title: CFEOM1-associated kinesin KIF21A is a cortical microtubule growth inhibitor.
abstract: Mechanisms controlling microtubule dynamics at the cell cortex play a crucial role in cell morphogenesis and neuronal development. Here, we identified kinesin-4 KIF21A as an inhibitor of microtubule growth at the cell cortex. In vitro, KIF21A suppresses microtubule growth and inhibits catastrophes. In cells, KIF21A restricts microtubule growth and participates in organizing microtubule arrays at the cell edge. KIF21A is recruited to the cortex by KANK1, which coclusters with liprin-α1/β1 and the components of the LL5β-containing cortical microtubule attachment complexes. Mutations in KIF21A have been linked to congenital fibrosis of the extraocular muscles type 1 (CFEOM1), a dominant disorder associated with neurodevelopmental defects. CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. Our study provides mechanistic insight into cortical microtubule regulation and suggests that altered microtubule dynamics contribute to CFEOM1 pathogenesis.
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Babet
authors.initials: B
authors.lastname: van der Vaart
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Wilhelmina E
authors.initials: WE
authors.lastname: van Riel
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Harinath
authors.initials: H
authors.lastname: Doodhi
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Josta T
authors.initials: JT
authors.lastname: Kevenaar
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Katrukha
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Gumy
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Bouchet
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Ilya
authors.initials: I
authors.lastname: Grigoriev
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Spangler
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Ka Lou
authors.initials: KL
authors.lastname: Yu
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Phebe S
authors.initials: PS
authors.lastname: Wulf
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
authors.forename: Jingchao
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Gideon
authors.initials: G
authors.lastname: Lansbergen
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: Eljo Y
authors.initials: EY
authors.lastname: van Battum
authors.affiliation: Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, 3584 CG, Utrecht, The Netherlands.
authors.forename: R Jeroen
authors.initials: RJ
authors.lastname: Pasterkamp
authors.affiliation: Kobe institute, RIKEN, Center for Developmental Biology, Optical Image Analysis Unit, Chuo-ku, Kobe 650-0047, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mimori-Kiyosue
authors.affiliation: Proteomics Center, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Biomolecular Research, Paul Scherrer Insitut, 5232 Villingen PSI, Switzerland.
authors.forename: Natacha
authors.initials: N
authors.lastname: Olieric
authors.affiliation: Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
authors.forename: Ivan V
authors.initials: IV
authors.lastname: Maly
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Neuroscience, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. Electronic address: c.hoogenraad@uu.nl.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands. Electronic address: a.akhmanova@uu.nl.
authors.forename: Anna
authors.initials: A
authors.lastname: Akhmanova
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis / Q000378:metabolism*; D006131:Growth Inhibitors; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015835:Ocular Motility Disorders / Q000378:metabolism*; D009886:Ophthalmoplegia; D034622:RNA Interference; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000093922:Congenital Cranial Dysinnervation Disorders
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D006131:Growth Inhibitors; C467739:KANK1 protein, human; C119023:KIF21A protein, human; D009419:Nerve Tissue Proteins; C471180:PHLDB2 protein, human; C094398:PPFIA1 protein, human; C449803:PPFIBP1 protein, human; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D016547:Kinesins