Proposed Microtubule (MT) related mechanisms of axon elongation

Neuron extending into a zone of attractant factor (blue dots), showing cell body (S), nucleus (N), axon (A), growth cone (GC), lamellipodia (L), filopodia (F), MTs (grey tubes) and F-actin (red lines). Numbered boxed areas are shown as close-ups and illustrate the following mechanisms: 1) Polymerisation dynamics: MT plus end-binding factors (orange ellipses) regulate the polymerisation dynamics of MT elongation (black arrows; >>>); 2-4) Anterograde transport: MT fragments, generated through katanin-mediated plus end severing of MTs (scissors; black ball, centrosome), contribute to axon extension by being transported anterogradely (dashed blue arrows); their rapid but discontinuous transport is mediated by dynein/dynactin (blue Y structure) anchored either to longer MTs or the F-actin network (>>>; >>>); 5) Bundling & stabilisation: microtubule associated proteins (tau, map1b, map2; green L's) organise MTs through cross-linking, enable MT-based transport through spacing of MTs, and tau protects MTs from the activity of severing factors (>>>; >>>); 6, 7) F-actin-MT interactions: MT advance into lamellipodia and filopodia occurs either through polymerisation (black arrow) or, potentially, through dynein or myosinX activity (not shown; >>>; >>>); MT advance is antagonised by myosin II-driven F-actin backflow (red arrows; >>>), but only if MTs and F-actin are coupled (yellow stars; >>>); 8) upon engagement with extracellular attractant, F-actin clears out from the local periphery, promoting efficient invasion of MTs (>>>), which might be further influenced by bundling factors (as suggested in 5).

The key question remaining in the field is how these various mechanisms interrelate and combine into the systemic output of regulated axon advance. Mapping spectraplakins as key integrators into these functional contexts lies at the heart of this problem.