Sonic Hedgehog Guides Axons via Zipcode Binding Protein 1-Mediated Local Translation

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Sonic hedgehog (Shh) is crucial for guiding spinal cord commissural axons.
• The precise molecular mechanisms by which Shh induces growth cone turning remain largely unknown.
• Axon guidance relies on growth cone cytoskeletal remodeling in response to guidance cues.

Purpose of the Study:

• To elucidate how Shh signaling elicits cytoskeletal changes for growth cone turning.
• To investigate the role of local protein synthesis in Shh-mediated axon guidance.
• To identify molecular mediators of noncanonical Shh signaling in axon guidance.

Main Methods:

• Assessed the requirement of protein synthesis for commissural axon turning in response to Shh gradients.
• Quantified β-actin protein levels in growth cones following Shh stimulation.
• Examined the role of zipcode binding protein 1 (ZBP1) phosphorylation and function in vitro and in vivo.

Main Results:

• Commissural axon turning toward Shh requires protein synthesis, specifically local translation of β-actin at the growth cone.
• Shh stimulation increases phospho-ZBP1 levels in the growth cone.
• Disruption of ZBP1 phosphorylation or function impairs Shh-mediated axon guidance in vitro and in vivo.

Conclusions:

• Shh induces local translation of β-actin at the growth cone, mediated by ZBP1.
• ZBP1 is essential for Shh-guided commissural axon navigation.
• Identifies ZBP1 as a novel mediator of noncanonical Shh signaling in axon guidance.