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

Zhang, Sheng; Zhu, Xiaoqing; Gui, Xuehong; Croteau, Christopher; Song, Lanying; Xu, Jie; Wang, Aijun; Bannerman, Peter; Guo, Fuzheng

doi:10.1523/jneurosci.1291-17.2018

Cited by 85 publications

(118 citation statements)

References 42 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…In MOLs, SOX2 expression is markedly downregulated, as are many of the genes within its regulatory network. Given that SOX2 expression is necessary for proper remyelination in the adult brain (Zhang et al, ), the network of genes proximally regulated by SOX2 would be informative to study in the context of remyelination failure.…”

Section: Discussionmentioning

confidence: 99%

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Perlman

Couturier

Yaqubi

et al. 2020

Glia

View full text Add to dashboard Cite

Characterizing the developmental trajectory of oligodendrocyte progenitor cells (OPC) is of great interest given the importance of these cells in the remyelination process. However, studies of human OPC development remain limited by the availability of whole cell samples and material that encompasses a wide age range, including time of peak myelination. In this study, we apply single cell RNA sequencing to viable whole cells across the age span and link transcriptomic signatures of oligodendrocyte‐lineage cells with stage‐specific functional properties. Cells were isolated from surgical tissue samples of second‐trimester fetal, 2‐year‐old pediatric, 13‐year‐old adolescent, and adult donors by mechanical and enzymatic digestion, followed by percoll gradient centrifugation. Gene expression was analyzed using droplet‐based RNA sequencing (10X Chromium). Louvain clustering analysis identified three distinct cellular subpopulations based on 5,613 genes, comprised of an early OPC (e‐OPC) group, a late OPC group (l‐OPC), and a mature OL (MOL) group. Gene ontology terms enriched for e‐OPCs included cell cycle and development, for l‐OPCs included extracellular matrix and cell adhesion, and for MOLs included myelination and cytoskeleton. The e‐OPCs were mostly confined to the premyelinating fetal group, and the l‐OPCs were most highly represented in the pediatric age group, corresponding to the peak age of myelination. Cells expressing a signature characteristic of l‐OPCs were identified in the adult brain in situ using RNAScope. These findings highlight the transcriptomic variability in OL‐lineage cells before, during, and after peak myelination and contribute to identifying novel pathways required to achieve remyelination.

show abstract

Section: Discussionmentioning

confidence: 99%

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Perlman

Couturier

Yaqubi

et al. 2020

Glia

View full text Add to dashboard Cite

show abstract

“…To define the role of physiological HIFα stabilization in developmental myelination, we used Cre-loxP-based genetic approach to conditionally disrupt HIFα function. Previous studies have demonstrated that Pdgfrα-CreER T2 drives gene disruption in OPCs whereas Cnp-Cre in later stages of oligodendrocyte development (Moyon et al, 2016;Zhang et al, 2018a;Zhang et al, 2018b). Our extensive analysis of HIF1α or HIF2α conditionally knockout mice driven by Pdgfrα-CreER T2 and Cnp-Cre revealed no phenotypic abnormalities of the oligodendroglial lineage, suggesting functional redundancy between HIF1α and HIF2α.…”

Section: Disrupting Hifα In Opcs But Not Ols Delays Developmental Myementioning

confidence: 51%

“…Tamoxifen was administered to PDGFRα:HIFα cKO and non-Cre littermate control (Hif1α fl/fl :Hif2α fl/fl ) pups at P1, P2, and P3 and the CNS tissue was analyzed at P8. Our previous data show that this tamoxifen paradigm induces ~90% of gene cKO efficiency in OPCs (Zhang et al, 2018a;Zhang et al, 2018b). The density of differentiated OLs but not OPCs was significantly decreased in the spinal cord white matter of PDGFRα:HIFα cKO mice compared with non-Cre littermate controls ( Fig.…”

Section: Disrupting Hifα In Opcs But Not Ols Delays Developmental Myementioning

confidence: 69%

“…Then the slices were incubated with Alkaline phosphatase (AP) anti-DIG secondary antibody (1:100,11093274910, Sigma) overnight after blocking with 10% donkey serum. The signal was determined by nitroblue tetrazolium (NBT) and 5-bromo-4chloro-3-indolyl phosphate (toluidine salt) (BCIP) (Sigma, 72091).Semithin sections for toluidine blue myelin staining and ultrathin section for TEM imaging were prepared according to our previous protocols (Zhang et al, 2018a;Zhang et al, 2018b). TEM imaging was conduction by the professionals at UC Davis Core Facility who were blinded to the mouse genotypes.…”

