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• W2992130201 abstract "•Sox17 ablation in CNS in vivo impairs oligodendrocyte development and regeneration•Sox17 promotes both oligodendrocyte progenitor expansion and maturation in vivo•Notch signaling mediates oligodendrocyte progenitor cell maintenance by Sox17•TCF7L2 expression in oligodendrocytes is regulated by Sox17 and Notch signaling Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology in vivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation in vivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair. Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology in vivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation in vivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair. SRY-Box (Sox)-containing transcription factors are evolutionarily conserved proteins (Gubbay et al., 1990Gubbay J. Collignon J. Koopman P. Capel B. Economou A. Münsterberg A. Vivian N. Goodfellow P. Lovell-Badge R. A gene mapping to the sex-determining region of the mouse Y chromosome is a member of a novel family of embryonically expressed genes.Nature. 1990; 346: 245-250Crossref PubMed Scopus (1340) Google Scholar) that are essential for the differentiation and maturation of a variety of tissue systems, including the developing nervous system (Chew and Gallo, 2009Chew L.J. Gallo V. The Yin and Yang of Sox proteins: Activation and repression in development and disease.J. Neurosci. Res. 2009; 87: 3277-3287Crossref PubMed Scopus (74) Google Scholar, Stolt and Wegner, 2010Stolt C.C. Wegner M. SoxE function in vertebrate nervous system development.Int. J. Biochem. Cell Biol. 2010; 42: 437-440Crossref PubMed Scopus (103) Google Scholar). Unlike the Sox D and E families, studies showing the physiological role of Sox F family members in the CNS in vivo are lacking, and Sox17 remains as the only member of the Sox F with established involvement in CNS glia development (Sohn et al., 2006Sohn J. Natale J. Chew L.J. Belachew S. Cheng Y. Aguirre A. Lytle J. Nait-Oumesmar B. Kerninon C. Kanai-Azuma M. et al.Identification of Sox17 as a transcription factor that regulates oligodendrocyte development.J. Neurosci. 2006; 26: 9722-9735Crossref PubMed Scopus (111) Google Scholar). Sox17 was originally identified as an obligate endodermal determinant (Kanai-Azuma et al., 2002Kanai-Azuma M. Kanai Y. Gad J.M. Tajima Y. Taya C. Kurohmaru M. Sanai Y. Yonekawa H. Yazaki K. Tam P.P.L. Hayashi Y. Depletion of definitive gut endoderm in Sox17-null mutant mice.Development. 2002; 129: 2367-2379Crossref PubMed Google Scholar), whereas Sox7, 17, and 18 regulate the vasculature (Matsui et al., 2006Matsui T. Kanai-Azuma M. Hara K. Matoba S. Hiramatsu R. Kawakami H. Kurohmaru M. Koopman P. Kanai Y. Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice.J. Cell Sci. 2006; 119: 3513-3526Crossref PubMed Scopus (158) Google Scholar, Wat and Wat, 2014Wat J.J. Wat M.J. Sox7 in vascular development: review, insights and potential mechanisms.Int. J. Dev. Biol. 2014; 58: 1-8Crossref Scopus (21) Google Scholar). In the postnatal mouse white matter (WM), Sox17 expression is developmentally associated with that of multiple myelin genes, and its peak of expression in pre-myelinating oligodendrocytes (OLs) is consistent with a role in regulating the transition to immature OLs (Sohn et al., 2006Sohn J. Natale J. Chew L.J. Belachew S. Cheng Y. Aguirre A. Lytle J. Nait-Oumesmar B. Kerninon C. Kanai-Azuma M. et al.Identification of Sox17 as a transcription factor that regulates oligodendrocyte development.J. Neurosci. 2006; 26: 9722-9735Crossref PubMed Scopus (111) Google Scholar). In the OL lineage, Sox17 regulates the Wingless/Int-1 (Wnt)/beta catenin signaling pathway and progenitor cell differentiation (Chew et al., 2011Chew L.J. Shen W. Ming X. Senatorov Jr., V.V.J. Chen H.L. Cheng Y. Hong E. Knoblach S. Gallo V. SRY-box containing gene 17 regulates the Wnt/β-catenin signaling pathway in oligodendrocyte progenitor cells.J. Neurosci. 