Publication Details

Title :

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

Journal:

Nat Commun.

Impact Factor:

11.880

Authors:

Ahmad ST1,2,3, Rogers AD2, Chen MJ2,3, Dixit R2,3,4, Adnani L3,4, Frankiw LS2,5, Lawn SO2,6, Blough MD2, Alshehri M2,7, Wu W2,8, Marra MA9, Robbins SM2, Cairncross JG2, Schuurmans C3,4, Chan JA10,11,12.

Affiliations:

1 Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada.

2 Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada.

3 Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada.

4 Sunnybrook Research Institute and the Department of Biochemistry, University of Toronto, Toronto, ON, Canada.

5 Department of Biology & Bioengineering, California Institute of Technology, Pasadena, CA, USA.

6 Zymeworks, Vancouver, BC, Canada.

7 King Abdullah International Medical Centre, Riyadh, Saudi Arabia.

8 University of California, San Francisco, CA, USA.

9 BC Genome Sciences Centre, Vancouver, BC, Canada.

10 Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, AB, Canada. jawchan@ucalgary.ca.

11 Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada. jawchan@ucalgary.ca.12 Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB, Canada. jawchan@ucalgary.ca.

Year of Publication:

2019

DOI:

10.1038/s41467-019-09949-6.

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.