Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination

• Published in: The Journal of neuroscience Vol. 33; no. 30; pp. 12528 - 12542
• Main Authors: Ming, Xiaotian, Chew, Li-Jin, Gallo, Vittorio
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 24.07.2013
• Subjects: Age Factors; Animals; Apoptosis - physiology; Cell Lineage - physiology; Corpus Callosum - cytology; Corpus Callosum - growth & development; Corpus Callosum - physiopathology; Demyelinating Diseases - chemically induced; Demyelinating Diseases - pathology; Demyelinating Diseases - physiopathology; Female; Gene Expression Regulation - physiology; Hedgehog Proteins - metabolism; HMGB Proteins - genetics; HMGB Proteins - metabolism; Immunohistochemistry; Lysophosphatidylcholines - toxicity; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Oligodendroglia - cytology; Oligodendroglia - physiology; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction - physiology; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.0536-13.2013

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.