Oligodendrocyte development is tightly controlled by extrinsic signals; however, mechanisms that modulate cellular responses to these factors remain unclear. Six-transmembrane glycerophosphodiester phosphodiesterases (GDEs) are emerging as central regulators of cellular differentiation via their ability to shed glycosylphosphatidylinositol (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 ciliary neurotrophic factor (CNTF)-mediated signaling through release of CNTFRα, the ligand-binding component of the CNTF-receptor multiprotein complex, which can function as a soluble factor to activate CNTF signaling. GDE3 releases soluble 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 regulation of OPC proliferation through release of CNTFRα.

Background: Oligodendrocytes generate specialized lipid-rich sheaths called myelin that wrap axons and facilitate the rapid, saltatory transmission of action potentials. Extrinsic signals and surface-mediated pathways coordinate oligodendrocyte development to ensure appropriate axonal myelination, but the mechanisms involved are not fully understood. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a six-transmembrane enzyme that regulates the activity of surface glycosylphosphatidylinositol (GPI)-anchored proteins by cleavage of the GPI-anchor. GDE2 is expressed in neurons where it promotes oligodendrocyte maturation through the release of neuronallyderived soluble factors. GDE2 is also expressed in oligodendrocytes but the function of oligodendroglial GDE2 is not known. Results: Using Cre-lox technology, we generated mice that lack GDE2 expression in oligodendrocytes (O-Gde2KO). O-Gde2KOs show normal production and proliferation of oligodendrocyte precursor cells. However, oligodendrocyte maturation is accelerated leading to the robust increase of myelin proteins and increased myelination during development. These in vivo observations are recapitulated in vitro using purified primary oligodendrocytes, supporting cellautonomous functions for GDE2 in oligodendrocyte maturation. Conclusions: These studies reveal that oligodendroglial GDE2 expression is required for controlling the pace of oligodendrocyte maturation. Thus, the celltype specific expression of GDE2 is important for the coordination of oligodendrocyte maturation and axonal myelination during neural development.