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Sox2 Is Essential for Oligodendroglial Proliferation and Differentiation During Postnatal Brain Myelination and CNS Remyelination

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Sox2 Is Essential for Oligodendroglial Proliferation and Differentiation During Postnatal Brain Myelination and CNS Remyelination 1802 • The Journal of Neuroscience, February 14, 2018 • 38(7):1802–1820 Development/Plasticity/Repair Sox2 Is Essential for Oligodendroglial Proliferation and Differentiation during Postnatal Brain Myelination and CNS Remyelination X Sheng Zhang,1,2* Xiaoqing Zhu,1,2,3* Xuehong Gui,1 Christopher Croteau,1 Lanying Song,1,2 Jie Xu,1 XAijun Wang,1,4 Peter Bannerman,1,5 and XFuzheng Guo1,2 1Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children, Northern California, California 95817, 2Department of Neurology, 3Cancer Institute, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China, 4Department of Surgery, and 5Department of Cell Biology and Human Anatomy, School of Medicine, University of California–Davis, California 95817 In the CNS, myelination and remyelination depend on the successful progression and maturation of oligodendroglial lineage cells, including proliferation and differentiation of oligodendroglial progenitor cells (OPCs). Previous studies have reported that Sox2 transiently regulates oligodendrocyte (OL) differentiation in the embryonic and perinatal spinal cord and appears dispensable for myelination in the postnatal spinal cord. However, the role of Sox2 in OL development in the brain has yet to be defined. We now report that Sox2 is an essential positive regulator of developmental myelination in the postnatal murine brain of both sexes. Stage-specific paradigms of genetic disruption demonstrated that Sox2 regulated brain myelination by coordinating upstream OPC population supply and downstream OL differentiation. Transcriptomic anal- yses further supported a crucial role of Sox2 in brain developmental myelination. Consistently, oligodendroglial Sox2-deficient mice developed severe tremors and ataxia, typical phenotypes indicative of hypomyelination, and displayed severe impairment of motor function and promi- nent deficits of brain OL differentiation and myelination persisting into the later CNS developmental stages. We also found that Sox2 was required for efficient OPC proliferation and expansion and OL regeneration during remyelination in the adult brain and spinal cord. Together, ourgeneticevidencerevealsanessentialroleofSox2inbrainmyelinationandCNSremyelination,andsuggeststhatmanipulationofSox2and/or Sox2-mediated downstream pathways may be therapeutic in promoting CNS myelin repair. Key words: myelination and remyelination; oligodendrocyte differentiation; oligodendrocyte regeneration; oligodendroglial lineage progression; oligodendroglial progenitor cells; Sox2 Significance Statement Promotingmyelinformationandrepairhastranslationalsignificanceintreatingmyelin-relatedneurologicaldisorders,suchasperiven- tricular leukomalacia and multiple sclerosis in which brain developmental myelin formation and myelin repair are severely affected, respectively.Inthisreport,analysesofaseriesofgeneticconditionalknock-outsystemstargetingdifferentoligodendrocytestagesreveal a previously unappreciated role of Sox2 in coordinating upstream proliferation and downstream differentiation of oligodendroglial lineage cells in the mouse brain during developmental myelination and CNS remyelination. Our study points to the potential of manip- ulating Sox2 and its downstream pathways to promote oligodendrocyte regeneration and CNS myelin repair. Introduction ties of stem cells, including neural stem cells (Zhang and Cui, The transcription factor SRY (sex-determining region)-box 2 2014), and it is the key determining factor for in vivo reprogram- (Sox2) is a critical transcription factor in regulating the proper- ming of differentiated neural cells into neural precursor cells (Niu et al., 2013; Heinrich et al., 2014). In the CNS, Sox2 was Received May 10, 2017; revised Dec. 11, 2017; accepted Jan. 8, 2018. Author contributions: S.Z., X.Z., and F.G. designed research; S.Z., X.Z., X.G., C.C., L.S., J.X., A.W., P.B., and F.G. The authors declare no competing financial interests. performed research; A.W., P.B., and F.G. contributed unpublished reagents/analytic tools; S.Z., X.Z., X.G., C.C., and *S.Z. and X.Z. contributed equally to this study as co-first authors. F.G. analyzed data; S.Z., X.Z., and F.G. wrote the paper. Correspondence should be addressed to Dr. Fuzheng Guo, Department of Neurology, University of California– This work was supported by the National Institutes of Health Grants R01NS094559 and R21NS093559 to F.G., Davis School of Medicine, c/o Shriners Hospitals for Children, 2425 Stockton Blvd, Sacramento, CA 95817. E-mail: NationalInstitutesofHealthGrantR01NS100761toA.W.,andShrinersHospitalsforChildrenresearchgrantstoF.G. [email