Robust neuronal symmetry breaking by Ras-triggered local positive feedback

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Signaling

Background:

• Neuronal polarity establishment involves symmetry breaking, where one neurite becomes the axon.
• Phosphatidylinositol 3-kinase (PI3K)-related signaling regulates axon formation by influencing cytoskeletal dynamics.
• The upstream signaling pathways governing initial symmetry breaking and single axon formation remain unclear.

Purpose of the Study:

• To identify the upstream signaling circuit responsible for symmetry breaking during neuronal polarity establishment.
• To elucidate the molecular mechanisms ensuring the formation of a single axon.

Main Methods:

• Live Förster Resonance Energy Transfer (FRET) imaging in hippocampal neurons.
• Tracking the activity of the small GTPase HRas in developing neurons.
• Mathematical modeling of signaling pathways.

Main Results:

• HRas activity significantly increases in the nascent axonal growth cone during symmetry breaking.
• A positive feedback loop between HRas and PI3K, reinforced by HRas vesicular transport, drives this increase.
• Reduced HRas concentration in other neurites suggests competition for a limited pool, ensuring single axon formation.

Conclusions:

• Local positive feedback between HRas and PI3K, combined with limited HRas recruitment, robustly drives symmetry breaking.
• This intrinsic mechanism guarantees single axon formation, independent of external spatial cues.