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

Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cics function in the brain. Here, we investigated the relationship between Cic expression and cell type specification in the brain. Cic is strongly expressed in astrocytic and neuronal lineage cells but is more weakly expressed in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we show 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 selection effects in the developing brain 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 is 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.