Capicua regulates neural stem cell proliferation and lineage specification through control of Ets factors

Abstract

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. We show that nuclear Cic expression is strongest in astrocytes and neurons but weaker in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we demonstrate that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage effects are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity. Our results identify Cic as an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.

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© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 24 May 2017; Accepted 28 March 2019; Published 01 May 2019. Data availability: The authors declare that all data supporting the findings of this study are available within the article and its Supplementary Information files. All biological materials used in this study are available from the corresponding author upon reasonable request. This work was funded by Canadian Institutes for Health Research (J.A.C.), Cancer Research Society (C.S., J.A.C.), Alberta Cancer Foundation (S.T.A., A.D.R., L.F., J.G.C.), Alberta Innovates Health Solutions (J.A.C., C.S.). We thank Edwin Herrenschmidt of Spine Visual Design for original graphic artwork. Author Contributions: Conceptualization, J.A.C., S.T.A.; methodology, J.A.C., C.S., S.T.A.; investigation, S.T.A., A.D.R., R.D., L.F., M.J.C., M.A., W.W., S.O.L., M.D.B.; acquisition, analyses, and interpretation of data, J.A.C., S.T.A., A.D.R.; writing—original draft, J.A.C., S.T.A.; writing—review & editing, J.A.C., C.S., J.G.C., S.M.R., M.A.M., W.W., R.D., S.O.L.; funding acquisition, J.A.C., J.G.C., C.S.; resources, L.A., M.A., C.S; supervision, J.A.C., C.S., J.G.C., S.M.R. The authors declare no competing interests.

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