Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation.
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Gkogka A, Malwade S, Koskuvi M, Ohtonen S, Molnar E, Bose R, Ceccatelli S, Koistinaho J, Tiihonen J, Schalling M, Samudyata S, Sellgren CM
Nat Commun 16 (1) 10612 [2025-12-05; online 2025-12-05]
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.
NGI Stockholm (Genomics Production) [Service]
National Genomics Infrastructure [Service]
PubMed 41350273
DOI 10.1038/s41467-025-66521-1
Crossref 10.1038/s41467-025-66521-1
pmc: PMC12680777
pii: 10.1038/s41467-025-66521-1