Cours: Axon Guidance

Development of the Nervous System: Axon Guidance

• Axon tracts rapidly increase in complexity during early development
• Shows diagrams demonstrating the growth and complexity of axon tracts over time (16-36 hours)
• Santiago Ramón y Cajal, Paul Weiss, and Roger Sperry are key figures in the history of axon guidance research
• Contact guidance by mechanical means was an early, disproven hypothesis.
• The chemoaffinity hypothesis, proposed by Roger Sperry, is the currently accepted model.
• Inputs from the retina form a topographic map in the tectum
  • Diagrams show "Normal" and "Rotated" frog eye connections to the tectum
  • Visual stimuli (e.g., a fly) elicit a corresponding response in the tectum according to its location.
• Sperry's chemoaffinity hypothesis
  • Neural connections are determined by molecular tags on axons and target cells.
• What are these molecular tags and how do axons find their target? (This is addressed in further materials)
• The labeled-pathway hypothesis is discussed (and further addressed).
• Axons use guidepost cells as intermediate targets
• Growth cones readily grow onto more attractive substrates
• Observations by Paul Letourneau suggest axons select pathways based on adhesive strength
• Strength of adhesion does not correlate with growth rate preference for more complex substrates
• Adhesion does play a role in axon guidance.
  • Diagrams show the various types of axon guidance
• Growth cones of PNS (peripheral nervous system) axons collapse upon contact with CNS (central nervous system) axons
  • Demonstrates collapse of growth cones via images.
• Semaphorin3A repels NGF-dependent sensory axons
  • Demonstrated via images.
• Axon guidance involves cooperation of attractive and repulsive cues
• Information from guidance cues is transmitted to the cytoskeleton via surface receptors.
• Molecules act as guidance cues or receptors, determining their attraction/repulsion.
  • Question: How many are there?
  • Question: Do all axons listen to the same cues?
• Axons are guided by positive and negative cues
• Commissural neurons in the dorsal spinal cord
• Netrin is a chemoattractant for commissural axons
  • Diagrams show the action of Netrin on commissural axons.
• Is netrin-1 sufficient for long-range guidance of commissural axons?
• Netrin is sufficient to attract commissural axons
  • Demonstrated via images.
• Additional cues, like Shh and VEGF, influence the development of the floor plate and axon growth
• Commissural axons are repelled by the roof plate
• BMP7 mimics the effect of the roof plate
• Draxin is expressed by the roof plate and repels commissural axons
• Short-range guidance cues
• Interaction between growth cone Axonin-1 and floor-plate NrCAM makes axons enter the floor plate
• NrCAM is a binding partner for Axonin-1 in commissural axon guidance
• Fasciculation is not required for commissural axon pathfinding in higher vertebrates
• Why do commissural axons ever leave the floor plate? (Target)
• The intermediate target loses its attractiveness
• Commissural axons lose responsiveness to Netrin after contact with the floor plate
• The midline glia in the ventral nerve cord is the equivalent of the floor plate in vertebrates
• Midline-derived guidance cues in the ventral nerve cord (diagrams)
• A screen for midline crossing mutants in Drosophila led to the identification of commissureless and roundabout.
• The upregulation of Roundabout expels axons from the floor plate.
• Balance between positive and negative signals shifts upon floor-plate contact
• RabGDI is required for Robo1 insertion into the growth cone membrane.
• Trafficking regulates protein expression on the growth cone
• How do axons switch their behavior at an intermediate target? (Mechanisms)
• Classical guidance cues for commissural axons
• Commissural axons turn rostrally upon floor-plate exit
• Wnts are expressed in a decreasing rostral to caudal gradient
• Wnt4 is an attractant for post-crossing commissural axons
• Sonic hedgehog guides commissural axons along the longitudinal axis of the spinal cord
• Wnt4 attracts and Shh repels postcommissural axons.
• Shh acts as a morphogen
• Shh acts as a chemoattractant for pre-crossing axons.
• Shh acts as a repellent cue for post-crossing commissural axons.
• Commissural axons change Shh receptors at the midline
• Glypican1 mediates the switch in commissural axon responsiveness to Shh at the midline
• Sfrp1 forms a Wnt activity gradient
• Shh guides postcommissural axons
• Why do axons only turn after contact with the intermediate target?
• PlexinA1 is stabilized.
• Cis-versus trans-interactions can change trans-interactions.