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

Front Mol Neurosci. 2023 Oct 19:16:1253801. doi: 10.3389/fnmol.2023.1253801. eCollection 2023.


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.

Keywords: Neogenin; RGMa; WAVE Regulatory Complex; actin cytoskeleton; netrin receptor; spine enlargement; synapse formation.

Grants and funding

This work was supported by the National Health and Medical Research Council of Australia (Grant numbers 1061512, 1063080, and 1141928). KS was supported by a University of Queensland Postgraduate Award. We are grateful to Frank and Patsy Youngleson for their generous support through a private donation. Imaging was performed in the Queensland Brain Institute’s Advanced Microscopy Facility generously supported by an Australian Research Council LIEF grant (Grant number LE130100078).