Exam 4 - Axon guidance

Growth cone structure

Specialized axon tip with FILOPODIA (finger-like) and LAMELLIPODIUM (sheet-like). F-actin in both; tyrosinated (dynamic) microtubules in the lamellar region; acetylated (stable) microtubules only in the elongating axon.

Cytoskeleton roles: actin vs microtubules

Actin polymerization/depolymerization regulates growth cone SHAPE and directed growth. Microtubules drive axon ELONGATION and transport of new components (receptors, channels, signaling molecules, vesicles).

G-actin and F-actin with attractive vs repulsive cues

G-actin (globular monomer) is incorporated into F-actin (filament) at the leading edge of a filopodium in response to ATTRACTIVE cues. REPULSIVE cues cause disassembly and retrograde flow of G-actin toward the lamellipodium.

Tubulin and microtubules in turning

Organized microtubules form the axon core; dispersed tubulin subunits sit at the transition zone. Dynamic microtubules assemble/disassemble to set direction; stable microtubules remain in the axon shaft once direction is chosen.

Ca2+ and membrane addition in growth cones

Growth cones show rapid Ca2+ changes (voltage-gated Ca2+ channels and TRP channels) that influence actin/tubulin assembly. Secretory vesicles fuse near filopodia to add membrane as the cone extends.

Neuron polarity: Par-3

Polarity scaffolding protein Par-3 (partitioning-defective) is localized to the TIP of the growing axon. When Par-3 is disrupted, ALL neurites take on axonal characteristics (e.g., tau).

Axon vs dendrite markers

Dendrites: MAP2. Axon: GAP-43 (and tau). Neurons are specialized epithelial cells with early-established polarity.

Motor proteins and trafficking in neurites

Microtubule + ends point toward the axon tip. KINESIN moves vesicle cargo toward the axon terminal (anterograde). DYNEIN carries endocytic vesicles (signals, lysosomal cargo) back to the cell body (retrograde). Dendrites use Golgi outposts/satellites.

Pioneer neurons and decision points

Pioneer cells lead; followers follow "guide ropes". Growth cones change shape at decision points (e.g., dorsal sensory relay neurons crossing the ventral midline to form the spinothalamic tract), then revert to simple shape after.

Four types of guidance cues

1) Chemoattractants (secreted, orient toward target); 2) Chemorepellents (secreted, tropic: turn away); 3) Contact-mediated attraction (permissive surface); 4) Contact-mediated repulsion (inhibitory). Some molecules are bifunctional.

Contact-mediated cues: ECM and integrins

ECM molecules (laminins, collagens, fibronectin) are secreted adhesion molecules binding INTEGRINS; important for peripheral neuron guidance along basal lamina.

Contact-mediated cues: CAMs

Ca2+-INDEPENDENT cell adhesion molecules with homophilic interactions (ligand and receptor) on growth cones and axons; bundle axons (fasciculation).

Contact-mediated cues: cadherins

Ca2+-DEPENDENT homophilic interactions; bundle axons (fasciculation) and play roles in synaptogenesis.

Contact-mediated cues: Eph and ephrins

Ephrin ligands bind Eph receptor tyrosine kinases; cell-cell recognition in pathfinding and synaptogenesis. Signaling is bidirectional and can promote or limit growth.

L1 CAM disorder

Disruption of L1 CAM -> partial agenesis of the corpus callosum (axon bundles connecting the two hemispheres): L1 syndrome.

Neurite outgrowth over great distances

Axons can extend enormous distances (e.g., motor axons in a 6 ft person). A postmitotic neuroblast initiates neurites and selects one as the axon.