RGMa and Neogenin control dendritic spine morphogenesis via WAVE Regulatory Complex-mediated actin remodeling.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Structural plasticity of dendritic spines is vital for synaptic strength and long-term potentiation (LTP), the basis of learning and memory.
• Branched actin polymerization drives spine enlargement, with the WAVE Regulatory Complex (WRC) controlling spine morphology.
• The precise molecular triggers for WRC activation during spine enlargement remain largely unelucidated.

Purpose of the Study:

• To identify molecular mechanisms regulating WRC activation during synaptic plasticity.
• To investigate the role of Neogenin and its ligand RGMa in spine enlargement and structural plasticity.
• To elucidate how Neogenin influences WRC-mediated actin remodeling.

Main Methods:

• Depletion of Neogenin or RGMa in neurons.
• Analysis of spine morphology using microscopy.
• Assessment of actin polymerization dynamics.
• Mutagenesis studies of Neogenin's binding domain.

Main Results:

• Neogenin and RGMa depletion increased filopodia and thin spines while decreasing mature mushroom spines.
• Neogenin directly binds to the WRC via a conserved Cyfip/Abi binding pocket.
• Wildtype Neogenin, but not a mutated version, rescued spine enlargement defects and restored actin polymerization.
• Neogenin depletion inhibited actin polymerization in spine heads.

Conclusions:

• RGMa and Neogenin are critical regulators of WRC-mediated actin polymerization, driving spine enlargement.
• Neogenin's interaction with WRC is essential for maintaining mature spine morphology.
• These findings provide mechanistic insight into Neogenin's role in structural plasticity and LTP induction.