title: DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1.
abstract: Disrupted-In-Schizophrenia 1 (DISC1) is a candidate gene for susceptibility to schizophrenia. DISC1 is reported to interact with NudE-like (NUDEL), which forms a complex with lissencephaly-1 (LIS1) and 14-3-3epsilon. 14-3-3epsilon is involved in the proper localization of NUDEL and LIS1 in axons. Although the functional significance of this complex in neuronal development has been reported, the transport mechanism of the complex into axons and their functions in axon formation remain essentially unknown. Here we report that Kinesin-1, a motor protein of anterograde axonal transport, was identified as a novel DISC1-interacting molecule. DISC1 directly interacted with kinesin heavy chain of Kinesin-1. Kinesin-1 interacted with the NUDEL/LIS1/14-3-3epsilon complex through DISC1, and these molecules localized mainly at cell bodies and partially in the distal part of the axons. DISC1 partially colocalized with Kinesin family member 5A, NUDEL, LIS1, and 14-3-3epsilon in the growth cones. The knockdown of DISC1 by RNA interference or the dominant-negative form of DISC1 inhibited the accumulation of NUDEL, LIS1, and 14-3-3epsilon at the axons and axon elongation. The knockdown or the dominant-negative form of Kinesin-1 inhibited the accumulation of DISC1 at the axons and axon elongation. Furthermore, the knockdown of NUDEL or LIS1 inhibited axon elongation. Together, these results indicate that DISC1 regulates the localization of NUDEL/LIS1/14-3-3epsilon complex into the axons as a cargo receptor for axon elongation.
authors.affiliation: Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya 466-8550, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Taya
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Shinoda
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tsuboi
authors.forename: Junko
authors.initials: J
authors.lastname: Asaki
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nagai
authors.forename: Takao
authors.initials: T
authors.lastname: Hikita
authors.forename: Setsuko
authors.initials: S
authors.lastname: Kuroda
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kuroda
authors.forename: Mariko
authors.initials: M
authors.lastname: Shimizu
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure*; D001693:Biological Transport, Active; D019556:COS Cells; D049108:Cell Enlargement; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D016547:Kinesins / Q000378:metabolism*; D020409:Molecular Motor Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats
chemical_list: D048948:14-3-3 Proteins; C498795:Disc1 protein, rat; D020409:Molecular Motor Proteins; D009419:Nerve Tissue Proteins; C516550:Pafah1b1 protein, rat; D003546:Cysteine Endopeptidases; C516549:Ndel1 protein, rat; D016547:Kinesins