Ran-dependent TPX2 activation promotes acentrosomal microtubule nucleation in neurons

Sci Rep. 2017 Feb 13:7:42297. doi: 10.1038/srep42297.

Abstract

The microtubule (MT) cytoskeleton is essential for the formation of morphologically appropriate neurons. The existence of the acentrosomal MT organizing center in neurons has been proposed but its identity remained elusive. Here we provide evidence showing that TPX2 is an important component of this acentrosomal MT organizing center. First, neurite elongation is compromised in TPX2-depleted neurons. In addition, TPX2 localizes to the centrosome and along the neurite shaft bound to MTs. Depleting TPX2 decreases MT formation frequency specifically at the tip and the base of the neurite, and these correlate precisely with the regions where active GTP-bound Ran proteins are enriched. Furthermore, overexpressing the downstream effector of Ran, importin, compromises MT formation and neuronal morphogenesis. Finally, applying a Ran-importin signaling interfering compound phenocopies the effect of TPX2 depletion on MT dynamics. Together, these data suggest a model in which Ran-dependent TPX2 activation promotes acentrosomal MT nucleation in neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism*
  • Centrosome / drug effects
  • Centrosome / metabolism*
  • Guanosine Triphosphate / metabolism
  • Hippocampus / cytology
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / metabolism*
  • Microtubules / drug effects
  • Microtubules / metabolism*
  • Models, Biological
  • Morphogenesis / drug effects
  • Neurites / drug effects
  • Neurites / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Nuclear Proteins / metabolism*
  • Protein Binding / drug effects
  • Protein Transport / drug effects
  • Quinazolines / pharmacology
  • alpha Karyopherins / metabolism
  • beta Karyopherins / metabolism
  • ran GTP-Binding Protein / metabolism*

Substances

  • Cell Cycle Proteins
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Quinazolines
  • TPX2 protein, mouse
  • alpha Karyopherins
  • beta Karyopherins
  • importazole
  • Guanosine Triphosphate
  • ran GTP-Binding Protein