Deletion of <i>CHD8</i> in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia, and psychiatric behavior in mice

Xiang Chen; Tong Chen; Chen Dong; Huiyao Chen; Xinran Dong; Lin Yang; Liyuan Hu; Huijun Wang; Bingbing Wu; Ye Yao; Yu Xiong; Man Xiong; Yifeng Lin; Wenhao Zhou

doi:10.1016/j.jgg.2022.02.011

Volume 49 Issue 9

Sep. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(9): 859-869

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Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia, ataxia, and psychiatric behavior in mice

doi: 10.1016/j.jgg.2022.02.011

a. Departments of Neonatology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China;
b. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
c. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China;
d. Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200032, China;
e. Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China;
f. Stem Cell Center, Children's Hospital of Fudan University, Shanghai 201102, China;
g. MOE Frontiers Center for Brain Science, Fudan University, Shanghai 201102, China

Funds:

We appreciated the patient and the family for their willingness and cooperation in the study. Thanks for the efforts of many colleagues and staff. Thanks for Qing Richard Lu lab (Cincinnati Children's Hospital Medical Center, USA) providing invaluable support for this study. Thanks for support by grants from the Science and Technology Commission of Shanghai Municipality (19411964400, 20ZR1408400), National Natural Science Foundation of China (81741034, 81720108018), Shanghai Municipal Science and Technology Major Project (2018SHZDZX01, 2018SHZDZX05) and ZJLab.

Received Date: 2021-12-02
Accepted Date: 2022-02-16
Rev Recd Date: 2022-02-13
Publish Date: 2022-02-26

Abstract

Abstract

CHD8 is a candidate gene for autism spectrum disorders and neurological development delay. It has been reported to be essential for neurogenesis in the cerebral cortex, but the function of CHD8 in cerebellum has not been comprehensively investigated. The potential relationship of cerebellum dysplasia with psychiatric disorders in patients with CHD8 mutations is still not clear. In this study, we establish different conditional knockout mouse models to investigate the roles of CHD8 in cerebellar development. Mice with neural stem cell-specific Chd8 deletion exhibit significant reduction of cerebellum volume and no layering structure is detected. Genetic deletion of Chd8 in cerebellar granule neuron progenitors (GNPs) leads to cerebellar hypoplasia, absent of proliferation layer and ectopic of Purkinje neuron. However, no substantial cerebellar dysplasia is detected in mice with Purkinje neuron- or oligodendrocyte-specific Chd8 ablation. Single-cell RNA sequencing indicates that ribosome-related genes and pathways are most significantly disrupted in GNPs, indicating the potential mechanism. Importantly, in addition to the ataxia phenotype, mice with GNP-specific Chd8 ablation present a neuropsychiatric phenotype in three-chamber and light/dark tests. Taken together, our results provide insights not only into the function of CHD8 in cerebellar development, but also the pathogenesis of neuropsychiatric disorders in patients with CHD8 mutations.
- Cerebellum,
- Granule neuron,
- CHD8,
- Autism spectrum disorder

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References(66)

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