GSK3β Promotes the Differentiation of Oligodendrocyte Precursor Cells via β-Catenin-Mediated Transcriptional Regulation

Abstract

Oligodendrocytes are generated by the differentiation and maturation of oligodendrocyte precursor cells (OPCs). The failure of OPC differentiation is a major cause of demyelinating diseases; thus, identifying the molecular mechanisms that affect OPC differentiation is critical for understanding the myelination process and repairing after demyelination. Although prevailing evidence shows that OPC differentiation is a highly coordinated process controlled by multiple extrinsic and intrinsic factors, such as growth factors, axon signals, and transcription factors, the intracellular signaling in OPC differentiation is still unclear. Here, we showed that glycogen synthase kinase 3β (GSK3β) is an essential positive modulator of OPC differentiation. Both pharmacologic inhibition and knockdown of GSK3β remarkably suppressed OPC differentiation. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assays and Ki67 staining showed that the effect of GSK3β on OPC differentiation was not via cell death. Conversely, activated GSK3β was sufficient to promote OPC differentiation. Our results also demonstrated that the transcription of myelin genes was regulated by GSK3β inhibition, accompanying accumulated nuclear β-catenin, and reduced the expression of transcriptional factors that are relevant to the expression of myelin genes. Taken together, our study identified GSK3β as a profound positive regulator of OPC differentiation, suggesting that GSK3β may contribute to the inefficient regeneration of oligodendrocytes and myelin repair after demyelination.

Canonical Wnt signaling in the oligodendroglial lineage-puzzles remain

“…This argues that other signaling pathways or factors modulated by GSK3β inhibition can override the effect of Wnt/β‐catenin activation and thereby promote oligodendroglial maturation (Azim and Butt, ; Doble and Woodgett, ). However, the inhibition of GSK3β was also recently reported to diminish oligodendroglial differentiation in vitro (Zhou et al, ), presumably reflecting an intrinsic difference between in vivo and in vitro contextual cues and differences among in vitro culture systems. Fancy et al () used the small‐molecule tankyrase inhibitor XAV939 to stabilize Axin (both constitutive Axin1 and inducible Axin2) protein, and hence enhancing proteasomal degradation of β‐catenin and antagonizing Wnt/β‐catenin activity (Huang et al, ).…”

Isoflurane Is More Deleterious to Developing Brain Than Desflurane: The Role of the Akt/GSK3βSignaling Pathway

“…Glycogen synthase kinase3 β (GSK3 β ), a serine/threonine kinase, is highly expressed in the developing brain [ 7 ] and can be phosphorylated at serine 9 by Akt (protein kinase B), causing its functional suppression [ 8 – 10 ]. GSK3 β plays important roles in normal brain development and memory formation via many mechanisms, including neuronal differentiation [ 11 , 12 ], dendritic growth [ 13 ], and axon growth [ 14 ]. Additionally, GSK3 β is involved in several pathophysiological processes, including apoptosis [ 15 ], autophagy [ 16 ], neural inflammation [ 17 ], and oxidative stress [ 17 ].…”

Effects of HIV‐1 Tat on oligodendrocyte viability are mediated by CaMKIIβ–GSK3β interactions

“…Survival during development is closely linked to differentiation, and GSK3β activation has been observed to positively (Zhou et al . ) or negatively (Azim and Butt ; Azim et al . ) affect OL maturation, in part depending on the dynamics of Wnt/β‐catenin signaling.…”

“…Although CaMKIIb levels or activity were not explored in the cuprizone study, it is striking that GSK3b activation is implicated in OL death resulting from these disparate insults. Survival during development is closely linked to differentiation, and GSK3b activation has been observed to positively (Zhou et al 2014) or negatively (Azim and Butt 2011;Azim et al 2014) affect OL maturation, in part depending on the dynamics of Wnt/bcatenin signaling. GSK3b activation appears to be at the crossroads of multiple developmental events whose outcomes may depend upon multiple factors related to specific stages in the OL lineage.…”