Deletion of CHD8 in cerebellar granule neuron progenitors leads to severe cerebellar hypoplasia,ataxia, and psychiatric behavior in mice |
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| Institution: | 1. Departments of Neonatology, Children''s Hospital of Fudan University, National Children''s Medical Center, Shanghai 201102, China;2. Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;3. Key Laboratory of Birth Defects, Children''s Hospital of Fudan University, National Children''s Medical Center, Shanghai 201102, China;4. Department of Biostatistics, School of Public Health, Fudan University, Shanghai 200032, China;5. Department of Obstetrics, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200090, China;6. Stem Cell Center, Children''s Hospital of Fudan University, Shanghai 201102, China;7. MOE Frontiers Center for Brain Science, Fudan University, Shanghai 201102, China;1. Key Laboratory of Soybean Molecular Design Breeding, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Harbin, Heilongjiang 150081, China;2. University of Chinese Academy of Sciences, Beijing 100049, China;3. College of Agriculture, Northeast Agricultural University, Harbin, Heilongjiang 150030, China;4. College of Life Sciences, Jiangxi Normal University, Nanchang, Jiangxi 330022, China;1. Department of Life Science and Medical Bio-Science, Waseda University, Shinjuku-ku, Tokyo 162-8480 Japan;2. Biomolecular Science Center, University of Central Florida, Biomolecular Science, Orlando, FL 32816, USA;3. Department of Molecular Pharmacology and Neurobiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan;1. Department of Neonatology, Children''s Hospital of Fudan University, National Children''s Medical Center, Shanghai, China;2. Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children’s Hospital of Fudan University, National Children''s Medical Center, Shanghai, China;3. Department of Rehabilitation, Children''s Hospital of Fudan University, National Children''s Medical Center, Shanghai, China;4. Key Laboratory of Birth Defects, Children''s Hospital of Fudan University, National Children''s Medical Center, Shanghai, China |
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| 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. |
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| Keywords: | Cerebellum Granule neuron CHD8 Autism spectrum disorder |
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