Human oligodendrocyte progenitor cells mediate synapse elimination through TAM receptor activation

Area of Science:

• Neuroscience
• Developmental Biology
• Cell Biology

Background:

• Oligodendrocyte progenitor cells (OPCs) are known to participate in synaptic remodeling in animal models.
• The precise mechanisms and relevance of OPCs in human brain development are not fully understood.

Purpose of the Study:

• To investigate the mechanisms by which OPCs interact with and internalize synaptic material in a human brain development model.
• To identify key signaling pathways involved in OPC-synapse interactions during early human brain development.

Main Methods:

• Generation of a human multi-lineage forebrain organoid model.
• Single-nucleus transcriptomic profiling and cell-cell communication analysis.
• Pharmacological inhibition and genetic manipulation of specific signaling pathways.

Main Results:

• OPCs in human organoids form close contacts with synapses and internalize synaptic material.
• The growth arrest-specific gene 6 (GAS6)-TYRO3, AXL, and MERTK (TAM) receptor axis was identified as a key signaling pathway.
• GAS6 is expressed by neurons and microglia, while AXL is expressed by a subset of OPCs.
• Inhibition of TAM receptors, particularly AXL, impaired synaptic uptake by OPCs.

Conclusions:

• GAS6-AXL signaling is crucial for synaptic material internalization by OPCs in early human brain development.
• This study reveals a novel function for AXL-expressing OPCs in synaptic remodeling.
• The findings provide insights into the complex interplay between glial cells and synapses during human neurodevelopment.