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CIC is a critical regulator of neuronal differentiation
Inah Hwang,, … , Hongwu Zheng,, Jihye Paik
Inah Hwang,, … , Hongwu Zheng,, Jihye Paik
Published March 31, 2020
Citation Information: JCI Insight. 2020;5(9):e135826. https://doi.org/10.1172/jci.insight.135826.
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Research Article Oncology Stem cells

CIC is a critical regulator of neuronal differentiation

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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 1

Defective cerebral cortex developments in CicKO mouse.

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Defective cerebral cortex developments in CicKO mouse.
(A) The picture (...
(A) The picture (left) and the plot for body weights (right) at P14. Statistical significance was determined by 1-way ANOVA. Mean ± SEM of 4–10 experimental animals. ***P < 0.001. (B) The brains at P14. (C) IF analysis for CIC in the cerebral cortex. Scale bar: 100 μm. (D) H&E staining of CicWT and CicKO brains. Scale bar: 1 mm. For B–D, 3 brains per group were examined, and representative images are shown. (E) Quantification of the thickness cerebral cortex (left) and cerebellar cortex (right) are plotted. Mean ± SEM of 3 experimental animals. (F) GSEA in CicKO versus CicWT brains. Two brains per group were analyzed. (G and H) IF analysis for NeuN, SATB2, and CTIP2 in the cerebral cortex of P14 mouse. Scale bar: 100 μm. (I) Quantifications at layers 2–4 of NeuN+ or SATB2+ and layers 5–6 of CTIP2+ numbers are plotted. Mean ± SEM of 200 DAPI+ nuclei from 3 animals. (J) Measurement the thickness for SATB2+ layers 2–4 and CTIP2+ layers 5–6. Mean ± SEM of 3 images from 3 animals. (K) WB analysis for indicated protein expressions in cerebral cortex lysates. Samples were run on 3 gels, and the most representative ACTB blot is shown. (L) Densitometry analysis of multiple WB in J is plotted. Mean ± SEM of 3 experimental animals. (M) qPCR results of indicated genes in P14 CicKO versus CicWT brains. Mean ± SEM of 5–7 experimental animals. For I, J, L, and M, statistical significance was determined by unpaired t test. ***P < 0.001.

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