A Genome-Wide Screen for Spatially Restricted Expression Patterns Identifies Transcription Factors That Regulate Glial Development

Fu, Hui; Cai, Jun; Clevers, Hans; Fast, Eva M.; Gray, Susan; Greenberg, Rachel S.; Jain, Mukesh K.; Ma, Qiufu; Qiu, Mengsheng; Rowitch, David H.; Taylor, Christopher M.; Stiles, Charles D.

doi:10.1523/jneurosci.0160-09.2009

Cited by 123 publications

(144 citation statements)

References 52 publications

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“…5L-N ). This result indicates that Sox2 is an intrinsic differentiation inhibitor, along with several other transcription factors such as hes5 (Kondo and Raff, 2000;John et al, 2002;Zhang et al, 2009), id2/4 (Kondo andRaff, 2000;Chen et al, 2012), and Tcf7l2 (Fu et al, 2009;.…”

Section: Decreased Expression Of Sox2 Is Necessary For Oligodendrocytmentioning

confidence: 97%

Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination

Zhao

Zawadzka

et al. 2015

J. Neurosci.

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The Sox family of transcription factors have been widely studied in the context of oligodendrocyte development. However, comparatively little is known about the role of Sox2, especially during CNS remyelination. Here we show that the expression of Sox2 occurs in oligodendrocyte progenitor cells (OPCs) in rodent models during myelination and in activated adult OPCs responding to demyelination, and is also detected in multiple sclerosis lesions. In normal adult white matter of both mice and rats, it is neither expressed by adult OPCs nor by oligodendrocytes (although it is expressed by a subpopulation of adult astrocytes). Overexpression of Sox2 in rat OPCs in vitro maintains the cells in a proliferative state and inhibits differentiation, while Sox2 knockout results in decreased OPC proliferation and survival, suggesting that Sox2 contributes to the expansion of OPCs during the recruitment phase of remyelination. Loss of function in cultured mouse OPCs also results in an impaired ability to undergo normal differentiation in response to differentiation signals, suggesting that Sox2 expression in activated OPCs also primes these cells to eventually undergo differentiation. In vivo studies on remyelination following experimental toxin-induced demyelination in mice with inducible loss of Sox2 revealed impaired remyelination, which was largely due to a profound attenuation of OPC recruitment and likely also due to impaired differentiation. Our results reveal a key role of Sox2 expression in OPCs responding to demyelination, enabling them to effectively contribute to remyelination.

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Section: Decreased Expression Of Sox2 Is Necessary For Oligodendrocytmentioning

confidence: 97%

Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination

Zhao

Zawadzka

et al. 2015

J. Neurosci.

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“…Tcf4 is expressed in the mouse white matter immediately after birth, but it is barely detectable in the adult [55][56][57]. However, following CNS injury, Tcf4 is reexpressed and upregulated in OPCs that are recruited to the lesion [56].…”

Section: Wnt Signalingmentioning

confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…For instance, inactivation of Wnt/␤-catenin signaling with dominant-negative forms of Tcf/Lef (Ye et al, 2009;Langseth et al, 2010) or Wnt antagonism (Shimizu et al, 2005;Langseth et al, 2010) increases the production of OL progenitors (OLPs). Activation of Wnt/␤-catenin signaling by ways such as ⌬Exon3 mutation of ␤-catenin (Fancy et al, 2009;Feigenson et al, 2009;Ye et al, 2009), Wnt3a treatment (Shimizu et al, 2005Feigenson et al, 2009;Azim and Butt, 2011), loss of function of the Wnt pathway inhibitor Apc (Apc Min ; Fancy et al, 2009), or Apc knock-out (Lang et al, 2013) significantly inhibit the maturation of OLs. Moreover, stabilization of Axin2 via inhibiting tankyrase with small molecule XAV939, or reduction of ␤-catenin concentration, accelerates OLP differentiation and myelination after hypoxic and demyelinating injury (Fancy et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Wnt/␤-catenin signaling has also been shown to be an essential direct driver of myelin gene expression in both Schwann cells and OLs (Tawk et al, 2011;Makoukji et al, 2012). In addition, Tcf7l2/Tcf4 is expressed specifically in premyelinating OLs in spinal cord (Fu et al, 2009), and knock-out of Tcf7l2 causes a myelin deficit phenotype (Fu et al, 2009;Ye et al, 2009). These studies suggest that the Wnt/␤-catenin pathways functions to promote OL differentiation.…”

Section: Introductionmentioning

confidence: 99%

Stage-Specific Regulation of Oligodendrocyte Development by Wnt/ -Catenin Signaling

Dai

Sun

Wang

et al. 2014

Journal of Neuroscience

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Oligodendrocytes are myelin-forming glia that ensheath the axons of neurons in the CNS. Recent studies have revealed that Wnt/␤-catenin signaling plays important roles in oligodendrocyte development and myelin formation. However, there are conflicting reports on the specific function of Wnt signaling components in oligodendrocyte specification and differentiation. In the present study, we demonstrate that activation of ␤-catenin in neural progenitor cells before gliogenesis inhibits the generation of oligodendrocyte progenitors (OLPs) in mice. Once OLPs are formed, ␤-catenin becomes necessary for oligodendrocyte differentiation. Disruption of ␤-catenin signaling instead leads to a significant delay of oligodendrocyte maturation. These findings suggest that Wnt/␤-catenin pathway regulates oligodendrocyte development in a stage-dependent manner.

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A Genome-Wide Screen for Spatially Restricted Expression Patterns Identifies Transcription Factors That Regulate Glial Development

Abstract: Forward genetic screens in genetically accessible invertebrate organisms such as

Cited by 123 publications

References 52 publications

Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination

Sox2 Sustains Recruitment of Oligodendrocyte Progenitor Cells following CNS Demyelination and Primes Them for Differentiation during Remyelination

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Stage-Specific Regulation of Oligodendrocyte Development by Wnt/ -Catenin Signaling

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