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Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation.

ABSTRACT: Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. In vitro cultured neural stem cells derived from Cic conditional knockout mice bypassed an EGF requirement for proliferation and displayed a defect in their potential for oligodendrocyte differentiation. Cic is known to participate in gene suppression that can be relieved by EGFR signal, but we found that cic also activated expression of a broad range of EGFR-independent genes. In an orthotopic mouse model of glioma, we found that Cic loss potentiated the formation and reduced the latency in tumor development. Collectively, our results define an important role for Cic in regulating neural cell proliferation and lineage specification, and suggest mechanistic explanations for how CIC mutations may impact the pathogenesis and therapeutic targeting of oligodendroglioma. Cancer Res; 77(22); 6097-108. ©2017 AACR.

SUBMITTER: Yang R

PROVIDER: S-EPMC5690824 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation.

Yang Rui R Chen Lee H LH Hansen Landon J LJ Carpenter Austin B AB Moure Casey J CJ Liu Heng H Pirozzi Christopher J CJ Diplas Bill H BH Waitkus Matthew S MS Greer Paula K PK Zhu Huishan H McLendon Roger E RE Bigner Darell D DD He Yiping Y Yan Hai H

Cancer research 20170922 22

Inactivating mutations in the transcriptional repression factor Capicua (CIC) occur in approximately 50% of human oligodendrogliomas, but mechanistic links to pathogenesis are unclear. To address this question, we generated Cic-deficient mice and human oligodendroglioma cell models. Genetic deficiency in mice resulted in a partially penetrant embryonic or perinatal lethal phenotype, with the production of an aberrant proliferative neural population in surviving animals. I ...[more]

PMID: 28939681

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Project description:Repetitive transcranial magnetic stimulation (rTMS) is a physical treatment applied during recovery after intracerebral hemorrhage (ICH). With in vivo and in vitro assays, the present study sought to investigate how rTMS influences neural stem cells (NSCs) after ICH and the possible mechanism. Following a collagenase-induced ICH, adult male C57BL/6 J mice were subjected to rTMS treatment every 24 h for 5 days using the following parameters: frequency, 10 Hz; duration, 2 s; wait time, 5.5 s; 960 trains (500 µV/div, 5 ms/div, default setting). Brain water content and neurobehavioral score were assessed at days 1, 3, and 5 after ICH. The proliferation and differentiation of NSCs were observed using immunofluorescence staining for Nestin, Ki-67, DCX, and GFAP on day 3 after ICH, and rTMS treatment with the same parameters was applied to NSCs in vitro. We found that rTMS significantly reduced brain edema and alleviated neural functional deficits. The mice that underwent ICH recovered faster after rTMS treatment, with apparent proliferation and neuronal differentiation of NSCs and attenuation of glial differentiation and GFAP aggregation. Accordingly, proliferation and neuronal differentiation of isolated NSCs were promoted, while glial differentiation was reduced. In addition, microarray analysis, western blotting assays, and calcium imaging were applied to initially investigate the potential mechanism. Bioinformatics showed that the positive effect of rTMS on NSCs after ICH was largely related to the MAPK signaling pathway, which might be a potential hub signaling pathway under the complex effect exerted by rTMS. The results of the microarray data analysis also revealed that Ca2+ might be the connection between physical treatment and the MAPK signaling pathway. These predictions were further identified by western blotting analysis and calcium imaging. Taken together, our findings showed that rTMS after ICH exhibited a restorative effect by enhancing the proliferation and neuronal differentiation of NSCs, potentially through the MAPK signaling pathway.

Dataset Information

Cic Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation.

Publications

<i>Cic</i> Loss Promotes Gliomagenesis via Aberrant Neural Stem Cell Proliferation and Differentiation.

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