(A) The central domain of the growth cone is the microtubule (MT)-rich region contiguous with the axon shaft. The peripheral domain is the outer-most part of the growth cone. The peripheral domain comprises a broad flat lamellar region in which actin filaments are arranged as a meshwork, as well as elongated thin filopodia in which actin filaments are arranged as aligned bundles. The transition zone is the region between these two domains. Retrograde flow of the actin cytoskeleton in the peripheral domain pushes back most microtubules, compacting them in the central domain. Individual microtubules from the central domain are able to penetrate the transition zone to enter the peripheral domain during growth cone advance. (B) During growth cone turning, microtubules extend from the central domain through the transition zone preferentially into one side of the peripheral domain.

(A) During growth cone advance, cytoplasmic dynein generates forces on microtubules (MT) that enable some of them to resist the retrograde flow of the actin cytoskeleton in the peripheral domain of the growth cone. Kinesin-5 and kinesin-12 generate forces that oppose dynein-driven forces on the microtubules to resist their entry into the peripheral domain. Kinesin-5 acts more in the transition zone, while kinesin-12 acts more in the filopodia. (B) During growth cone turning, kinesin-5 and kinesin-12 forces become polarized to the side of the growth cone opposite to the direction of the turn. This enables microtubules to preferentially enter the side of the growth cone in the direction of the turn.

(A) During growth cone advance, dynein-driven forces permit a portion of the microtubules to overcome the retrograde flow of actin filaments so that these microtubules can invade the peripheral domain and filopodia. The invasion occurs in a nonpolarized fashion throughout the peripheral domain, so that the axon grows in a relatively straight trajectory. Severing in the labile portion of the microtubule (shown in dark blue) regulates the length of that portion of the microtubule, while severing in the stable portion of the microtubule (shown in light blue) creates short mobile microtubules. (B) When the growth cone pauses, the advance of the microtubule array results in a growth cone no longer compartmentalized into central and peripheral domains, dominated by a curved bundle of microtubules. (C) When the axon resumes growth, microtubules are rapidly unbundled, and microtubule severing is increased so that more short microtubules are propelled away from the bundle. (D) During turning, kinesin-5 and/or kinesin-12 forces become polarized to the side of the growth cone opposite to the direction of the turn, so that dynein-driven forces enable microtubule invasion only on the side of the growth cone in the direction of the turn. Small arrows indicate direction of movement of short microtubules. Large red arrows indicate retrograde actin flow.