GDE3 Function in Oligodendrocyte Precursor Cell Proliferation
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Oligodendrocyte specification, proliferation and differentiation are tightly controlled by extrinsic signals; however, proteins that modulate cellular response to these factors remain unclear. Six-transmembrane GDEs are emerging as central regulators of cellular differentiation via their unique ability to shed GPI-anchored proteins from the cell surface. We show here that GDE3 controls the pace of oligodendrocyte generation by negatively regulating oligodendrocyte precursor cell (OPC) proliferation. GDE3 inhibits OPC proliferation by stimulating CNTF-mediated signaling through release of CNTFRα, the ligand-binding component of the gp130/LIFRβ CNTF receptor complex that can function as a soluble factor. GDE3 releases CNTFRα by GPI-anchor cleavage from the plasma membrane and from extracellular vesicles (EVs) after co-recruitment of CNTFRα in EVs. These studies uncover new physiological roles for GDE3 in gliogenesis and identify GDE3 as a key regulator of CNTF-dependent inhibition of OPC proliferation through bi-modal release of CNTFRα.