title: Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination.
abstract: Developmental axon remodeling is characterized by the selective removal of branches from axon arbors. The mechanisms that underlie such branch loss are largely unknown. Additionally, how neuronal resources are specifically assigned to the branches of remodeling arbors is not understood. Here we show that axon branch loss at the developing mouse neuromuscular junction is mediated by branch-specific microtubule severing, which results in local disassembly of the microtubule cytoskeleton and loss of axonal transport in branches that will subsequently dismantle. Accordingly, pharmacological microtubule stabilization delays neuromuscular synapse elimination. This branch-specific disassembly of the cytoskeleton appears to be mediated by the microtubule-severing enzyme spastin, which is dysfunctional in some forms of upper motor neuron disease. Our results demonstrate a physiological role for a neurodegeneration-associated modulator of the cytoskeleton, reveal unexpected cell biology of branch-specific axon plasticity and underscore the mechanistic similarities of axon loss in development and disease.
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany. Electronic address: monika.brill@lrz.tum.de.
authors: Monika S
authors: MS
authors: Brill
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Tatjana
authors: T
authors: Kleele
authors: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology (ZMNH), Institute for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors: Laura
authors: L
authors: Ruschkies
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Mengzhe
authors: M
authors: Wang
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Natalia A
authors: NA
authors: Marahori
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Miriam S
authors: MS
authors: Reuter
authors: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology (ZMNH), Institute for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors: Torben J
authors: TJ
authors: Hausrat
authors: Ball State University, Department of Biology, 2000 West University, Muncie, IN 47306, USA.
authors: Emily
authors: E
authors: Weigand
authors: Ball State University, Department of Biology, 2000 West University, Muncie, IN 47306, USA.
authors: Matthew
authors: M
authors: Fisher
authors: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; German Center for Cardiovascular Research, DZHK, Partner site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Andrea
authors: A
authors: Ahles
authors: Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; German Center for Cardiovascular Research, DZHK, Partner site Munich Heart Alliance, Biedersteiner Straße 29, 80802 Munich, Germany.
authors: Stefan
authors: S
authors: Engelhardt
authors: Indiana University School of Medicine, Department of Cellular and Integrative Physiology, Medical Science Building 385, Indianapolis, IN 46202, USA; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 W. 15(th) Street, Indianapolis, IN 46202, USA.
authors: Derron L
authors: DL
authors: Bishop
authors: University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology (ZMNH), Institute for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
authors: Matthias
authors: M
authors: Kneussel
authors: Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany; Center of Integrated Protein Science (CIPSM), Butenandtstraße 5-13, 81377 Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen-Straße 17, 81377 Munich, Germany; Munich Cluster of Systems Neurology (SyNergy), Feodor-Lynen-Straße 17, 81377 Munich, Germany. Electronic address: thomas.misgeld@tum.de.
authors: Thomas
authors: T
authors: Misgeld
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D003599:Cytoskeleton / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism*; D016472:Motor Neuron Disease / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism*; D009473:Neuronal Plasticity; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C498515:Spast protein, mouse
keywords: axonal transport; cytoskeleton; microtubule; neuromuscular junction; synapse elimination