2011; 31: 13921-13935Crossref PubMed Scopus (79) Google Scholar). Consistent with a role in OL regeneration, recent studies have shown that Sox17 expression in multiple sclerosis and experimental demyelinated lesions is localized in newly generated OL cells of actively remyelinating WM (Moll et al., 2013Moll N.M. Hong E. Fauveau M. Naruse M. Kerninon C. Tepavcevic V. Klopstein A. Seilhean D. Chew L.J. Gallo V. Nait Oumesmar B. SOX17 is expressed in regenerating oligodendrocytes in experimental models of demyelination and in multiple sclerosis.Glia. 2013; 61: 1659-1672Crossref PubMed Scopus (26) Google Scholar). However, functional involvement of endogenous Sox17 in postnatal OL development and regeneration in WM in vivo has not been investigated. We have generated a conditional mouse allele to study Sox17 function in the oligodendroglia lineage in vivo by breeding this floxed strain with the CNP-Cre strain (Lappe-Siefke et al., 2003Lappe-Siefke C. Goebbels S. Gravel M. Nicksch E. Lee J. Braun P.E. Griffiths I.R. Nave K.A. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination.Nat. Genet. 2003; 33: 366-374Crossref PubMed Scopus (782) Google Scholar). Our characterization shows that Sox17 ablation disrupts OL differentiation in the postnatal subcortical WM. In contrast to previous in vitro studies of Sox17, the evidence indicates that OL loss arises initially from a reduction in oligodendrocyte progenitor cells (OPCs). The eventual decrease in OL lineage cells was accompanied by reduced myelin protein expression, thin myelin sheaths, and motor deficits. Sox17 ablation using PDGFRαCreERT2 produced similar changes in progenitor cells and OLs, indicating a progenitor-specific role for Sox17. In addition, Sox17 ablation resulted in a significantly reduced capacity for OL regeneration following lyso-phosphatidylcholine (LPC)-induced demyelination. Similar to postnatal development, OPC induction was reduced and fewer mature OLs were observed in Sox17-deficient WM lesions. In addition to Sox17 regulation of Notch1 receptor and Hes effectors, we identified TCF7L2 expression to be regulated by both Sox17 and Notch. These studies demonstrate that Sox17 plays an important role in promoting a program of OL development by progenitor expansion and maturation and which operates to regulate the regenerative potential of the adult WM. To determine the physiological role of Sox17 in developing OLs, a conditional mouse Sox17 allele was created. This Sox17 allele has exons 4 and 5 flanked by loxP sites, allowing for Cre-mediated excision of the two largest exons (Figure 1A). Genomic deletion of Sox17 exons 4 and 5 that was validated by PCR was performed on DNA isolated from subcortical white matter (SCWM) of CNP-Cre/+;Sox17f/f (conditional knockout [CKO]) and Cre-negative (control [Ctrl]) littermates (Figure S1A). Decreased Sox17 expression in vivo was previously shown in fluorescence-activated cell sorting (FACS)-purified OL lineage cells of this conditional mutant at postnatal day 10 (P10) (Chew et al., 2011Chew L.J. Shen W. Ming X. Senatorov Jr., V.V.J. Chen H.L. Cheng Y. Hong E. Knoblach S. Gallo V. SRY-box containing gene 17 regulates the Wnt/β-catenin signaling pathway in oligodendrocyte progenitor cells.J. Neurosci. 2011; 31: 13921-13935Crossref PubMed Scopus (79) Google Scholar). Quantitative PCR using P18 WM tissue showed reduced Sox17 and myelin protein RNA (Figure S1B). Previous characterization of Sox17 expression in WM OLs, as well as loss- and gain-of-function studies in cultured OPCs indicate a role for Sox17 in OL development (Sohn et al., 2006Sohn J. Natale J. Chew L.J. Belachew S. Cheng Y. Aguirre A. Lytle J. Nait-Oumesmar B. Kerninon C. Kanai-Azuma M. et al.Identification of Sox17 as a transcription factor that regulates oligodendrocyte development.J. Neurosci. 