2025/12/05 by Asimenia Gkogka, Susmita Malwade, Marja Koskuvi +9 · 1 voice
Neuroscience · Medicine · #Neurogenesis and neuroplasticity mechanisms #Glioma Diagnosis and Treatment #Neuroinflammation and Neurodegeneration Mechanisms
paper · pdf · doi:10.1038/s41467-025-66521-1
openalex created_date 2025/12/05 · openalex publication_date 2025/12/05 · openalex updated_date 2026/08/01
Oligodendrocyte progenitor cells (OPCs) have been implicated in synaptic remodelling in animal models, but the underlying mechanisms and their relevance to human brain development remain unclear. Here, we generate a human multi-lineage forebrain organoid model in which OPCs, together with microglia, form close contacts with synapses and spontaneously internalize synaptic material. Single-nucleus transcriptomic profiling with unbiased cell-cell communication analysis identifies the growth arrest-specific gene 6 (GAS6)-TYRO3, AXL, and MERTK (TAM) receptor axis as a key signalling pathway, with neurons and microglia expressing GAS6 and a subset of OPCs expressing AXL. Further, dose-dependent pharmacological inhibition of TAM receptors demonstrates the importance of AXL, and targeted reduction of AXL expression in OPCs impairs synaptic uptake. These findings reveal a role for GAS6-AXL signalling in driving synaptic internalisation by AXL+ OPCs during early human brain development.