GSK3β negatively regulates oligodendrocyte differentiation and myelination <i>in vivo</i>

Azim, Kasum; Butt, Arthur M.

doi:10.1002/glia.21122

Cited by 178 publications

(202 citation statements)

References 41 publications

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“…GSK3-b inhibition by lithium and other compounds promotes differentiation of oligodendrocytes from their precursors, myelination, and remyelination of lesions in the brain (Azim and Butt, 2011), as well as, in other districts, recovery of spinal lesions (Dill et al, 2008) and differentiation and myelination of Schwann cells (Ogata et al, 2004). Consistent data showed that GSK3-b is critical for establishing neuronal polarity, promoting neurite outgrowth, and turning mature neurites into axons in CNS neurons (Yoshimura et al, 2005).…”

Section: Introductionmentioning

confidence: 86%

“…Concerning myelin, GSK3-b inhibition by lithium and other compounds promotes differentiation of oligodendrocytes from their precursors, myelination, and remyelination of lesions in the brain (Azim and Butt, 2011). This pivotal study showed that GSK3-b inhibition promotes the proliferation of oligodendrocytes precursors and their differentiation into mature oligodendrocytes both in vivo in the adult and in the developing brain and ex vivo in organotypic cultures of optic nerve, and confirmed that when GSK3-b is inhibited by lithium, these effects involve an interaction between the Wnt pathway and other mechanisms (Azim and Butt, 2011).…”

Section: Lithium and Gsk3-b Effects On White Matter F Benedetti Et Almentioning

confidence: 99%

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Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Benedetti

Bollettini

Barberi

et al. 2012

Neuropsychopharmacol

145

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Lithium is the mainstay for the treatment of bipolar disorder (BD) and inhibits glycogen synthase kinase 3-b (GSK3-b). The less active GSK3-b promoter gene variants have been associated with less detrimental clinical features of BD. GSK3-b gene variants and lithium can influence brain gray matter structure in psychiatric conditions. Diffusion tensor imaging (DTI) measures of white matter (WM) integrity showed widespred disruption of WM structure in BD. In a sample of 70 patients affected by a major depressive episode in course of BD, we investigated the effect of ongoing long-term lithium treatment and GSK3-b promoter rs334558 polymorphism on WM microstructure, using DTI and tract-based spatial statistics with threshold-free cluster enhancement. We report that the less active GSK3-b rs334558*C gene-promoter variants, and the long-term administration of the GSK3-b inhibitor lithium, were associated with increases of DTI measures of axial diffusivity (AD) in several WM fiber tracts, including corpus callosum, forceps major, anterior and posterior cingulum bundle (bilaterally including its hippocampal part), left superior and inferior longitudinal fasciculus, left inferior fronto-occipital fasciculus, left posterior thalamic radiation, bilateral superior and posterior corona radiata, and bilateral corticospinal tract. AD reflects the integrity of axons and myelin sheaths. We suggest that GSK3-b inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.

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Section: Introductionmentioning

confidence: 86%

Section: Lithium and Gsk3-b Effects On White Matter F Benedetti Et Almentioning

confidence: 99%

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Benedetti

Bollettini

Barberi

et al. 2012

Neuropsychopharmacol

145

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“…Right: A heavily myelinated peri-plaque region with rare FoxO3-labeled nuclei (black arrowheads). (D) FoxO3-labeled nuclei in a preterm WM lesion (Supplemental Table 1A; case 1) and MS plaques (Supplemental Table 1B tors of GSK3β Ser9 phosphorylation (e.g., LiCl, 6BIO) (46), which may account for observations that these inhibitors promoted OPC maturation (31). Several findings supported that bHAf regulates FoxO3 to block preOL maturation.…”

Section: Foxo3 Expression Is Markedly Increased In Oligodendroglia Inmentioning

confidence: 93%

“…However, there were no observed changes in mTOR phosphorylation status in response to bHAf that would suggest a role in bHAf signaling (Supplemental Figure 6D). Prior observations suggested that AKT inactivation results in GSK3β activation and that GSK3β inhibition enhances OPC maturation (31). We thus hypothesized that if bHAf blocked OPC maturation via GSK3β activation, treatment with a GSK3β kinase inhibitor should promote OPC maturation.…”