2006; 26: 9722-9735Crossref PubMed Scopus (111) Google Scholar). We, therefore, hypothesized that Sox17 ablation in the OL lineage would impair progenitor cell differentiation and lead to a reduction of mature OLs, with functional deficits resulting from developmental hypomyelination. Immunohistochemical characterization of subcortical WM in either CNP-Cre/+;Sox17+/+ (CNP-Cre), or Cre-negative (Ctrl) and CKO mice over the course of postnatal development revealed age-specific changes in the numbers of oligodendroglial lineage cells. Myelinating OLs labeled with the mouse monoclonal antibody clone CC1 were significantly reduced in the Sox17 CKO animals at P30 and P45 (Figure 1B). A reduction in mature MAG+ OLs was observed at P30 and P45 (Figure S1C). The number Olig2 cells was also decreased at P30 and P45 (Figure 1C). Interestingly, there was a significant increase in OLs at P18 (Figures 1B–1D). This transient rise in differentiation was accompanied by reduced cell survival, as total terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining showed a modest but significant increase in CKO WM (1.6714 ± 0.922 versus 5.987 ± 1.065 per 106 μm3, p = 0.01085 Student’s unpaired t test). TUNEL+ cells included CC1+ and MAG+ OLs (Figure 1E), likely contributing to OL loss by P30 (Figure 1F). The protein levels of myelin proteins were also analyzed across development by using micro-dissected corpus callosum from CKO and wild-type (WT) siblings. Accordingly, a transient increase in MBP, CNP, MAG protein levels at P18 in Sox17 mutants was followed by a significant decrease in these proteins at P30 compared with littermate controls (Figure 1G). To determine whether the decline in OLs affected myelination, we analyzed axonal ultrastructure by transmission electron microscopy. Figure 1H shows that, although the average diameter of myelinated axons and axonal integrity remained unchanged, myelin thickness, as quantified in Figure 1I by G ratio, was significantly reduced, together with a decrease in myelinated axons (Figure 1J). The size of the corpus callosum was also found to be reduced in P30 CKO (Figures S1D and S1E). To determine whether these changes led to functional impairment in behavioral tasks, control and Sox17 CKO animals were tested on the inclined beam task at both P30 and P60. While the 2cm beam could not distinguish between controls and CKO, the more challenging 1cm beam revealed significant functional deficit of the Sox17 CKO at both P30 and P60 (Figure 1K; 1-cm control 0.13 ± 0.09 foot slips/trial, CKO 1.10 ± 0.23 foot slips/trial, p = 0.0002; 2-cm control 0.20 ± 0.14, CKO 0.60 ± 0.22 foot slips/trial, p = 0.13). Because the decrease in OLs occurs during active postnatal oligodendrogenesis and myelination, it is possible that Sox17 deficiency disrupted OPC differentiation and/or OPC production. NG2+ cells were found significantly decreased in the P18 CKO (Figures 2A and 2B ). This is due to reduced proliferation, as evidenced by reduced Ki67+ and NG2+BrdU+ cells (Figure 2C). To determine whether this change arose from the cell-autonomous loss of Sox17, an analysis of NG2 cell proliferation in P18 CNP-Cre/+;Sox17f/f;Rosa26YFP (CKO;RosaYFP) mice was performed. As shown in Figures 2D and 2E, compared with CNP-Cre/+;Rosa26YFP, fewer yellow fluorescent protein (YFP)-expressing OPCs, or NG2+YFP+ cells were present in the P18 CKO;Rosa26YFP WM than were bromodeoxyuridine positive (BrdU+). The CNP-Cre-targeted recombination rate within the NG2 cell population was estimated at about 25% (Figures S2A and S2B). Within the YFP+ population, Sox17 ablation produced a significant decrease in proliferating NG2+ cells. Among CNP-Cre/+;Rosa26YFP-expressing cells, the loss of Sox17 caused a decrease in the percentage of Sox2-expressing progenitor cells at P18 (Figure 2F). Sox2+BrdU+YFP+ OPCs are detectable at P18 in less intense YFP+ cells in this mouse strain (Figure S2C). When the total Sox2 population was analyzed, there was a significant decrease over postnatal WM development in the CKO (Figures 2G and 2H). This was due to reduced cell proliferation (Figures S2D–S2F). To