Gillespie Shawn M, Kim Yoon Seok, Geraghty Anna C, Yalçın Belgin, Mancusi Rebecca, Hysinger Jared, Ivec Alexis English, Reed James, Drexler Richard, Quezada Michael, Malacon Karen, Woo Pamelyn, Mount Christopher, Yang Aerin, Lam Mable, Pan Yuan, Zuchero J Bradley, Trotter Jacqueline, Monje Michelle
bioRxiv. 2025 Jul 17:2025.07.12.664340. doi: 10.1101/2025.07.12.664340.
Glioma pathophysiology is robustly regulated by interactions with neurons. Key to these interactions is the role of neuroligin-3 (NLGN3), a synaptic adhesion molecule shed in response to neuronal activity that functions as a paracrine factor crucial for glioma growth. Here, we elucidate the mechanistic pathway whereby shed NLGN3 interacts with glioma and their normal glial counterpart. NLGN3 interacts with Chondroitin Sulfate Proteoglycan 4 (CSPG4) on both glioma and healthy oligodendrocyte precursor cells (OPCs) , facilitating CSPG4 shedding by ADAM10. NLGN3-CSPG4 interactions and consequent shedding alter membrane tension, thereby activating PIEZO1 mechanosensitive channels and causing membrane depolarization. The NLGN3-CSPG4-PIEZO1 axis maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring important functional roles for the NLGN3-CSPG4-PIEZO1 axis in both healthy and malignant glial precursors.
胶质瘤的病理生理学受到与神经元相互作用的强烈调节。这些相互作用的关键是神经连接蛋白3（NLGN3）的作用，它是一种响应神经元活动而释放的突触粘附分子，作为旁分泌因子对胶质瘤生长至关重要。在这里，我们阐明了释放的NLGN3与胶质瘤及其正常神经胶质对应物相互作用的机制途径。NLGN3与胶质瘤和健康少突胶质前体细胞（OPC）上的硫酸软骨素蛋白聚糖4（CSPG4）相互作用，促进ADAM10介导的CSPG4脱落。NLGN3-CSPG4相互作用及随后的脱落改变膜张力，从而激活PIEZO1机械敏感通道并导致膜去极化。NLGN3-CSPG4-PIEZO1轴使OPC维持在未分化的干细胞样状态并促进胶质瘤增殖，突出了NLGN3-CSPG4-PIEZO1轴在健康和恶性神经胶质前体细胞中的重要功能作用。
