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Neuron. 2016 Nov 23;92(4):845-856. doi: 10.1016/j.neuron.2016.09.049. Epub 2016 Oct 20.

Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss during Neuromuscular Synapse Elimination.

Author information

1
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany. Electronic address: monika.brill@lrz.tum.de.
2
Institute of Neuronal Cell Biology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany.
3
University Medical Center Hamburg-Eppendorf, Center for Molecular Neurobiology (ZMNH), Institute for Molecular Neurogenetics, Falkenried 94, 20251 Hamburg, Germany.
4
Ball State University, Department of Biology, 2000 West University, Muncie, IN 47306, USA.
5
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.
6
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.
7
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.

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.

KEYWORDS:

axonal transport; cytoskeleton; microtubule; neuromuscular junction; synapse elimination

PMID:
27773584
PMCID:
PMC5133389
DOI:
10.1016/j.neuron.2016.09.049
[Indexed for MEDLINE]
Free PMC Article

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