determine whether Sox17 loss in OPCs was sufficient to produce the observed biphasic change in OLs during postnatal development, we generated CNS-progenitor-targeted Sox17 mutants by breeding PDGFRaCreERT2 with Sox17f/f mice. Analysis of PDGFRaCreERT2/+;Sox17f/f (PCKO) mice over postnatal development revealed a pattern of change in the oligodendroglial lineage similar to that observed in CKO. Figure 3A shows that early postnatal ablation with tamoxifen (Tam) at P4–P6 reduces NG2 progenitor cells at P8 without altering CC1 OLs. Subsequently, analysis at P18 shows a smaller reduction in NG2 progenitors, but this change is accompanied by an increase in CC1 OLs (Figure 3B). Tam injections at P7 were estimated by in situ hybridization to lead to Cre-based recombination in about 70% of PDGFRa-expressing OPCs (Figures S3A and S3B), which was sufficient to induce a detectable change in overall Sox17 expression (Figures S3C–S3E). By P28, CC1 OLs are significantly reduced (Figure 3C). At this time point, the numbers of progenitor cells are no longer significantly different, based on NG2 and Sox2 cell analysis (Figure 3C). The decrease in Olig2- and MAG-expressing cells (Figure 3C) indicates a sustained disruption of differentiation despite progenitor recovery. Given the importance of Sox2-expressing progenitor cells in both OPC proliferation and differentiation (Zhang et al., 2018Zhang S. Zhu X. Gui X. Croteau C. Song L. Xu J. Wang A. Bannerman P. Guo F. Sox2 is essential for Oligodendroglial proliferation and differentiation during postnatal brain myelination and CNS remyelination.J. Neurosci. 2018; 38: 1802-1820Crossref PubMed Scopus (51) Google Scholar), it is likely that Sox17 control of Sox2 and NG2 cell populations impacts progenitor-dependent cell regeneration following injury in the adult WM. To determine whether Sox17 ablation impedes OL regeneration in demyelinating lesions, LPC or lysolecithin (LYSO)-induced focal demyelination lesions in the P60 cingulate WM were analyzed. The density of MAG+ cells labeled by cytoplasmic staining was significantly lower in the CKO at 14 days post lesion (DPL) (Figures 4A and 4B ). At 10 DPL, MAG cells were reduced in CKO lesions (Ctrl 22.36 ± 2.41 versus CKO 15.52 ± 1.55 per 106 μm3, p < 0.05, Student’s unpaired t test), and BrdU pulse labeling (Figure 4C) revealed fewer newly formed MAG+ cells in CKO lesions (Figure 4D). The diminished response of Olig2 cells in CKO lesions (Figure 4E) suggests altered induction or activation of OPCs. Indeed, the production of NG2 cells in response to demyelination at 7 DPL was deficient in the CKO (Figures 4F and 4G). Similar to development, Sox17 ablation diminished the demyelination-induced increase in BrdU+ cells, including regenerative Sox2-expressing cells in WM at 7 DPL (Figures 4H–4J). To understand mechanisms that underlie Sox17 regulation of OL formation in the WM, we sought to determine the expression of factors that control progenitor cell expansion and maturation, such as Sox2 (Zhang et al., 2018Zhang S. Zhu X. Gui X. Croteau C. Song L. Xu J. Wang A. Bannerman P. Guo F. Sox2 is essential for Oligodendroglial proliferation and differentiation during postnatal brain myelination and CNS remyelination.J. Neurosci. 2018; 38: 1802-1820Crossref PubMed Scopus (51) Google Scholar) and TCF7L2 (Hammond et al., 2015Hammond E. Lang J. Maeda Y. Pleasure D. Angus-Hill M. Xu J. Horiuchi M. Deng W. Guo F. The Wnt effector transcription factor 7-like 2 positively regulates oligodendrocyte differentiation in a manner independent of Wnt/β-catenin signaling.J. Neurosci. 2015; 35: 5007-5022Crossref PubMed Scopus (60) Google Scholar, Zhao et al., 2016Zhao C. Deng Y. Liu L. Yu K. Zhang L. Wang H. He X. Wang J. Lu C. Wu L.N. et al.Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.Nat. Commun. 