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

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

3. Axon Growth

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

5. Neural crest

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

7. Sperry & Stone

8. Control of growth

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

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

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

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

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

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

15. Regeneration

16. Spectrum of ability

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

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

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