Kinesin-5 is essential for growth-cone turning.
Inhibition of kinesin-5, a mitotic motor protein also expressed in neurons, causes axons to grow faster as a result of alterations in the forces on microtubules (MTs) in the axonal shaft. 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.
Nadar
Vidya C
VC
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Ketschek
Andrea
A
Myers
Kenneth A
KA
Gallo
Gianluca
G
Baas
Peter W
PW
D000818:Animals; D002478:Cells, Cultured; D004398:Dyneins / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000187:drug effects / Q000254:growth & development / Q000502:physiology / Q000648:ultrastructure; D020439:Growth Cones / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D066298:In Vitro Techniques; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D009068:Movement / Q000187:drug effects / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D013871:Thiones / Q000494:pharmacology
D011743:Pyrimidines; D034741:RNA, Small Interfering; D013871:Thiones; C400223:monastrol; D020932:Nerve Growth Factor; C502895:Kif11 protein, rat; D004398:Dyneins; D016547:Kinesins