2016; 7: 10883Crossref PubMed Scopus (90) Google Scholar). Figure 5A shows that Sox17 knockdown in cultured OPCs revealed a surprisingly selective effect on TCF7L2 protein, rather than on Sox2. This selectivity was confirmed at the RNA level by quantitative PCR (Figure 5B). We hypothesized that because Sox17 did not regulate Sox2 expression in OPCs, its control of the Sox2 cells could be mediated through signaling, which regulates the progenitor population (Zhang et al., 2009Zhang Y. Argaw A.T. Gurfein B.T. Zameer A. Snyder B.J. Ge C. Lu Q.R. Rowitch D.H. Raine C.S. Brosnan C.F. John G.R. Notch1 signaling plays a role in regulating precursor differentiation during CNS remyelination.Proc. Natl. Acad. Sci. USA. 2009; 106: 19162-19167Crossref PubMed Scopus (162) Google Scholar), such as Notch. Indeed, the protein levels of cleaved or activated Notch1 (Act N1; Figure 5A) and RNA levels of Notch1 receptor and signaling effectors Hes1 and Hes5 were significantly reduced by Sox17 siRNA (Figure 5B). To determine whether Notch signaling regulated TCF7L2 or Sox2 gene expression in cultured OPCs, we applied the gamma secretase inhibitor N-[(3,5-Difluorophenyl)acetyl]-L-alanyl-2-phenyl]glycine-1,1-dimethylethyl ester (DAPT) for 2–3 days and found that TCF7L2 RNA was reduced, whereas Sox2 remained unaffected (Figure 5C). Notch1 was found to mediate this change in TCF7L2 expression because Notch1 small interfering RNA (siRNA) transfection of cultured OPCs also decreased TCF7L2 without affecting Sox2 RNA (Figure 5D). DAPT decreased the percentage of proliferating Sox2 cells in culture (Figure 5E-F), ultimately decreasing the total number of Sox2 cells (Figure S4A), indicating that Notch regulates the expansion of Sox2-expressing OPCs, rather than its expression. Although 1 μM and 2 μM DAPT were found to reduce cell viability to a similar extent (Figure S4B), 1 μM was selected for subsequent assays analyzing differentiation (below). Based on Sox17-induced changes in Notch1 expression, we investigated the possibility that Sox17 might interact with a Notch1 enhancer region in developing WM. A recent study of SoxF factors by Chiang et al., 2017Chiang I.K. Fritzsche M. Pichol-Thievend C. Neal A. Holmes K. Lagendijk A. Overman J. D’Angelo D. Omini A. Hermkens D. et al.SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development.Development. 2017; 144: 2629-2639Crossref Scopus (37) Google Scholar in arterial development identified two Sox consensus-containing intronic enhancers within the Notch1 gene that bound recombinant Sox7 and Sox18. Using these sequences as electrophoretic mobility shift assay (EMSA) probes, we found that the sequence corresponding to HmSox-a (Chiang et al., 2017Chiang I.K. Fritzsche M. Pichol-Thievend C. Neal A. Holmes K. Lagendijk A. Overman J. D’Angelo D. Omini A. Hermkens D. et al.SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development.Development. 2017; 144: 2629-2639Crossref Scopus (37) Google Scholar), which we call SoxA in this study, formed a sequence-specific complex with nuclear proteins from P12 WM (Figures 5G and 5H), whereas HmSox-b or SoxB did not. Figure 5I shows that the complex is vulnerable to disruption by anti-Sox17 antibody, indicating the presence of Sox17 in this complex from WM. To determine whether Sox17 in proliferating OPCs bound the SoxA sequence, we performed EMSA analysis by using nuclear extract isolated from rat OPCs cultured for 2 days in platelet-derived growth factor (PDGF). Figures 5J shows that a SoxA-specific complex was detected that was disrupted by Sox17 antibodies from two vendor sources (Figure 5K; antibody S1 and S2). These data are consistent with the notion of direct control of Notch1 expression by Sox17 that could underlie progenitor cell expansion. To determine whether Notch signaling in vivo was altered by Sox17 loss, the number of WM cells expressing Notch mediators Hes1 and Hes5 was analyzed. These were decreased in CKO WM at P8 and P18 (Figures 5L and 5M). Hes1 distribution at P18 was not exclusively nuclear, unlike Hes5 at P8 (Figure 5N), but total Hes1- and Hes5-expressing cells were decreased in number in CKO (Figure 