Neuroligin-3–CSPG4 interaction maintains oligodendrocyte precursor cell progenitor state and promotes glioma proliferation through mechanotransduction

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 counterparts. NLGN3 binds to chondroitin sulfate proteoglycan 4 (CSPG4, also known as NG2) on both glioma and healthy oligodendrocyte precursor cells (OPCs), facilitating CSPG4 shedding by ADAM10. NLGN3–CSPG4 interactions alter membrane tension, thereby activating mechanotransducers, primarily PIEZO1, leading to membrane depolarization and subsequent ADAM10-mediated CSPG4 shedding. The NLGN3–CSPG4–PIEZO1 pathway maintains OPCs in an undifferentiated, stem-like state and promotes glioma proliferation, underscoring its dual roles in healthy and malignant contexts. This study finds that shed NLGN3 interacts with the glycosylated surface protein CSPG4 on both normal and malignant glial cells, activating mechanotransduction pathways that drive glioma growth and maintain oligodendroglial progenitor states.