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Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway

Takeshi Yoshimura1, Nariko Arimura, Yoji Kawano

  • 1Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya, Aichi 466-8550, Japan.

Biochemical and Biophysical Research Communications
|December 14, 2005
PubMed

Insights

Small GTPase Ras is crucial for neuronal polarity, promoting single axon formation. It acts upstream of key signaling pathways, including PI3-kinase/Akt and MAPK, influencing neuron differentiation.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Neuronal differentiation requires establishing a polarized morphology with a single axon and multiple dendrites.
  • Glycogen synthase kinase-3beta (GSK-3beta) is known to regulate axon/dendrite fate via CRMP-2 phosphorylation.

Purpose of the Study:

  • To investigate the role of the small GTPase Ras in neuronal polarity and axon formation.
  • To elucidate the signaling pathways downstream of Ras involved in neuronal differentiation.

Main Methods:

  • Overexpression and dominant-negative expression of Ras in cultured hippocampal neurons.
  • Inhibition of phosphatidylinositol-3-kinase (PI3-kinase) and mitogen-activated protein kinase kinase (MEK).
  • Expression of constitutively active PI3-kinase and Akt.

Main Results:

  • Ras overexpression induced multiple axon formation; dominant-negative Ras inhibited axon formation.
  • PI3-kinase and MEK inhibition suppressed Ras-induced multiple axon formation.
  • Active PI3-kinase or Akt promoted multiple axon formation.
  • Ras overexpression blocked CRMP-2 phosphorylation by GSK-3beta.

Conclusions:

  • Ras plays a critical role in establishing neuronal polarity.
  • Ras acts upstream of the PI3-kinase/Akt/GSK-3beta/CRMP-2 and MAPK pathways.
  • These findings provide insights into the molecular mechanisms of neuronal differentiation.

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