protected]. and postdoctoral fellowship grant to S.Z. We thank Dr. Q. Richard Lu (University of Cincinnati, Cincinnati) for critical DOI:10.1523/JNEUROSCI.1291-17.2018 comments on the manuscript; and Daffcar Erol (University of California–Davis) for the editions. Copyright © 2018 the authors 0270-6474/18/381802-19$15.00/0 Zhang, Zhu et al. • Sox2 Regulates Brain Myelination and Remyelination J. Neurosci., February 14, 2018 • 38(7):1802–1820 • 1803 originally thought to inhibit the neuronal differentiation of neu- demyelination/remyelination, adult (2–3 months old) Pdgfr␣-CreERT2, ral stem/progenitor cells (NSPCs) (Graham et al., 2003). How- Sox2 fl/fl mice and Sox2 fl/fl controls were intraperitoneally injected with 5 d ever, later genetic studies demonstrate that Sox2 positively course of daily tamoxifen at a dose of 1 mg per day. regulates neuronal differentiation from NSPCs (Ferri et al., 2004; BrdU or EdU preparation and administration. BrdU (B5002, Sigma) or Episkopou, 2005). EdU (A10044, Thermo Fisher Scientific) was dissolved in 0.9% sterile saline at a concentration of 10 mg/ml. BrdU or EdU was intraperitoneally In oligodendroglial lineage cells, Sox2 has been reported to be injected to Sox2 cKO and Sox2 fl/fl control littermates at a dose of 100 absent from in vitro oligodendroglial progenitor cells (OPCs) ␮g/g body weight at time points indicated in the figures. (Kondo and Raff, 2004; Lyssiotis et al., 2007). Recent studies Myelin oligodendrocyte glycoprotein peptide 35-35-induced experimental demonstrate that in vivo OPCs constantly express low levels of autoimmune encephalomyelitis (MOG-peptide35-55 EAE) and cuprizone ani- Sox2 (Shen et al., 2008; Dai et al., 2015) and propose that Sox2 mal models of CNS demyelination. The procedures of MOG-peptide35-55 maintains OPC proliferation and plays an inhibitory role in oli- EAE were conducted as described in our previous study (Guo et al., 2012). godendrocyte (OL) differentiation and regeneration (Shen et al., Complete Freund’s adjuvant (CFA)-immunized mice were used as CFA 2008; Pedre et al., 2011). Until recently, genetic evidence suggests controls for MOG-peptide35-55 EAE. In the MOG-peptide35-55 EAE animal that Sox2 is an essential regulator of OL terminal differentiation, model, multifocal inflammatory and demyelination lesions predominantly but dispensable for OPC proliferation and migration in the em- appear in the lumbar segment of spinal cord. Tamoxifen was intraperitone- ␣ fl/fl bryonic and perinatal spinal cord (Hoffmann et al., 2014). A ally injected to Pdgfr -Sox2 cKO and Sox2 mice for 5 consecutive days starting when mice showed a clinical score Ն2(Guo et al., 2012). The subsequent study by Zhao et al. (2015) shows that Sox2 appears cuprizone-induced demyelination model was conducted according to our dispensable for developmental myelination in the postnatal spi- published protocols (Hammond et al., 2015). In the cuprizone model, dif- nal cord; instead, it has a crucial role in recruiting adult OPCs fused demyelination lesions predominantly occur in the forebrain corpus into the chemical-induced spinal demyelinating lesions during callosum. spinal cord myelin repair. These discrepant results strongly sug- Antibodies and primers. The antibodies used in immunohistochemical gest that Sox2 may play a context-dependent role in regulating staining and Western blotting included the following: Olig2 (AF2418, RRID: CNS oligodendrocyte development and regeneration. In this re- AB_2157554, 1:100; R&D Systems), Olig2 (18953, RRID:AB_494617, 1:100; gard, the functions of Sox2 in brain myelination and remyelina- IBL), NG2 (AB5320, RRID:AB_91789, 1:200; Millipore), PDGFR␣ (sc-338, tion have yet to be defined. RRID:AB_631064, 1:150; Santa Cruz Biotechnology), O4 (MAB345, RRID: We found that Sox2 is expressed in all OPCs in the postnatal AB_94872, 1:200; Millipore), Sox2 (sc-17320, RRID:AB_2286684, 1:500; Santa Cruz Biotechnology), ␤-actin (3700, RRID:AB_2242334, 1:1000; Cell and adult CNS, and that Sox2 is transiently upregulated in newly Signaling Technology), Sox10 (sc-17342, RRID:AB_2195374, 1:100; Santa differentiated OLs during developmental myelination and in Cruz Biotechnology), BrdU (sc-70441, RRID:AB_1119696, 1:100; Santa newly regenerated OLs during remyelination. Using in vivo gene Cruz Biotechnology), Ki67 (9129, RRID:AB_10989986,1:200; Cell Signaling conditional knock-out (cKO), we demonstrate that Sox2 is essen- Technology), EYFP/GFP (06–896, RRID:AB_310288, 1:500; Millipore), tial not only for OPC proliferation and population expansion, TCF7l2 (2569S, RRID:AB_2199816,1:200; Cell Signaling Technology; sc- but also for downstream OL differentiation during developmen- 8632, RRID:AB_2199825, 1:100; Santa Cruz Biotechnology), MBP (NB600- tal myelination in the murine brain. We also demonstrate that 717, RRID:AB_2139899, 1:200; Novus), SMI312 (SMI-312R, RRID: Sox2 is required for OPC proliferation
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