How does an axon grow Compare the processes

Relevance • Treatment of disease – Neurodegenerative – Spinal trauma • Scientific – puzzle:

How connections achieved • Prespecification • Random connections – Target induced specification • endplate

Growth cone mechanisms • Filopodia, lamellipodia • Actin polymerisation – ABPs, Ca / P

Diffusible factors • NGF – Tyrosine kinase (trk) Chemoattractant • netrin – commissure formation

Cellular molecules • N-Cadherin – Ca-dependent • Ig superfamily – – N-CAM Ng. CAM

Matrix molecules • Fibronectin • Laminin • Tenascin Glycoproteins: bind to • Integrins •

Molecules • Ig superfamily – N-CAM – Ng. CAM – TAG-1 (transient axonal glycoprotein)

Molecules (continued) • Trophic (prevent death) – Neurotrophins • NGF – via retrograde transport

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

Not the neurone • but the environment – CNS / PNS

Normal response to injury • PNS – distal segment • degeneration (phagocytes) • Schwann

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

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How does an axon grow? Compare the processes of axonal regeneration in peripheral and central nervous system. Dr Sanjay Manohar University of Oxford http: //www. smanohar. com

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

Axon Growth

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

Neural crest

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

Sperry & Stone

Control of growth

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

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

Matrix molecules • Fibronectin • Laminin • Tenascin Glycoproteins: bind to • Integrins • large variety • ab 12 x 6

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

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)

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

Regeneration

Spectrum of ability

Not the neurone • but the environment – CNS / PNS

Normal response to injury • 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 Prevented by trophic factors

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