Cours: Axon Growth and Survival

Axon Growth and Survival

• Axons must survive, grow, find and reach their target cells, recognize their targets, and connect to them.
• The complexity of axon tracts increases rapidly during early stages of development, as shown by diagrams of developing nervous system structures at various time points.
• Neurons require trophic factors for survival. Dorsal root ganglion (DRG) neurons, without nerve growth factor (NGF), show reduced survival compared to those with NGF.
• Viktor Hamburger (1900-2001) and Rita Levi-Montalcini (1909-2012) were pivotal in identifying the importance of growth factors and NGF in neuronal development. Montalcini's work won her a Nobel Prize in 1986.
• Reducing the target area promotes cell death during neural development. Removal of a limb bud led to less survival of DRG and motor neurons.
• The number of surviving neurons correlates with the size of the target tissue; adding a limb bud increased neuron survival, while removal reduced it.
• NGF is the first identified neurotrophic factor (responsible for regulating growth and survival of neurons during development).
• Apoptosis (programmed cell death) requires protein synthesis. Blocking protein synthesis interferes with apoptosis.
• Neurotrophins (including NGF, BDNF, NT3, and NT4) support different sensory neuron subtypes via specific receptor engagement (trk receptors and p75).
• Neurotrophins are released in a target-specific manner, influencing development of different types of nerve cells in different regions.
• Neurotrophins (e.g., NGF) adapt innervation according to tissue size. Smaller or removed target tissues lead to less cell death in DRG neurons.
• Neurotrophin signaling involves endocytosis and retrograde transport, influencing cell survival and growth.
• Neurotrophins prevent apoptosis and support synaptogenesis (formation of synapses).
• Axons extend long processes to connect to their targets.
• Axons grow through adding new microtubules at the distal end, and by stretching.
• Growth cones come in different shapes depending on their environment and phase of growth (fascicle, choice point, target region).
• Growth cone speed varies depending on location.
• Non-permissive substrates trigger growth cone turns at boundary areas.
• In vertebrate growth cones, actin filaments and microtubules interact at the peripheral zone.
• Actin and tubulin form the growth cone's cytoskeleton (filopodia, lamellipodia-like veil, etc.).
• Filopodia exhibit force exertion and trigger growth cone turns.
• The cytoskeleton directs growth cone movement through actin and microtubule depolymerization and stabilization.
• Guidance cues (semaphores, netrin receptors) and molecules such as Eph ligands, Ig CAMs, cadherins, and ECM components influence axon interactions.
• Actin filaments are essential for axon guidance and contribute to the clutch mechanism used to move the growth cone.
• A pathway, involving Rho GTPases, transmits signals to the cytoskeleton to coordinate growth cone movement and shape.
• Axon branching via growth cone bifurcation or collateral branching is vital for neuronal connectivity.
• Branch formation requires actin filaments and microtubules in a set of well-regulated steps.
• Molecules play a role as guidance cues, affecting how many and which axons follow a given pathway.