Abstract
Capicua (CIC), a member of the high mobility group-box (HMG-box) superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. However, its functions in brain development and tumorigenesis remain poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblasts to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogate involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified the BRG1-containing mSWI/SNF complex whose function is necessary for transcriptional repression by CIC. Together, this study uncovers a potentially novel regulatory pathway of CIC-dependent neuronal differentiation and may implicate these molecular mechanisms in CIC-dependent brain tumorigenesis.
Highlights
Oligodendroglioma, a diffusely infiltrating primary malignant brain tumor in adults, is histologically characterized by its composition of neoplastic cells morphologically resembling oligodendroglial cells
Histologic examination of CicKO pups at P14 further revealed significant reductions of cerebral and cerebellar cortical thickness compared with CicWT littermates (n = 10) (Figure 1, D and E), indicating that CIC is required for early brain development
CIC is frequently mutated in oligodendrogliomas [34]
Summary
Oligodendroglioma, a diffusely infiltrating primary malignant brain tumor in adults, is histologically characterized by its composition of neoplastic cells morphologically resembling oligodendroglial cells Despite their generally better prognosis and response to early chemotherapy, most oligodendroglial tumors recur eventually, with many of them progressing to a higher-grade lesion [1]. An additional study using Foxg1-cre revealed that mouse forebrain–specific deletion of Cic caused abnormal increase of oligodendrocyte progenitor cells (OPC) and immature oligodendrocytes populations [15, 16], likely at the expense of neuronal propagation. Despite those efforts, the molecular functions of CIC in brain development and tumorigenesis remain poorly understood.
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