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Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes

Nature Neuroscience volume 17, pages 1322–1329 (2014)Cite this article

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Abstract

Lineage progression and diversification is regulated by the coordinated action of unique sets of transcription factors. Oligodendrocytes (OL) and astrocytes (AS) comprise the glial sub-lineages in the CNS, and the manner in which their associated regulatory factors orchestrate lineage diversification during development and disease remains an open question. Sox10 and NFIA are key transcriptional regulators of gliogenesis associated with OL and AS. We found that NFIA inhibited Sox10 induction of OL differentiation through direct association and antagonism of its function. Conversely, we found that Sox10 antagonized NFIA function and suppressed AS differentiation in mouse and chick systems. Using this developmental paradigm as a model for glioma, we found that this relationship similarly regulated the generation of glioma subtypes. Our results describe the antagonistic relationship between Sox10 and NFIA that regulates the balance of OL and AS fate during development and demonstrate for the first time, to the best of our knowledge, that the transcriptional processes governing glial sub-lineage diversification oversee the generation of glioma subtypes.

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Figure 1: NFIA antagonizes Sox10 induction of myelin genes.
Figure 2: NFIA associates with Sox10 and inhibits its activity.
Figure 3: Sox10 antagonized NFIA induction of AS-related genes.
Figure 4: Loss of Sox10 promotes AS development.
Figure 5: Olig2 facilitates Sox10/NFIA interactions NFIA and Sox activity on AS and myelin gene promoters.
Figure 6: NFIA regulates generation of glioma subtypes.

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Acknowledgements

We thank A. Groves for assistance with the GST pull-down studies. This work was supported by grants from the National Multiple Sclerosis Society (RG 4623A1/2 to B.D.), the Sontag Foundation (B.D.), and the US National Institutes of Health (R01 NS071153 to B.D., R01 HD062553 to J.L.N., R01HD055655 and R01MH056524 to J.J.L., 5-T32HL092332-08 to S.G.). The GFAP-Luc reporter was a kind gift from M. Brenner (University of Alabama-Birmingham).

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Authors and Affiliations

  1. Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, USA

    Stacey M Glasgow, Wenyi Zhu & Benjamin Deneen

  2. Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas, USA

    Wenyi Zhu & Benjamin Deneen

  3. Institut für Biochemie, Emil-Fischer-Zentrum, Universität Erlangen-Nürnberg, Erlangen, Germany

    C Claus Stolt & Michael Wegner

  4. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA

    Teng-Wei Huang, Jeffrey L Neul & Benjamin Deneen

  5. Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas, USA

    Teng-Wei Huang, Jeffrey L Neul & Benjamin Deneen

  6. Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut, USA

    Fuyi Chen & Joseph J LoTurco

  7. Department of Pediatrics, Neurology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Jeffrey L Neul & Benjamin Deneen

  8. Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA

    Jeffrey L Neul & Benjamin Deneen

  9. Department of Pathology, Texas Children's Hospital, Houston, Texas, USA

    Carrie Mohila

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  1. Stacey M Glasgow
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Contributions

B.D. and S.M.G. conceived the project, designed the experiments and wrote the manuscript. S.M.G. and W.Z. performed all of the experiments. B.D., S.M.G., W.Z. and C.M. analyzed the data. C.C.S., M.W., T.-W.H., J.L.N., J.J.L. and F.C. provided essential reagents.

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Correspondence to Benjamin Deneen.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 NFIA and Sox10 expression during OLP development

NFIA is co-expressed with Sox10 in the spinal cord at E12.5 (B). NFIA is expressed in OLPs as demonstrated by co-expression with Sox10 (C, filled arrows) at E18.5, but not markers of mature OLs MBP (D, E) or PLP (F, G), denoted by unfilled arrows. These expression dynamics are summarized schematically in A. Sox10 is co-expressed with Glast::dsRed (H) and Olig2 (I) in the VZ at E12.5.

Supplementary Figure 2 NFIA antagonizes ectopic induction of OLP markers by Sox10.

Overexpression of NFIA (A), Sox10 (B), or Sox10+NFIA (C) in the chick spinal cord. Sections are adjacent or near adjacent to the ones presented in Figure 1A-H. Arrow in B denotes ectopic Olig2 expression, while arrow in C denotes absence of Olig2. Graph in E represents analysis of Caspase 3 staining in adjacent sections. Image in F is from Figure 1F, boxed region is shown at higher magnification in G to demonstrate overlapping expression of Sox10 and NFIA. (H) Quantification of Sox10 expression using fluorescence intensity on chick spinal cord sections stained with α-HA to detect ectopic Sox10 expression in these studies. (I-J) Cultured OLPs infected with NFIA or GFP control viruses prior to mitogen removal and differentiation, stained with the OLP marker, Nkx2.2 Arrows denote viral infected, Nkx2.2-expressing OLP populations. Quantification in D-E and H is from 8 independent spinal cords, 8 sections/spinal cord.

