Glycogen Synthase Kinase 3β (GSK3β) Regulates Differentiation and Proliferation in Neural Stem Cells from the Rat Subventricular Zone

Abstract

On the basis of its inhibition by SB216763, we identified the multifunctional enzyme Glycogen Synthase Kinase 3β (GSK3β) as a central regulator for differentiation and cell survival of adult neural stem cells. Detected by proteomic approaches, members of the Wnt/β-catenin signaling pathway appear to participate in enhanced neuronal differentiation and activated transcription of β-catenin target genes during GSK3β inhibition, associated with decreased apoptosis. Keywords: Neural stem cell • Neurosphere • Glycogen Synthase Kinase 3β • Two-dimensional gel electrophoresis • Rat • Subventricular zone

GSK-3β: a signaling pathway node modulating neural stem cell and endothelial cell interactions

“…Central to the ability of NSC to undergo self-renewal and differentiation and endothelial cells to undergo angiogenesis and vessel formation is the modulation of GSK-3b expression, localization, and activation state, which in turn regulates a variety of signaling pathways, transcription factors, cytoskeletal components and structural proteins [6,8,29]. This, in combination with recent reports illustrating strain differences in a variety of physiological and behavior parameters in mice [9,[30][31][32][33][34] prompted us to investigate the role of GSK-3b in neurovascular cells of two distinct mouse strains that exhibit significant differences in angiogenesis, neurogenesis and behavior [2,5,9] in response to hypoxic insult.…”

“…The existence of similar disparities in the human population could help explain the wide range of responses to and variable recoveries from CNS injury [2,5,9]. Given its wide substrate range and the number of potential signaling pathways involving GSK-3b [6,29], we investigated GSK-3b's potential as a signaling node affecting the distinct strain-dependent cell behaviors observed in our model. Our data illustrate differential GSK-3b modulation of proliferation, and markers of differentiation (nestin, b-III-tubulin and cleaved notch-1) in NSC, BEC, and SVZ tissues that is strain-dependent.…”

GSK3β, But Not GSK3α, Inhibits the Neuronal Differentiation of Neural Progenitor Cells As a Downstream Target of Mammalian Target of Rapamycin Complex1

“…In several previous studies, chemical inhibitors of GSK3 have been used in attempts to define the roles of GSK3 [7][8][9]. To confirm the effect of GSK3 inhibition on the differentiation of NPCs, we used SB216763, an ATP-competitive inhibitor of GSK3 [21].…”

“…In contrast, mutant Drosophila that are defective in the shaggy gene, a GSK3 homologue, show increased neuronal differentiation [6]. The use of GSK3 inhibitors also promotes neuronal differentiation of human NPCs, rat ventral midbrain precursors, and rat neural stem cells [7][8][9]. Due to the conflicting results of these studies, the functions of GSK3 in the differentiation of NPCs and the exact effects of GSK3a and GSK3b still remain elusive.…”

The Pivotal Roles of GSK3β in Glioma Biology

“…GSK3 signaling also plays an essential role in regulating the differentiation and proliferation of adult neural stem cells. Inhibition of GSK3 results in transcriptional activation of distinct target genes viacatenin, leading to an increase in the number of neurons that differentiated from neurospheres (Maurer et al, 2007).…”