BIOLOGY 2C03 Lecture Notes - Neural Cell Adhesion Molecule, Trochlear Nerve, Myelin

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Published on 28 Jan 2013
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Outline of Lecture 12 (02-20 E; Kolodkin)
Development III (Axon Guidance)
I. Principles of axon guidance
A) Historical perspective: early evidence of axonal guidance cues
- Cajal and Harrison observe dynamic nature of axonal growth cone
- Sperry demonstrates topographic mapping in retina-to-tectum
- Spinal cord inversion does not affect how motor axons select peripheral pathways
B) Sequence of events: pathfinding, target selection, synapse formation and refinement
II. Neuronal growth cone organization
- Growth cone has filopodia and lamellipodia
- Actin: found in growth cone, undergoes treadmilling via myosin and actin polymerization;
adhesive molecules and myosin mediate membrane protrusion
- Microtubules: found polymerized in axon shaft, fills in voids in growth cone when actin is
attached to membrane complexes in response to extracellular cues (this is the method of growth
cone advance)
- Individual filopodia can steer entire growth cone via mechanism above
III. Molecular regulation of axonal guidance (see also Lec 18 for list of sources of guidance cues)
A) RHO GTPases and cytoskeleton
- RHO family members (Cdc42, Rac, Rho) are GTPases that modulate actin cytoskeleton and are
regulated by GEFs and GAPs
- Cdc42 (filopodia) Rac (lamellipodia) Rho (stress fibers, focal adhesions)
- Cdc42 and Rac promote axon and dendrite growth, whereas Rho limits it
B) ECM cues (a form of short range guidance)
- Laminin in ECM are permissive to pathfinding (binds integrin receptors)
C) Guidepost neurons (a form of short range guidance)
- Guideposts help reorient growth cone (e.g. turn corners) via contact mediated steering
D) Selective fasciculation (a form of neuron/neuron guidance)
- Pioneer axons provide pathway for later axons to pathfind correctly (hence, fascicles)
- Neural cell adhesion molecules (NCAM) label cell surfaces and guide pathfinding through
available choices of substrates
- Differential expression of CAMs in time allow changes in pathfinding trajectory
E) Contact mediated inhibitory interactions
- Temporal (posterior) retinal cells express EphA3, a receptor for ephrin A-2 found in the posterior
tectum; interaction is inhibitory (growth cone collapse), which generates inverted
topographical mapping
F) Floor plate chemotropic guidance (a form of long range guidance)
- Netrin in floor plate is an attractant for commissural axons but a repellant for CN IV
G) Sensory afferent patterning
- Ventral spinal cord secretes semaphorins, a signal inhibitory to NGF-responsive afferents (these
terminate in dorsal spinal cord) but not to NT3-responsive afferents (these reach ventral
motoneurons)
IV. Axon regeneration
- CNS environment is not permissive to axonal growth/regeneration
- CNS myelin (oligodendrocytes) contains Nogo which suppresses axon growth
- Blocking Nogo could be key in axonal regeneration therapy (expt’ly, done with IN-1 antibody)
- NgR is the Nogo receptor on axons; Nogo and NgR are associated with other proteins
Summary of major points
- See “Key Points” on p. 1 of lecture
- Understand general classes of axon guidance cues and roles of Cdc42, Rac, Rho, Laminin,
NCAM, ephrin A-2/EphA3, Netrin, Nogo
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