Sempert Kai, Shohayeb Belal, Lanoue Vanessa, O'Brien Elizabeth A, Flores Cecilia, Cooper Helen M
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
Department of Psychiatry, McGill University, Montréal, QC, Canada.
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.
结构可塑性，即树突棘响应突触刺激改变其体积的能力，是突触强度和长时程增强（LTP）的重要决定因素，而LTP被认为是学习和记忆的细胞基础。分支肌动蛋白聚合是驱动棘突增大并维持结构可塑性的主要力量。WAVE调节复合物（WRC）是一种关键的分支肌动蛋白调节因子，控制棘突形态，进而控制结构可塑性。然而，在棘突增大过程中控制WRC激活的分子机制在很大程度上尚不清楚。在这里，我们确定了新生成蛋白及其配体RGMa（排斥性导向分子a）在通过激活WRC介导 的分支肌动蛋白重塑促进棘突增大方面的关键作用。我们证明，新生成蛋白通过与WRC内高度保守的Cyfip/Abi结合口袋结合来调节WRC活性。我们发现，在新生成蛋白或RGMa缺失后，丝状伪足和未成熟细棘突的比例显著增加，成熟蘑菇状棘突的数量随之减少。野生型新生成蛋白，而非在Cyfip/Abi结合基序中携带突变的新生成蛋白，能够挽救棘突增大缺陷。此外，新生成蛋白缺失抑制了棘突头部的肌动蛋白聚合，这种效应不能被突变体恢复。我们得出结论，RGMa和新生成蛋白是WRC介导的分支肌动蛋白聚合促进棘突增大的关键调节因子。这项研究还为新生成蛋白在LTP诱导中日益显现的作用提供了机制性见解。
