The Rac activator DOCK7 regulates neuronal polarity through local phosphorylation of stathmin/Op18

Neuron. 2006 Sep 21;51(6):727-39. doi: 10.1016/j.neuron.2006.07.020.

Abstract

The polarization of a neuron generally results in the formation of one axon and multiple dendrites, allowing for the establishment of neuronal circuitry. The molecular mechanisms involved in priming one neurite to become the axon, particularly those regulating the microtubule network, remain elusive. Here we report the identification of DOCK7, a member of the DOCK180-related protein superfamily, as a Rac GTPase activator that is asymmetrically distributed in unpolarized hippocampal neurons and selectively expressed in the axon. Knockdown of DOCK7 expression prevents axon formation, whereas overexpression induces formation of multiple axons. We further demonstrate that DOCK7 and Rac activation lead to phosphorylation and inactivation of the microtubule destabilizing protein stathmin/Op18 in the nascent axon and that this event is important for axon development. Our findings unveil a pathway linking the Rac activator DOCK7 to a microtubule regulatory protein and highlight the contribution of microtubule network regulation to axon development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Axons / metabolism
  • Blotting, Western
  • Brain / growth & development
  • Brain / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cell Polarity
  • Cells, Cultured
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Microscopy, Confocal
  • Microscopy, Fluorescence
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Binding
  • Rats
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Stathmin / genetics
  • Stathmin / metabolism*
  • Time Factors
  • Transfection
  • Two-Hybrid System Techniques
  • rac GTP-Binding Proteins / genetics
  • rac GTP-Binding Proteins / metabolism*

Substances

  • DOCK7 protein, human
  • GTPase-Activating Proteins
  • Recombinant Fusion Proteins
  • Stathmin
  • Green Fluorescent Proteins
  • rac GTP-Binding Proteins