GSK3β regulates oligodendrogenesis in the dorsal microdomain of the subventricular zone via Wnt-β-catenin signaling

Abstract

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 3β (GSK3β), an effector of multiple converging signaling pathways in postnatal mice. The expression of GSK3β by 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 GSK3β 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 GSK3β inhibition on the dorsal SVZ were largely attributable to stimulation of the canonical Wnt/β-catenin signaling pathway over other pathways. The results indicate GSK3β is a key endogenous factor for specifically regulating oligodendrogenesis from the dorsal SVZ microdomain under the control of Wnt-signaling.

Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways

“…This result is at odds with the negative effect of Wnt/b-catenin on oligodendroglial cell differentiation described in other studies (Fancy et al, 2009;Ye et al, 2009). Indeed, Azim and Butt pointed out the divergent effects of LiCl and Wnt/b-catenin on terminal differentiation of oligodendrocytes during re/myelination processes (Azim et al, 2014b). They hypothesized that the concomitant activation of Akt/CREB seen with LiCl overrides the inhibitory Wnt influence on terminal oligodendrocyte differentiation (Azim and Butt, 2011).…”

Adding a spatial dimension to postnatal ventricular-subventricular zone neurogenesis

“…Some of these interactions are likely to be antagonistic in nature. For example, the infusion of exogenous BMP4 or EGF into the LV represses downstream Wnt signaling in the dorsal V-SVZ (Azim et al, 2014a). Other interactions are likely to be synergistic.…”

“…Other interactions are likely to be synergistic. For example, FGF2, which promotes NSC self-renewal, amplification of TAPs and, subsequently, OB neuron generation (Kuhn et al, 1997;Zheng et al, 2004;Azim et al, 2012a), cross-reacts with canonical Wnt signaling to inhibit GSK3β and increase the nuclear translocation of β-catenin in the postnatal dorsal V-SVZ (Azim et al, 2014a).…”

Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis

“…Axin2 is expressed in OPCs in active MS lesions and in human hypoxic-ischemic white matter lesions (Fancy et al, 2011b), suggesting it may be a viable therapeutic target. More work is needed to elucidate the mechanisms by which Wnt signaling regulates oligodendrocyte lineage cells embryonically, postnatally, and following injury (Azim et al, 2014; Dai et al, 2014; Rodriguez et al, 2014) in order to resolve the ongoing debate about how and when to modulate Wnt signaling to effectively stimulate remyelination (Guo et al, 2015). Several Wnt inhibitory compounds have been identified as potential anti-cancer therapies (Le et al, 2014).…”