Sox17 Promotes Oligodendrocyte Regeneration by Dual Modulation of Hedgehog and Wnt Signaling

Ming, Xiaotian; Dupree, Jeffrey L.; Gallo, Vittorio; Chew, Li‐Jin

doi:10.1016/j.isci.2020.101592

Cited by 8 publications

(6 citation statements)

References 59 publications

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“…In this case, we have shown that Gli2 expression depends on RxRγ expression, since RxRγ gene silencing abrogates Gli2 expression in Oli-neuM under Clobetasol or Gefitinib treatments ( Nocita et al, 2019 ). The recent demonstration that Sox17-induced oligodendrocyte regeneration in adult myelin lesions occurs by suppressing lesion-induced Wnt/beta-catenin signaling through an increase in Shh/Smo/Gli2 activity ( Ming et al, 2020 ) supports the importance of Gli2 upregulation for the differentiation program under Gli1 downregulation. Along the same line, Gli2 has been reported to promote the differentiation of Gli1-null NPCs into OLs in a cuprizone model of demyelination.…”

Section: Discussionmentioning

confidence: 91%

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

Giovane

Russo

Tirou

et al. 2022

Front. Cell. Neurosci.

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The regeneration of myelin is known to restore axonal conduction velocity after a demyelinating event. Remyelination failure in the central nervous system contributes to the severity and progression of demyelinating diseases such as multiple sclerosis. Remyelination is controlled by many signaling pathways, such as the Sonic hedgehog (Shh) pathway, as shown by the canonical activation of its key effector Smoothened (Smo), which increases the proliferation of oligodendrocyte precursor cells via the upregulation of the transcription factor Gli1. On the other hand, the inhibition of Gli1 was also found to promote the recruitment of a subset of adult neural stem cells and their subsequent differentiation into oligodendrocytes. Since Smo is also able to transduce Shh signals via various non-canonical pathways such as the blockade of Gli1, we addressed the potential of non-canonical Smo signaling to contribute to oligodendroglial cell maturation in myelinating cells using the non-canonical Smo agonist GSA-10, which downregulates Gli1. Using the Oli-neuM cell line, we show that GSA-10 promotes Gli2 upregulation, MBP and MAL/OPALIN expression via Smo/AMP-activated Protein Kinase (AMPK) signaling, and efficiently increases the number of axonal contact/ensheathment for each oligodendroglial cell. Moreover, GSA-10 promotes the recruitment and differentiation of oligodendroglial progenitors into the demyelinated corpus callosum in vivo. Altogether, our data indicate that non-canonical signaling involving Smo/AMPK modulation and Gli1 downregulation promotes oligodendroglia maturation until axon engagement. Thus, GSA-10, by activation of this signaling pathway, represents a novel potential remyelinating agent.

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Section: Discussionmentioning

confidence: 91%

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

Giovane

Russo

Tirou

et al. 2022

Front. Cell. Neurosci.

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“…Interestingly, Smo activation by GSA-10 led to Gli2 upregulation, which is consistent with the recent report that ablation of Gli1 increased the expression of Gli2 in NPCs following Cuprizone-induced demyelination [ 86 ]. In the same line, Sox17 has also been found to induce OL regeneration in demyelinated areas through an increase in Shh/Smo/Gli2 activity [ 92 ], further supporting the importance of Gli2 upregulation for the differentiation program under Gli1 downregulation.…”

Section: The Complex Involvement Of Canonical and Non-canonical Hedge...mentioning

confidence: 93%

Hedgehog Signaling in CNS Remyelination

Fang

Tang

Qiu

et al. 2022

Cells

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Remyelination is a fundamental repair process in the central nervous system (CNS) that is triggered by demyelinating events. In demyelinating diseases, oligodendrocytes (OLs) are targeted, leading to myelin loss, axonal damage, and severe functional impairment. While spontaneous remyelination often fails in the progression of demyelinating diseases, increased understanding of the mechanisms and identification of targets that regulate myelin regeneration becomes crucial. To date, several signaling pathways have been implicated in the remyelination process, including the Hedgehog (Hh) signaling pathway. This review summarizes the current data concerning the complicated roles of the Hh signaling pathway in the context of remyelination. We will highlight the open issues that have to be clarified prior to bringing molecules targeting the Hh signaling to demyelinating therapy.

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“…In cuprizone mice, following myelin injury, the rapid mobilization of OPCs from the corpus callosum to the demyelination area promotes a temporally and spatially orchestrated activation of a complex panel of lineage-specific TFs, including Olig1-2, MyrF, Sox 17 and Sox10, the inhibition of adhesion G protein-coupled receptors, and Wnt signaling [ 95 ]. MyRF-regulated gene transcription, together with chromatin remodeling factors, regulates the step-wise oligodendrocyte lineage differentiation process of primitive oligodendrocyte progenitor cells (pre-OPCs), also known as uncommitted OPCs (Olig1/2+/A2B5+/PDGFRαlow), to the committed OPCs expressing high levels of PDGFRα and NG2.…”

Section: The Biological Basis Of Cns Remyelinationmentioning

confidence: 99%

The Current Challenges for Drug Discovery in CNS Remyelination

Balestri

Giovane

Sposato

et al. 2021

IJMS

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The myelin sheath wraps around axons, allowing saltatory currents to be transmitted along neurons. Several genetic, viral, or environmental factors can damage the central nervous system (CNS) myelin sheath during life. Unless the myelin sheath is repaired, these insults will lead to neurodegeneration. Remyelination occurs spontaneously upon myelin injury in healthy individuals but can fail in several demyelination pathologies or as a consequence of aging. Thus, pharmacological intervention that promotes CNS remyelination could have a major impact on patient’s lives by delaying or even preventing neurodegeneration. Drugs promoting CNS remyelination in animal models have been identified recently, mostly as a result of repurposing phenotypical screening campaigns that used novel oligodendrocyte cellular models. Although none of these have as yet arrived in the clinic, promising candidates are on the way. Many questions remain. Among the most relevant is the question if there is a time window when remyelination drugs should be administrated and why adult remyelination fails in many neurodegenerative pathologies. Moreover, a significant challenge in the field is how to reconstitute the oligodendrocyte/axon interaction environment representative of healthy as well as disease microenvironments in drug screening campaigns, so that drugs can be screened in the most appropriate disease-relevant conditions. Here we will provide an overview of how the field of in vitro models developed over recent years and recent biological findings about how oligodendrocytes mature after reactivation of their staminal niche. These data have posed novel questions and opened new views about how the adult brain is repaired after myelin injury and we will discuss how these new findings might change future drug screening campaigns for CNS regenerative drugs.

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Sox17 Promotes Oligodendrocyte Regeneration by Dual Modulation of Hedgehog and Wnt Signaling

Cited by 8 publications

References 59 publications

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

Smoothened/AMP-Activated Protein Kinase Signaling in Oligodendroglial Cell Maturation

Hedgehog Signaling in CNS Remyelination

The Current Challenges for Drug Discovery in CNS Remyelination

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