title: TRIM46 Controls Neuronal Polarity and Axon Specification by Driving the Formation of Parallel Microtubule Arrays.
abstract: Axon formation, the initial step in establishing neuronal polarity, critically depends on local microtubule reorganization and is characterized by the formation of parallel microtubule bundles. How uniform microtubule polarity is achieved during axonal development remains an outstanding question. Here, we show that the tripartite motif containing (TRIM) protein TRIM46 plays an instructive role in the initial polarization of neuronal cells. TRIM46 is specifically localized to the newly specified axon and, at later stages, partly overlaps with the axon initial segment (AIS). TRIM46 specifically forms closely spaced parallel microtubule bundles oriented with their plus-end out. Without TRIM46, all neurites have a dendrite-like mixed microtubule organization resulting in Tau missorting and altered cargo trafficking. By forming uniform microtubule bundles in the axon, TRIM46 is required for neuronal polarity and axon specification in vitro and in vivo. Thus, TRIM46 defines a unique axonal cytoskeletal compartment for regulating microtubule organization during neuronal development.
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Sam F B
authors.initials: SFB
authors.lastname: van Beuningen
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Lena
authors.initials: L
authors.lastname: Will
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Harterink
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Anaël
authors.initials: A
authors.lastname: Chazeau
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: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Cátia P
authors.initials: CP
authors.lastname: Frias
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Mariella A M
authors.initials: MAM
authors.lastname: Franker
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Eugene A
authors.initials: EA
authors.lastname: Katrukha
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands; Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences and The Netherlands Proteomics Centre, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Stucchi
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Vocking
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Ana T
authors.initials: AT
authors.lastname: Antunes
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Lotte
authors.initials: L
authors.lastname: Slenders
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Sofia
authors.initials: S
authors.lastname: Doulkeridou
authors.affiliation: Department of Neurology, Erasmus Medical Center, 3015 CE Rotterdam, the Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Sillevis Smitt
authors.affiliation: Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht Institute for Pharmaceutical Sciences and The Netherlands Proteomics Centre, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: A F Maarten
authors.initials: AFM
authors.lastname: Altelaar
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Post
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: Akhmanova
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: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Kapitein
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands. Electronic address: e.degraaff@uu.nl.
authors.forename: Esther
authors.initials: E
authors.lastname: de Graaff
authors.affiliation: Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands. Electronic address: c.hoogenraad@uu.nl.
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure*; D019556:COS Cells; D016764:Cell Polarity / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000196:embryology / Q000502:physiology / Q000648:ultrastructure; D002522:Chlorocebus aethiops; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000502:physiology* / Q000648:ultrastructure*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000502:physiology* / Q000648:ultrastructure*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D011247:Pregnancy; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology / Q000648:ultrastructure
chemical_list: D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C000607105:TRIM46 protein, mouse
keywords: TRIM; axon formation; axon initial segment; cross-bridges; cytoskeleton; fascicles; microtubule; neuronal polarity; parallel bundles; transport