Signaling Differentiation: The six-transmembrane protein GDE2 promotes differentiation through extracellular glycerophosphodiester phosphodiesterase (GDPD) activity and induces neuronal differentiation through inhibition of Notch signaling—a major pathway that maintains stem or progenitor cell states and is implicated in multiple cancers. How then, does GDPD activity inhibit Notch signaling, given that GDPD enzymes are known to metabolize glycerophosphodiesters into glycerol-3-phosphate and corresponding alcohols? Park et al. (p. 324 ) show that the six-transmembrane GDPDs such as GDE2, do not function as conventional GDPD enzymes, but instead cleave the glycosylphosphatidylinositol (GPI) anchors of GPI-anchored proteins. GDE2 GDPD activity cleaves and inactivates the GPI-anchored protein RECK, which normally acts to prevent shedding of the Notch ligand Delta. Accordingly, RECK inactivation stimulates Delta shedding leading to Notch inactivation in progenitors and the initiation of cellular differentiation.

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.

Neural progenitors and terminally differentiated neurons show distinct redox profiles, suggesting that coupled-redox cascades regulate the initiation and progression of neuronal differentiation. Discrete cellular compartments have different redox environments and how they contribute to differentiation is unclear. Here we show that Prdx4, an endoplasmic reticulum (ER) enzyme that metabolizes H₂O₂, acts as a tunable regulator of neurogenesis via its compartmentalized thiol-oxidative function. Prdx4 ablation causes premature motor neuron differentiation and progenitor depletion, leading to imbalances in subtype-specific motor neurons. GDE2, a six-transmembrane protein that induces differentiation by downregulating Notch signalling through surface cleavage of GPI-anchored proteins, is targeted by Prdx4 oxidative activity. Prdx4 dimers generated by H₂O₂ metabolism oxidize two cysteine residues within the GDE2 enzymatic domain, which blocks GDE2 trafficking to the plasma membrane and prevents GDE2 neurogeneic function. Thus, Prdx4 oxidative activity acts as a sensor to directly couple neuronal differentiation with redox environments in the ER.