Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation
Asimenia Gkogka1, Susmita Malwade1, Marja Koskuvi1
1Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
None:
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.
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