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

Abstract

Highlights d GDE2 is expressed in neurons and a subset of oligodendrocytes d Loss of neuronal GDE2 delays oligodendrocyte maturation and impairs myelination d GDE2 stimulates canonical Wnt signaling in neurons, which releases phosphacan d Neuronally derived phosphacan promotes oligodendrocyte maturation

GDE2 expression in oligodendroglia regulates the pace of oligodendrocyte maturation

“…Previous studies have shown that Cre-dependent excision of exon 11 results in the complete loss of GDE2 protein expression, validating this strategy to be an effective method to ablate cellular function of GDE2 in vivo [32][33][34] . For this study, we utilized an established inducible mouse line (PDGFαR-CreER) where administration of 4 hydroxytamoxifen (4-HT) induces active Cre recombinase expression under the control of Platelet derived growth factor α receptor (PDGFαR) regulatory sequences in OPCs.…”

“…Previous studies have shown that GDE2 is highly expressed in neurons and that during the period of developmental myelination, neuronal GDE2 stimulates the release of soluble factors that promote OL maturation without affecting OPC generation or proliferation. 26,31,34 While GDE2 function in OLs also does not affect OPC generation and proliferation, the differences in the roles of neuronal and oligodendroglial GDE2 in regulating OL maturation are striking. Neuronal and oligodendroglial GDE2 appear to have opposing functions with neuronal GDE2 promoting OL maturation and oligodendroglial GDE2 slowing the development of OLs into myelinating OLs.…”

“…In addition to increased myelin protein expression, maturing OLs in vitro undergo stereotypic morphological changes manifest by changes in the F-actin network that can be visualized by phalloidin staining. Previous studies have defined three stages of OL maturation based on their morphology, MBP expression and phalloidin staining 34,43 ( Figure 4C). Differentiating Olig2+ OLs in vitro initially show arborized morphology with weak MBP expression in and around the cell body with robust phalloidin labeling throughout the cell body and in distal processes (stage 1, immature).…”

“…29 A recent study discovered that neuronal GDE2 function contributes to neuron-glial communication pathways that regulate the timing of OL maturation during developmental myelination. 34 Loss of neuronal GDE2 in the postnatal brain results in delayed OL maturation and myelination. Mechanistically, neuronal GDE2 maintains canonical Wnt signaling in neurons, which is responsible for the release of neuronally-derived soluble factors that promote OL maturation.…”

Targeting the Wnt/β-catenin signaling pathway in cancer

“…The Wnt/β-catenin signaling pathway, also called the canonical Wnt signaling pathway, is a conserved signaling axis participating in diverse physiological processes such as proliferation, differentiation, apoptosis, migration, invasion and tissue homeostasis [1][2][3]. Increasing evidence indicates that dysregulation of the Wnt/β-catenin cascade contributed to the development and progression of some solid tumors and hematological malignancies [4][5][6][7][8].…”