Branch-Specific Microtubule Destabilization Mediates Axon Branch Loss During Neuromuscular Synapse Elimination

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

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.

Publication types

  • Video-Audio Media

MeSH terms

  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Axonal Transport*
  • Cytoskeleton / metabolism
  • Mice
  • Mice, Knockout
  • Microtubules / metabolism*
  • Motor Neuron Disease / metabolism
  • Neuromuscular Junction / metabolism*
  • Neuronal Plasticity*
  • Spastin

Substances

  • Adenosine Triphosphatases
  • Spastin
  • Spast protein, mouse