Section: In Situ Hybridization and Transmission Electron Microscopy (mentioning

confidence: 99%

See 1 more Smart Citation

HIFα regulates developmental myelination independent of autocrine Wnt signaling

Zhang

Wang

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

words)The developing CNS is exposed to physiological hypoxia, under which hypoxia inducible factor alpha (HIFα) is stabilized and plays a crucial role in regulating neural development. The cellular and molecular mechanism of HIFα in developmental myelination remain incompletely understood. Previous concept proposes that HIFα regulates CNS developmental myelination by activating the autocrine Wnt/β-catenin signaling in oligodendrocyte progenitor cells (OPCs).Here, by analyzing a battery of genetic mice of both sexes, we presented in vivo evidence supporting an alternative understanding of oligodendroglial HIFα-regulated developmental myelination. At the cellular level, we found that HIFα was required for developmental myelination by transiently controlling upstream OPC differentiation but not downstream oligodendrocyte maturation and that HIFα dysregulation in OPCs but not oligodendrocytes disturbed normal developmental myelination. We demonstrated that HIFα played a minor, if any, role in regulating canonical Wnt signaling in the oligodendroglial lineage or in the CNS. At the molecular level, blocking the autocrine Wnt signaling did not affect HIFα-regulated OPC differentiation and myelination. We further identified HIFα-Sox9 regulatory axis as an underlying molecular mechanism in HIFα-regulated OPC differentiation. Our findings support a concept shift in our mechanistic understanding of HIFα-regulated CNS myelination from the previous Wnt-dependent view to a Wnt-independent one and unveil a previously unappreciated HIFα-Sox9 pathway in regulating OPC differentiation. Significant statement (100 words)Promoting disturbed developmental myelination is a promising option in treating periventricular leukomalacia, a major form of brain white matter injury affecting premature infants. In the developing CNS, HIFα is a master regulator that adapts neural cells to physiological and pathological hypoxic cues. The role and mechanism of HIFα in oligodendroglial myelination, which is developmentally disturbed in preterm infants affected with 3 periventricular leukomalacia, are incompletely understood. Our findings presented here represent a concept shift in our mechanistic understanding of HIFα-regulated developmental myelination and suggest the potential of intervening oligodendroglial HIFα-mediated signaling pathway in mitigating disturbed myelination in premature white matter injury.

show abstract

“…In addition, vitamin D3-induced transcription factors (GO Cellular Component (GO-CC) "nuclear transcription factor complex", Supplementary Fig. S2) included Sox2, whose role in OL differentiation was recently reported 45,46 and CCAAT/enhancer binding protein beta (Cebpb), a VDR-responsive gene that controls the differentiation of myeloid leukaemia cells 47 .…”

Section: Functional Enrichment Analysis Of the Genes Uniquely Down-rementioning

confidence: 99%

Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line

Mengozzi

Hesketh

Bucca

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractVitamin D deficiency increases the risk of developing multiple sclerosis (MS) but there is uncertainty about what dose and form of vitamin D could improve the clinical course of MS. The mechanisms underlying the effects of vitamin D in MS are not clear. Vitamin D3 increases the rate of differentiation of primary oligodendrocyte precursor cells (OPCs), suggesting that it might help remyelination in addition to modulating the immune response. Here we analyzed the transcriptome of differentiating rat CG4 OPCs treated with vitamin D2 or with D3 at 24 h and 72 h following onset of differentiation. Differentiation alone changed the expression of about 10% of the genes at 72 h compared to 24 h. Vitamin D2 and D3 exerted different effects on gene expression, with D3 influencing 1,272 genes and D2 574 at 24 h. The expression of the vast majority of these genes was either not changed in differentiating cells not exposed to vitamin D or followed the same trajectory as the latter. D3-repressed genes were enriched for gene ontology categories including transcription factors and the Notch pathway, while D3-induced genes were enriched for the Ras pathway. These findings should help to identify mechanisms mediating D3 action in MS.

show abstract

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

Cited by 85 publications

References 42 publications

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

Developmental trajectory of oligodendrocyte progenitor cells in the human brain revealed by single cell RNA sequencing

HIFα regulates developmental myelination independent of autocrine Wnt signaling

Vitamins D3 and D2 have marked but different global effects on gene expression in a rat oligodendrocyte precursor cell line

Contact Info

Product

Resources

About