Kinesin-5 Is Essential for Growth-Cone Turning

Inhibition of kinesin-5, a mitotic motor protein also expressed in neurons [1], causes axons to grow faster as a result of alterations in the forces on microtubules (MTs) in the axonal shaft [2-4]. Here, we investigate whether kinesin-5 plays a role in growth-cone guidance. Growth-cone turning requires that MTs in the central (C-) domain enter the peripheral (P-) domain in the direction of the turn. We found that inhibition of kinesin-5 in cultured neurons prevents MTs from polarizing within growth cones and causes them to grow past cues that would normally cause them to turn. We found that kinesin-5 is enriched in the transition (T-) zone of the growth cone and that kinesin-5 is preferentially phosphorylated on the side opposite the invasion of MTs. Moreover, when a growth cone encounters a turning cue, phospho-kinesin-5 polarizes even before the growth cone turns. Additional studies indicate that kinesin-5 works in part by antagonizing cytoplasmic dynein and that these motor-driven forces function together with the dynamic properties of the MTs to determine whether MTs can enter the P-domain. We propose that kinesin-5 permits MTs to selectively invade one side of the growth cone by opposing their entry into the other side.