Neural differentiation is increased by GSK-3β inhibition and decreased by tankyrase inhibition in human neural precursor cells

Abstract

Glycogen synthase kinase-3β (GSK-3β) and tankyrase-1/2 (TANK) are two enzymes known to play multiple roles in cell biology, including regulation of proliferation, differentiation and metabolism. Both of them act on the canonical Wnt/β-Catenin pathway, but are also involved in many other independent intracellular mechanisms.More importantly, GSK-3β and TANK have been shown to play crucial roles in different diseases, including cancer and neurological disorders. The GSK-3β-inhibitor 'CHIR' and the TANK-inhibitor 'XAV' are two pyrimidine molecules, holding high potential as possible therapeutic drugs. However, their effect on neural tissue is poorly understood. In this study, we tested the effects of CHIR and XAV on human neural precursor cells (hNPCs) derived from human embryonic stem cells. We found that CHIR-mediated inhibition of GSK-3β promotes neural differentiation. In contrast, XAV-mediated inhibition of TANK leads to de-differentiation. These results highlight the relative importance of these two enzymes in determining the neurodevelopmental status of hNPCs. Furthermore, they shed light on the roles of Wnt signaling during early human neurogenesis.

GSK‐3β S9A overexpression leads murine hippocampal neural precursors to acquire an astroglial phenotype in vivo

“…Given the importance of GSK-3β in the field of neurobiology and neuropathology, its overexpression and inhibition have been addressed using transgenic animals (Hernandez et al, 2010) and retroviral vectors (Llorens-Martin et al, 2016). GSK-3β is a key protein in signaling pathways related to neurogenesis (Telias & Ben-Yosef, 2019). In this regard, it plays a crucial role in the Wnt pathway (Jurado-Arjona et al, 2016) by inducing a phosphorylation-dependent degradation of the downstream effector β-catenin, thus blocking this pathway (Hodges & Lugo, 2018).…”