5P). We then determined whether Notch1 activation was regulated in CNP-Cre-targeted cells. Figure 5Q shows that in P18 controls, CNP-Cre-targeted YFP reporter expression (green) was colocalized with activated Notch1(ActN1, red). The percentage of YFP cells that colocalized with ActN1 was significantly decreased (Figure 5R), indicating that Sox17 ablation cell autonomously downregulated Notch1 activation in P18 CKO WM. Given the function of Notch in progenitor maintenance, the biphasic change in TCF7L2 cells of the developing CKO WM (Figures 6A and 6B ) suggests bona fide changes in differentiation events—disrupted progenitor expansion and enhanced precocious differentiation, followed by unsustained differentiation and eventual OL reduction. Progenitor-targeted Sox17 ablation reproduced the biphasic change in TCF7L2-expressing cells between P18 and P28 (Figures 6C and S5). We wanted to determine whether Sox17 also similarly regulated TCF7L2 in OL regeneration. In the intact adult WM, TCF7L2 is undetectable (Zhao et al., 2016Zhao C. Deng Y. Liu L. Yu K. Zhang L. Wang H. He X. Wang J. Lu C. Wu L.N. et al.Dual regulatory switch through interactions of Tcf7l2/Tcf4 with stage-specific partners propels oligodendroglial maturation.Nat. Commun. 2016; 7: 10883Crossref PubMed Scopus (90) Google Scholar), but its upregulation upon demyelination is dependent on Sox17 (Figures 6D and 6E). As in CKO development, the change in total TCF7L2-expressing cells undergoes an initial increase at 7 DPL, followed by decrease at 10 DPL (Figure 6F). BrdU pulse-labeling showed fewer newly formed TCF7L2 cells in the CKO by 10 DPL (Figure 6G). It is possible that the initial increase in TCF7L2 lies downstream of Notch inhibition, as cultured OPCs treated with DAPT also show enhanced differentiation based on increased O4 and TCF7L2-expressing cells (Figures 6H and 6I). Together, the observations are consistent with the interpretation that TCF7L2 may contribute to Sox17 functions in differentiation, and thus Sox17 regulates the number of OLs in the adult WM through progenitor expansion and subsequent differentiation. To determine whether Sox17 ablation in adult OPCs regulated oligodendroglial regeneration, we performed LPC lesions in P60 PCKO mice, which received Tam injections 3 days prior to demyelination (Figure 7A). At 7 DPL, the number of NG2 progenitor cells was attenuated in PCKO (Figures 7B and 7C), accompanied by decreased ActN1 (Figures 7D and 7E). Lesion-induced Sox2-expressing oligodendroglial lineage cells, which co-express YFP reporter in controls (Figure S6A), were found to be significantly reduced in PCKO lesions along with Hes1 (Figures S6B and S6C). Olig2 cells were decreased in PCKO lesions, indicating an impaired oligodendroglial cell response (Figures 7F and 7G). The increased numbers of lightly stained Olig2 cells in intact PCKO may be due to progenitor maturation (Figure 7G, Sal). These observations support the interpretation that Sox17 in OPCs controls Notch1 activation, which enhances progenitor cell expansion in response to demyelination. To determine whether Sox17 gain-of-function in vivo increases the progenitor cell population through Notch, we analyzed adult CNPSox17 transgenic mice at P60 when Ctrl progenitor proliferation had declined. This transgenic strain, which overexpresses recombinant, full-length mouse Sox17 in NG2, O4, and CC1 cells of subcortical WM, displays increased numbers of OLs in adult WM (Ming et al., 2013Ming X. Chew L.J. Gallo V. Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.J. Neurosci. 2013; 33: 12528-12542Crossref PubMed Scopus (27) Google Scholar). Figures S7A and S7B show that Sox2-expressing cells in the intact CNPSox17 WM were significantly increased over Ctrl (saline), consistent with previous findings of greater numbers of NG2-expressing cells (Ming et al., 2013Ming X. Chew L.J. Gallo V. Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.J. Neurosci. 