Section: Tlr4mentioning

confidence: 94%

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Srivastava¹,

Diba²,

Dean³

et al. 2018

Journal of Clinical Investigation

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ers by interactions of FoxO3 with the chromatin-remodeling factor Brg1 and the TF Olig2, which are involved in control of OPC differentiation (14-16). Hence, central myelination failure is regulated by a noncanonical TLR4/AKT/FoxO3 signaling pathway utilized by bHAf to induce a tolerance-like state that selectively constrains OPC maturation and myelination. ResultsNeonatal hypoxic-ischemic WMI promotes MDa HA depolymerization. To investigate the status of MDa HA in chronic neonatal WMI, we employed our preterm-equivalent rat hypoxia-ischemia (H-I) model, which generates myelination failure and replicates key features of human WMI ( Figure 1A) (17). MDa HA turnover in the ECM after H-I was visualized with a biotinylated HA-binding protein (HABP) and costained with glial fibrillary acidic protein (GFAP) as a marker of WMI. Unlike in age-matched uninpro-myelination signal (13). This tolerance-like action of bHAf was mediated through TLR4 but not via CD44 or TLR2. As in TLR4-mediated IT, bHAf 's influence on myelination was reversible when MDa HA depolymerization was attenuated or bHAf was removed. AKT desensitization was similarly reversible in vivo in neonatal WMI. Moreover, bHAf actions were mediated via a noncanonical TRIF-dependent pathway, also involved in IT, rather than the canonical MyD88 arm of TLR4 signaling. AKT desensitization resulted in maturation-dependent activation of the FoxO3 transcription factor (TF), which selectively constrained preOL maturation in a bHAf-dependent fashion. A role for activated FoxO3 in human myelination failure was supported by selective localization of nuclear FoxO3 to OPCs in human preterm WMI and multiple sclerosis (MS) plaques. bHAf-mediated OPC maturation arrest appears to be regulated at the FoxO3 and myelin basic protein (MBP) promot- (Contralateral). Only the lesion group had a significant reduction in HA recovery. (E) Incubation of MDa HA with the lesion lysate generated HAf below ~650 kDa. Lesion-lysate activity was sensitive to heat inactivation but insensitive to deferoxamine (50 μM). B and C: control n = 2; H-I n = 4 animals for each age group (P4 and P14). D: n = 6 (H-I), n = 5 (control), and n = 4 (hypoxia) animals (P7). E: n = 4 separate experiments on 4 different animals at P4 after H-I at P3; one representative experiment is shown. *P < 0.05 by ANOVA. Mean ± SD. Scale bars: 300 μm (B and C). The Journal of Clinical Investigation R E S E A R C H A R T I C L E2 0 2 7 jci.orgVolume 128 Number 5 May 2018 with MBP-labeled oligodendrocytes (Supplemental Figure 2A). To confirm de novo progressive myelin generation, we undertook ultrastructural studies that identified axons wrapped with multilamellar myelin sheaths ( Figure 2B). In contrast to vehicle-treated slices, which displayed robust myelination of the corpus callosum, slices incubated with MDa HA until 21 days in vitro (DIV21) displayed a pronounced reduction in myelinated axons ( Figure 2C). Myelination failure was not related to decreased OPC survival, since MDa HA treatment did not enhance OPC degeneratio...

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“…Despite previous studies demonstrating up-regulation of Wnt signaling components in MS/EAE lesions, a role for this pathway in the pathogenesis of neuroinflammatory diseases remains unclear, because its effect depends on the specific cell type in which the pathway is active. Activation in oligodendrocytes suppresses their differentiation and myelination, and may be detrimental for repair processes within the CNS (44,46); however, Wnt signaling in dendritic cells suppresses neuroinflammation and ameliorates EAE by diminishing Th1/ Th17 immune responses (47).…”

mentioning

confidence: 99%

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

Lengfeld

Lutz

Smith

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

127

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Disruption of the blood-brain barrier (BBB) is a defining and early feature of multiple sclerosis (MS) that directly damages the central nervous system (CNS), promotes immune cell infiltration, and influences clinical outcomes. There is an urgent need for new therapies to protect and restore BBB function, either by strengthening endothelial tight junctions or suppressing endothelial vesicular transcytosis. Although wingless integrated MMTV (Wnt)/β-catenin signaling plays an essential role in BBB formation and maintenance in healthy CNS, its role in BBB repair in neurologic diseases such as MS remains unclear. Using a Wnt/β-catenin reporter mouse and several downstream targets, we demonstrate that the Wnt/ β-catenin pathway is up-regulated in CNS endothelial cells in both human MS and the mouse model experimental autoimmune encephalomyelitis (EAE). Increased Wnt/β-catenin activity in CNS blood vessels during EAE progression correlates with up-regulation of neuronal Wnt3 expression, as well as breakdown of endothelial cell junctions. Genetic inhibition of the Wnt/β-catenin pathway in CNS endothelium before disease onset exacerbates the clinical presentation of EAE, CD4 + T-cell infiltration into the CNS, and demyelination by increasing expression of vascular cell adhesion molecule-1 and the transcytosis protein Caveolin-1 and promoting endothelial transcytosis. However, Wnt signaling attenuation does not affect the progressive degradation of tight junction proteins or paracellular BBB leakage. These results suggest that reactivation of Wnt/β-catenin signaling in CNS vessels during EAE/MS partially restores functional BBB integrity and limits immune cell infiltration into the CNS.blood-brain barrier | endothelial cell | Wnt/β-catenin signaling | MS | EAE I n both multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), leukocytes infiltrate the central nervous system (CNS) across a damaged blood-brain barrier (BBB) to mediate myelin destruction and neuronal damage (1). BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2-4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5-9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7, 11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7, 13-15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.The BBB achieves its highly selective permeability through the presence of (i) tight junctions (TJs) that prevent paracellular diffusion of small molecules and immune cells between endothelial cells (ECs), (ii) very few endocytotic vesicles that restrict movement of large mo...

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GSK3β negatively regulates oligodendrocyte differentiation and myelination in vivo

Cited by 178 publications

References 41 publications

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

Lithium and GSK3-β Promoter Gene Variants Influence White Matter Microstructure in Bipolar Disorder

A TLR/AKT/FoxO3 immune tolerance–like pathway disrupts the repair capacity of oligodendrocyte progenitors

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

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