How does an axon grow?

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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
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Relevance

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

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Axon Growth
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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

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Neural crest
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Growth cone mechanisms

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

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Sperry Stone
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Control of growth
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Diffusible factors

• NGF
• Tyrosine kinase (trk)
• netrin
• commissure formation
• Semaphorin

Chemoattractant
Chemorepellant
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Cellular molecules

• N-Cadherin
• Ca-dependent
• Ig superfamily
• N-CAM
• NgCAM
• Fasciclin II
• TAG-1
• transient axonal glycoprotein

homophilic

• Fasciculation
• Substrate binding
• axon-Schwann cell interaction

heterophilic
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Matrix molecules
Glycoproteins bind to

• Fibronectin
• Laminin
• Tenascin

• Integrins
• large variety
• ab 12x6

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Molecules

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

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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)

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Guidance

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

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Regeneration
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Spectrum of ability
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Not the neurone

• but the environment CNS / PNS

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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
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Inhibition of regrowth

• Nogo (Schwab, 1985)
• Myelin associated glycoprotein (MAG)