GDE2 expression in oligodendroglia regulates the pace of oligodendrocyte maturation

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 neuronally‐derived 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 cell‐autonomous 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 cell‐type specific expression of GDE2 is important for the coordination of oligodendrocyte maturation and axonal myelination during neural development. Key Findings GDE2 is expressed in oligodendrocytes. Loss of GDE2 in oligodendrocytes does not impact oligodendrocyte precursor proliferation. GDE2 ablation in oligodendrocytes accelerates oligodendrocyte maturation and developmental myelination. GDE2 functions in oligodendrocytes to regulate the pace of developmental myelination.