title: Pavarotti/MKLP1 regulates microtubule sliding and neurite outgrowth in Drosophila neurons.
abstract: Recently, we demonstrated that kinesin-1 can slide microtubules against each other, providing the mechanical force required for initial neurite extension in Drosophila neurons. This sliding is only observed in young neurons actively forming neurites and is dramatically downregulated in older neurons. The downregulation is not caused by the global shutdown of kinesin-1, as the ability of kinesin-1 to transport membrane organelles is not diminished in mature neurons, suggesting that microtubule sliding is regulated by a dedicated mechanism. Here, we have identified the "mitotic" kinesin-6 Pavarotti (Pav-KLP) as an inhibitor of kinesin-1-driven microtubule sliding. Depletion of Pav-KLP in neurons strongly stimulated the sliding of long microtubules and neurite outgrowth, while its ectopic overexpression in the cytoplasm blocked both of these processes. Furthermore, postmitotic depletion of Pav-KLP in Drosophila neurons in vivo reduced embryonic and larval viability, with only a few animals surviving to the third instar larval stage. A detailed examination of motor neurons in the surviving larvae revealed the overextension of axons and mistargeting of neuromuscular junctions, resulting in uncoordinated locomotion. Taken together, our results identify a new role for Pav-KLP as a negative regulator of kinesin-1-driven neurite formation. These data suggest an important parallel between long microtubule-microtubule sliding in anaphase B and sliding of interphase microtubules during neurite formation.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA; IKERBASQUE, Basque Foundation for Science, Bilbao 48011, Spain.
authors.forename: Urko
authors.initials: U
authors.lastname: Del Castillo
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Lu
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Winding
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: Lakonishok
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611, USA. Electronic address: vgelfand@northwestern.edu.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Gelfand
mesh_terms: D000705:Anaphase; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D007399:Interphase; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D007814:Larva / Q000254:growth & development / Q000502:physiology; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000502:physiology*; D016501:Neurites / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D008869:Microtubule-Associated Proteins; C490516:pav protein, Drosophila; C515209:Khc protein, Drosophila; D016547:Kinesins