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.

Regulation and function of capicua in mammals

“…Upon the induction of differentiation in vitro, Cic null NSCs could not differentiate into mature oligodendrocytes and instead were maintained in an oligodendrocyte progenitor cell (OPC)-like stemness state 27 . A similar result was obtained using another forebrainspecific Cic null (Cic f/f ;Foxg1-Cre) mouse model, in which Olig2 + Sox2 + cells and Olig2 + Pdgfra + OPCs are increased and CNPase + immature oligodendrocytes are decreased in the cortex 29 . Moreover, CIC deficiency enhanced the self-renewal capacity and promoted the symmetric division of NSCs 29 .…”

“…A similar result was obtained using another forebrainspecific Cic null (Cic f/f ;Foxg1-Cre) mouse model, in which Olig2 + Sox2 + cells and Olig2 + Pdgfra + OPCs are increased and CNPase + immature oligodendrocytes are decreased in the cortex 29 . Moreover, CIC deficiency enhanced the self-renewal capacity and promoted the symmetric division of NSCs 29 . Mechanistically, the derepression of Etv5 mediated the effects of CIC deficiency in NSCs 29 .…”

“…Cic null NSCs presented EGF-independent hyperproliferative characteristics 27 . Hyperproliferation of NSCs by the loss of Cic was also confirmed in E13 embryos by a 5-ethynyl-2′-deoxyuridine (EdU) labeling experiment 29 . Upon the induction of differentiation in vitro, Cic null NSCs could not differentiate into mature oligodendrocytes and instead were maintained in an oligodendrocyte progenitor cell (OPC)-like stemness state 27 .…”

“…Moreover, CIC deficiency enhanced the self-renewal capacity and promoted the symmetric division of NSCs 29 . Mechanistically, the derepression of Etv5 mediated the effects of CIC deficiency in NSCs 29 . Thus, CIC is a key transcription factor that controls brain development and function as well as the pathogenesis of neurological disorders.…”

“…Endogenous functions of CIC have been elucidated by examinations of the phenotypes of Cic mutant mice. CIC deficiency results in defects in lung development, bile acid homeostasis, abdominal wall closure during embryogenesis, neuronal cell differentiation, brain development, and T cell subset differentiation [25][26][27][29][30][31][32][33][34] . In this review, I focus on the roles of CIC in mammals; in particular, I summarize recent studies of (1) its functions in diseases, including neurological diseases and cancer, (2) its functions in development, and (3) its underlying regulatory mechanisms in mammalian cells.…”