A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• The Wnt pathway regulates crucial biological processes, including neuronal development.
• Wnt proteins mediate opposing axonal responses (extension and repulsion), but mechanisms remain unclear.

Purpose of the Study:

• Investigate the molecular mechanisms of Wnt-mediated axonal guidance at the optic chiasm.
• Elucidate the role of Wnt5a and Zic2 in regulating axonal responses.

Main Methods:

• Analysis of Wnt5a expression at the optic chiasm midline.
• Investigating an alternative Wnt pathway involving β-catenin accumulation.
• Studying the role of transcription factor Zic2 in regulating Wnt receptors and intracellular proteins.
• Examining the interaction between Wnt pathway and EphB1 receptor signaling.

Main Results:

• Wnt5a promotes retinal axon crossing by activating an alternative Wnt pathway independent of canonical Wnt signaling.
• Zic2 regulates Wnt receptors and intracellular proteins in ipsilateral neurons, switching the alternative Wnt pathway.
• Asymmetric EphB1 receptor activation phosphorylates β-catenin, leading to axonal repulsion.

Conclusions:

• An alternative Wnt pathway, modulated by Zic2, controls bidirectional Wnt responses in developing neurons.
• This pathway and its switch mechanism are critical for proper axonal guidance at the optic chiasm.
• The findings suggest a broader role for this alternative Wnt pathway in other biological contexts.