2013; 33: 12528-12542Crossref PubMed Scopus (27) Google Scholar). Following LPC demyelination, at 3DPL—before the well-defined peak of progenitor proliferation in Ctrl mice reported to be at 7 days (Aguirre et al., 2007Aguirre A. Dupree J.L. Mangin J.M. Gallo V. A functional role for EGFR signaling in myelination and remyelination.Nat. Neurosci. 2007; 10: 990-1002Crossref PubMed Scopus (275) Google Scholar, Nait-Oumesmar et al., 1999Nait-Oumesmar B. Decker L. Lachapelle F. Avellana-Adalid V. Bachelin C. Baron-Van Evercooren A. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination.Eur. J. Neurosci. 1999; 11: 4357-4366Crossref PubMed Scopus (455) Google Scholar, Watanabe et al., 2002Watanabe M. Toyama Y. Nishiyama A. Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion.J. Neurosci. Res. 2002; 69: 826-836Crossref PubMed Scopus (214) Google Scholar, Woodruff and Franklin, 1999Woodruff R.H. Franklin R.J.M. Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide, and complement/anti-galactocerebroside: a comparative study.Glia. 1999; 25: 216-228Crossref PubMed Scopus (258) Google Scholar)—the CNPSox17 mouse showed an additional Sox2 cell response that was absent in Ctrl (Figure S7B). Sox17 overexpression was also previously shown to elevate the numbers of TCF7L2 cells (Ming et al., 2013Ming X. Chew L.J. Gallo V. Transgenic overexpression of Sox17 promotes oligodendrocyte development and attenuates demyelination.J. Neurosci. 2013; 33: 12528-12542Crossref PubMed Scopus (27) Google Scholar). Our observation that WM lesions selectively stimulated an increase in TCF7L2 cells only in WT mice (Figure S7C) suggests that signaling mechanisms upregulating TCF7L2 and Sox2 cells in the CNPSox17 mouse were already intrinsically stimulated. Figure 7H shows that ActN1 is elevated in intact P60 CNPSox17 WM over WT controls. A single stereotaxic injection of 50 μM DAPT significantly reduced ActN1 levels in CNPSox17 (Figure 7H). To determine whether the increased population of NG2- and Sox2-expressing cells in the intact adult CNPSox17 transgenic WM was produced by enhanced Notch signaling, the numbers of NG2 and Sox2 cells were analyzed after stereotaxic injection of 50 μM DAPT (Figures 7I and 7J). These experiments showing a reduction of NG2 and Sox2 cells in the CNPSox17 WM by DAPT implicate Notch signaling in progenitor maintenance. In Lyso lesions of the CNPSox17, this dose of DAPT was effective in decreasing lesion-induced ActN1, NG2, and Sox2 cells and increasing OPC differentiation, indicated by Olig2 and CC1 cells at 3 DPL (Figures S7D and S7E). Taken together, our studies provide evidence of a programmatic role for Sox17 in the control of Notch expression and in OL production through progenitor expansion and subsequent differentiation. Sox factors control many aspects of development in OLs, ranging from lineage specification to effects on proliferation and survival, with the majority of the literature focused on the SoxD and SoxE families. SoxF factors are involved in hematopoietic progenitor regulation (He et al., 2011He S. Kim I. Lim M.S. Morrison S.J. Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors.Genes Dev. 2011; 25: 1613-1627Crossref PubMed Scopus (91) Google Scholar), tumor angiogenesis (Yang et al., 2013Yang H. Lee S. Lee S. Kim K. Yang Y. Kim J.H. Adams R.H. Wells J.M. Morrison S.J. Koh G.Y. Kim I. Sox17 promotes tumor angiogenesis and destabilizes tumor vessels in mice.J. Clin. Invest. 2013; 123: 418-431Crossref PubMed Scopus (68) Google Scholar), and arterial development (Chiang et al., 2017Chiang I.K. Fritzsche M. Pichol-Thievend C. Neal A. Holmes K. Lagendijk A. Overman J. D’Angelo D. Omini A. Hermkens D. et al.SoxF factors ind" @default.
• W2992130201 created "2019-12-13" @default.
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• W2992130201 title "Sox17 Regulates a Program of Oligodendrocyte Progenitor Cell Expansion and Differentiation during Development and Repair" @default.
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