CIC is a critical regulator of neuronal differentiation
Inah Hwang,, Heng Pan,, Jun Yao, Olivier Elemento,, Hongwu Zheng,, Jihye Paik
Inah Hwang,, Heng Pan,, Jun Yao, Olivier Elemento,, Hongwu Zheng,, Jihye Paik
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Research Article Oncology Stem cells

CIC is a critical regulator of neuronal differentiation

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.

Authors

Inah Hwang,, Heng Pan,, Jun Yao, Olivier Elemento,, Hongwu Zheng,, Jihye Paik

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Figure 4

Aberrant expression of VGF compromises neurogenesis in CIC-deficient brains.

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Aberrant expression of VGF compromises neurogenesis in CIC-deficient bra...
(A) Biological replicates of CIC ChIP-seq tracks at Vgf promoter regions. (B) WB analysis in P0.5 brains of CicWT and CicKO mouse. SE, short exposure; LE, long exposure. The blots were run on same gel. Mean ± SEM of 3 experimental animals. (C) IF analysis for VGF in the P14 brains of CicWT and CicKO. Scale bar: 100 μm. (D) WB analysis for VGF in NTKD NPC and CicKD NPC during differentiation. The blots were run on same gel. (E) IF analysis for Flag, VGF, NeuN, and BrdU in VGF-Flag–expressed NPC (VGF-F) and control NPC (con) at 7 days of differentiation. Scale bar: 50 μm. (F) Quantitations for NeuN+ or BrdU+ numbers are plotted. Mean ± SEM of 100 DAPI+ nuclei from 3 experiments. (G) WB analysis for indicated proteins in control NPC and VGF-F NPC at 5 days of differentiation. (H) WB analysis for indicated proteins in NTKD NPC and CicKD NPC at 4 days of differentiation. sg-NT, nontargeted control single-guide RNA. For G and H, samples were run on 2 gels, and the representative ACTB blot is shown. (I) IF analysis for NEUN in NTKD NPC and CicKD NPC at 7 days of differentiation. (J) Quantifications for images from I are plotted. Mean ± SEM of 100 DAPI+ nuclei from 3 experiments. Statistical significance was determined by unpaired t test for B and F and 1-way ANOVA for J. *** P < 0.001. For C, D, E, G, H, and I, 3 experiments were conducted, and each representative result is shown.