Supplementary Figure 3 NFI and Sox binding sites are present in myelin and astrocyte gene promoters

Schematic representation of myelin gene promoters (MBP, PLP, MAG) and astrocyte gene promoters (GFAP, APCDD1) depicting the location of Sox and NFI sites. Also shown is the conservation of these sites between human and mouse promoters.

Supplementary Figure 4 Single-channel images from Figure 3s–u.

A, GFP control, B, NFIA transfection, Sox10 transfection. Filled arrows denote overlap between GFP and GFAP, Open arrow denote non-overlapping GFP and GFAP expression. The extent of GFAP/GFP overlap is increased in the NFIA transfections (B) and decreased in the Sox10 transfections (C), compared to the control sample (A). See Figure 3W for quantification.

Supplementary Figure 5 Sox10-positive cells give rise to gray- and white-matter astrocytes

The Sox10-Cre;Rosa26-LacZ mouse line was used to trace the fate of Sox10-expressing cells in the spinal cord from P0-P1 neonatal mice. Sox10 expressing cells give rise to AldoC- (A), GFAP-(B), S100β-(C), and GS-(D) expressing white matter astrocytes (A-C) and grey-matter astrocytes (A, C-D).

Supplementary Figure 6 Sox10LacZ/LacZ neural stem cells demonstrate increased astrocyte production.

Neural stem cells from Sox10LacZ/+ and Sox10LacZ/LacZ E13.5 spinal cord were infected with dsRed control (A-B) or Sox10-dsRed (C) retrovirus and allowed to differentiation. Five days after plating on adherent substrate, cultures were fixed and stained with GFAP. Quantification in D is derived from four independent experiments, on two independently derived sets of neural stem cells from Sox10LacZ/+ and Sox10LacZ/LacZ litters. In D, Het is Sox10LacZ/+ and KO is Sox10LacZ/LacZ. *p<0.001. All error bars represent SD.

Supplementary Figure 7 Loss of Sox10 does not result in an increase in white matter astrocytes

In the absence of Sox10 no change in the number of NKX6.1+/NFIA-expressing cells is observed (A-C, filled arrows). In addition, no difference was observed in the number of β-gal/NKX6.1 or β-gal/Pax6 WMAs in the absence of Sox10 (D-I, unfilled arrows). In C, F, I, “Het” corresponds to Sox10LacZ/+ and “KO” corresponds to Sox10LacZ/LacZ. Analysis of Ki-67 in Sox10LacZ/+ and Sox10LacZ/LacZ embryos did not reveal any changes in proliferation (J-L). All quantifications are derived from three embryos of each genotype from two independent litters.

Supplementary Figure 8 Generation of oligodendroglioma using IUE and PiggyBacs to target OL lineages with oncogenes

Brain from P14 mouse IUE at E16.5 with GLAST-PBase and MBP-GFPt2aRas (A). Arrow denotes region electroporated and dotted line denotes cross section analyzed in B; dotted line in B is midlne. H&E staining of tumors (C-D). Tumors demonstrate pathological hallmarks of oligodendrolglioma, including small monomorphic nuclei lacking processes, perineuronal satellitosis, and invasion into perivascular and subpial spaces. Dashed box in C is magnified area in D. Circle in D demonstrates typical perineuronal satellitosis. Olig2 staining in mouse oligodendroglioma (E-H). Co-expression of ectopic HA-NFIA with Ras-GFP expressing cells in astrocytoma-like tumors (H-J).

Supplementary Figure 9 Checks and balances of NFIA and Sox10 function during glial sub-lineage differentiation and tumorigenesis.

Supplementary Figure 10 Uncropped gel and blot images.

(A) Reprint of Figure 5E with individual blots labeled 1-7 (ie. αFlag-1, etc.). (B) Corresponding uncropped blots of those shown in “A” and Figure 5E. Uncropped blots are the size of the membrane which was blotted. Membranes were often cut at or below 50kDa to enable blotting for multiple antibodies. Representative blots WB α-Flag-1 and WB α-Olig2-2 were taken from the same membrane, where the dashed line represents where the membrane was cut. Lanes are numbered under the blot image and L indicates the ladder lane. The protein standards are depicted to the right of the blots. (C) Uncropped image of exposed GST pulldown assay and western blot. (D) Uncropped blots of Co-IP shown in Figure 2A. The protein standards are depicted to the right of the blots. (E) Uncropped images of DNA gels for ChIP analysis for experiments performed in Figures 2B,C,D and 3L,M.

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Glasgow, S., Zhu, W., Stolt, C. et al. Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes. Nat Neurosci 17, 1322–1329 (2014). https://doi.org/10.1038/nn.3790

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