GSK3β Regulates Oligodendrogenesis in the Dorsal Microdomain of the Subventricular Zone via Wnt- β- catenin Signaling

Oligodendrocytes, the myelinating cells of the CNS, are derived postnatally from oligodendrocyte precursors (OPs) of the subventricular zone (SVZ). However, the mechanisms that regulate their generation from SVZ neural stem cells (NSC) are poorly understood. Here, we have examined the role of glycogen synthase kinase 3 (GSK3), an effector of multiple converging signaling pathways in postnatal mice. The expression of GSK3by rt-qPCR was most prominent in the SVZ and in the developing white matter, around the first 1-2 weeks of postnatal life, coinciding with the peak periods of OP differentiation. Intraventricular infusion of the GSK3 inhibitor ARA-014418 in mice aged postnatal day (P) 8-11 significantly increased generation of OPs in the dorsal microdomain of the SVZ, as shown by expression of cell specific markers using rt-qPCR and immunolabelling. Analysis of stage specific markers revealed that the augmentation of OPs occurred via increased specification from earlier SVZ cell types. These effects of GSK3 inhibition on the dorsal SVZ were largely attributable to stimulation of the canonical Wnt/-catenin signaling pathway over other pathways. The results indicate GSK3 is a key endogenous factor for specifically regulating oligodendrogenesis from the dorsal SVZ microdomain under the control of Wnt-signaling. GLIA 2014;62:778-789