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Negative guidance factor-induced macropinocytosis in the growth cone plays a critical role in repulsive axon turning

Adrianne L Kolpak1, Jun Jiang, Daorong Guo

  • 1Department of Medicine and Cell Biology, Program in Neuroscience, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|August 28, 2009
PubMed

Insights

Sonic hedgehog (Shh) protein triggers macropinocytosis in axons, a process crucial for axon guidance. This finding reveals macropinocytosis as a key mechanism in cellular responses to negative guidance cues.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Macropinocytosis is a poorly understood form of fluid-phase endocytosis.
  • Axon guidance relies on cellular mechanisms responding to guidance cues.

Purpose of the Study:

  • To investigate the role of Sonic hedgehog (Shh) in inducing macropinocytosis in axons.
  • To elucidate the signaling pathways and cellular mechanisms involved in Shh-induced macropinocytosis and its effect on axon growth.

Main Methods:

  • Utilized biochemical assays and inhibitors to study macropinocytosis in axons.
  • Investigated the involvement of Rho GTPase, nonmuscle myosin II, dynamin, and clathrin-mediated endocytosis.
  • Examined the effects of macropinocytosis modulation on growth cone collapse and axon turning.

Main Results:

  • Sonic hedgehog (Shh) protein induces macropinocytosis in axons via a noncanonical pathway involving Rho GTPase and nonmuscle myosin II.
  • Shh-induced macropinocytosis is independent of clathrin but dependent on dynamin, myosin II, and Rho GTPase.
  • Inhibiting macropinocytosis blocked Shh's negative effects on axonal growth, including growth cone collapse and chemorepulsive turning.
  • Ephrin-A2 also induced macropinocytosis, and dynamin inhibition blocked ephrin-A2-induced repulsive axon turning.
  • High Shh levels induced macropinocytosis ex vivo, correlating with axon retraction.

Conclusions:

  • Macropinocytosis is a critical cellular mechanism mediating axon chemorepulsion by negative guidance factors.
  • Shh-induced macropinocytosis plays a significant role in regulating axonal growth and guidance decisions.

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