GDE2-Dependent Activation of Canonical Wnt Signaling in Neurons Regulates Oligodendrocyte Maturation

Neurons and oligodendrocytes communicate to regulate oligodendrocyte development and ensure appropriate axonal myelination. Here, we show that Glycerophosphodiester phosphodiesterase 2 (GDE2) signaling underlies a neuronal pathway that promotes oligodendrocyte maturation through the release of soluble neuronally derived factors. Mice lacking global or neuronal GDE2 expression have reduced mature oligodendrocytes and myelin proteins but retain normal numbers of oligodendrocyte precursor cells (OPCs). Wild-type (WT) OPCs cultured in conditioned medium (CM) from Gde2-null (Gde2KO) neurons exhibit delayed maturation, recapitulating in vivo phenotypes. Gde2KO neurons show robust reduction in canonical Wnt signaling, and genetic activation of Wnt signaling in Gde2KO neurons rescues in vivo and in vitro oligodendrocyte maturation. Phosphacan, a known stimulant of oligodendrocyte maturation, is reduced in CM from Gde2KO neurons but is restored when Wnt signaling is activated. These studies identify GDE2 control of Wnt signaling as a neuronal pathway that signals to oligodendroglia to promote oligodendrocyte maturation. [Display omitted] •GDE2 is expressed in neurons and a subset of oligodendrocytes•Loss of neuronal GDE2 delays oligodendrocyte maturation and impairs myelination•GDE2 stimulates canonical Wnt signaling in neurons, which releases phosphacan•Neuronally derived phosphacan promotes oligodendrocyte maturation Communication between neurons and oligodendroglial cells regulates oligodendrocyte development. Here, Choi et al. show that the six-transmembrane GPI-anchor-cleaving enzyme GDE2 stimulates canonical Wnt signaling in neurons to release soluble factors, such as phosphacan, to promote oligodendrocyte maturation.