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

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Cecilia Flores¹  Kai Sempert²  Helen M. Cooper²  Vanessa Lanoue²  Belal Shohayeb²  Elizabeth A. O’Brien² 

[1] Department of Psychiatry, McGill University, Montréal, QC, Canada;Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada;Douglas Mental Health University Institute, Montréal, QC, Canada;Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia;

关键词: spine enlargement;    actin cytoskeleton;    synapse formation;    Neogenin;    RGMa;    netrin receptor;    WAVE Regulatory Complex;   

DOI  :  10.3389/fnmol.2023.1253801

 received in 2023-07-06, accepted in 2023-10-06,  发布年份 2023

来源: Frontiers

【 摘 要 】

Structural plasticity, the ability of dendritic spines to change their volume in response to synaptic stimulation, is an essential determinant of synaptic strength and long-term potentiation (LTP), the proposed cellular substrate for learning and memory. Branched actin polymerization is a major force driving spine enlargement and sustains structural plasticity. The WAVE Regulatory Complex (WRC), a pivotal branched actin regulator, controls spine morphology and therefore structural plasticity. However, the molecular mechanisms that govern WRC activation during spine enlargement are largely unknown. Here we identify a critical role for Neogenin and its ligand RGMa (Repulsive Guidance Molecule a) in promoting spine enlargement through the activation of WRC-mediated branched actin remodeling. We demonstrate that Neogenin regulates WRC activity by binding to the highly conserved Cyfip/Abi binding pocket within the WRC. We find that after Neogenin or RGMa depletion, the proportions of filopodia and immature thin spines are dramatically increased, and the number of mature mushroom spines concomitantly decreased. Wildtype Neogenin, but not Neogenin bearing mutations in the Cyfip/Abi binding motif, is able to rescue the spine enlargement defect. Furthermore, Neogenin depletion inhibits actin polymerization in the spine head, an effect that is not restored by the mutant. We conclude that RGMa and Neogenin are critical modulators of WRC-mediated branched actin polymerization promoting spine enlargement. This study also provides mechanistic insight into Neogenin’s emerging role in LTP induction.

【 授权许可】

Unknown   
Copyright © 2023 Sempert, Shohayeb, Lanoue, O’Brien, Flores and Cooper.