regeneration in Peripheral vs. Central Nervous System

This discussion explores the intricate processes of axonal growth and regeneration, contrasting mechanisms in the peripheral nervous system (PNS) with those in the central nervous system (CNS). Key factors influencing axon regeneration, such as growth cones, trophic factors, and extracellular matrix interactions, are examined. Understanding these processes is crucial for developing treatments for neurodegenerative diseases and spinal trauma. The significance of environmental factors in regeneration, as well as potential inhibitory elements like Nogo, are also highlighted.

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Axonal Growth: Understanding Regeneration in Peripheral vs. Central Nervous System

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  1. How does an axon grow? Compare the processes of axonal regeneration in peripheral and central nervous system.

  2. Relevance • Treatment of disease • Neurodegenerative • Spinal trauma • Scientific • puzzle: how so few genes encode such complex structure • wiring determines operation • ? axonal refashioning & memory formation

  3. Axon Growth

  4. How connections achieved • Prespecification • Random connections • Target induced specification • endplate formation, postsynaptic terminals • Death of incorrectly wired neurones • Motor neurones (Levi-Montalcini) • Pruning of synapses & arbors • muscle fibres

  5. Neural crest

  6. Growth cone mechanisms • Filopodia, lamellipodia • Actin polymerisation • ABPs, Ca / P • Vesicle fusion • Matrix anchoring • Protease secretion

  7. Sperry & Stone

  8. Control of growth

  9. Diffusible factors • NGF • Tyrosine kinase (trk) • netrin • commissure formation • Semaphorin Chemoattractant Chemorepellant

  10. N-Cadherin Ca-dependent Ig superfamily N-CAM NgCAM Fasciclin II TAG-1 transient axonal glycoprotein Fasciculation Substrate binding axon-Schwann cell interaction Cellular molecules homophilic heterophilic

  11. Fibronectin Laminin Tenascin Integrins large variety ab 12x6 Matrix molecules Glycoproteins: bind to

  12. Molecules • Ig superfamily • N-CAM • NgCAM • TAG-1 (transient axonal glycoprotein) • N-cadherin • Matrix - bind to Integrins (ab) • laminin • fibronectin • Tenascin

  13. Molecules (continued) • Trophic (prevent death) • Neurotrophins • NGF • via retrograde transport to soma • induces NA synthesis • required during a critical period • BDNF (in DRG) • sphingolipids eg. Ceramide • Chemotactic • NGF via Tyr K (trk)

  14. Guidance • Location of neurone • Axon destination neurone • Axon position on neurone

  15. Regeneration

  16. Spectrum of ability

  17. Not the neurone • but the environment – CNS / PNS

  18. PNS distal segment degeneration (phagocytes) Schwann cell didifferentiation proximal segment axon regrowth CNS distal segment degeneration (microglia) oligos proliferate proximal segment degenerates cell body may die Normal response to injury Prevented by trophic factors

  19. Inhibition of regrowth • Nogo (Schwab, 1985) • Myelin associated glycoprotein (MAG)

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