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Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.

ABSTRACT: We have previously demonstrated that Sox17 regulates cell cycle exit and differentiation in oligodendrocyte progenitor cells. Here we investigated its function in white matter (WM) development and adult injury with a newly generated transgenic mouse overexpressing Sox17 in the oligodendrocyte lineage under the CNPase promoter. Sox17 overexpression in CNP-Sox17 mice sequentially promoted postnatal oligodendrogenesis, increasing NG2 progenitor cells from postnatal day (P) 15, then O4+ and CC1+ cells at P30 and P120, respectively. Total Olig2+ oligodendrocyte lineage cells first decreased between P8 and P22 through Sox17-mediated increase in apoptotic cell death, and thereafter significantly exceeded WT levels from P30 when cell death had ceased. CNP-Sox17 mice showed increased Gli2 protein levels and Gli2+ cells in WM, indicating that Sox17 promotes the generation of oligodendrocyte lineage cells through Hedgehog signaling. Sox17 overexpression prevented cell loss after lysolecithin-induced demyelination by increasing Olig2+ and CC1+ cells in response to injury. Furthermore, Sox17 overexpression abolished the injury-induced increase in TCF7L2/TCF4+ cells, and protected oligodendrocytes from apoptosis by preventing decreases in Gli2 and Bcl-2 expression that were observed in WT lesions. Our study thus reveals a biphasic effect of Sox17 overexpression on cell survival and oligodendrocyte formation in the developing WM, and that its potentiation of oligodendrocyte survival in the adult confers resistance to injury and myelin loss. This study demonstrates that overexpression of this transcription factor might be a viable protective strategy to mitigate the consequences of demyelination in the adult WM.

SUBMITTER: Ming X

PROVIDER: S-EPMC3721852 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.

Ming Xiaotian X Chew Li-Jin LJ Gallo Vittorio V

The Journal of neuroscience : the official journal of the Society for Neuroscience 20130701 30

We have previously demonstrated that Sox17 regulates cell cycle exit and differentiation in oligodendrocyte progenitor cells. Here we investigated its function in white matter (WM) development and adult injury with a newly generated transgenic mouse overexpressing Sox17 in the oligodendrocyte lineage under the CNPase promoter. Sox17 overexpression in CNP-Sox17 mice sequentially promoted postnatal oligodendrogenesis, increasing NG2 progenitor cells from postnatal day (P) 15, then O4+ and CC1+ cel ...[more]

PMID: 23884956

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Project description:Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation.Induction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-? receptor under the human glial fibrillary acidic protein promoter (GFAP?R1?) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAP?R1? mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation.More severe and enlarged demyelinating lesions in GFAP?R1? compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1+Olig2+ OLG within lesions, as well as impaired upregulation of TNF receptor-2, suggesting impaired OPC differentiation. TNF blockade during acute EAE in GFAP?R1? both limited OLG apoptosis and enhanced OPC differentiation consistent with reduced lesion size and clinical recovery. TNF neutralization further limited increasing endothelin-1 (ET-1) expression in astrocytes and myeloid cells noted in lesions during disease progression in GFAP?R1? mice, supporting inhibitory effects of ET-1 on OPC maturation.Our data implicate that IFN? signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.

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Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.

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Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.

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