KCTD10 regulates brain development by destabilizing brain disorder-associated protein KCTD13

• 成果类型: Article
• 署名作者: Cheng, Jianbo; Wang, Zhen; Tang, Manpei; Zhang, Wen; Li, Guozhong; Tan, Senwei; Mu, Chenjun; Hu, Mengyuan; Zhang, Dan; Jia, Xiangbin; Wen, Yangxuan; Guo, Hui; Xu, Dan; Liu, Liang; Li, Jiada; Xia, Kun; Li, Faxiang; Duan, Ranhui; Xu, Zhiheng; Yuan, Ling
• 署名单位: Central South University; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Institute of Genetics & Developmental Biology, CAS; Central South University; Fujian Medical University; Capital Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9135
• DOI: 10.1073/pnas.2315707121
• 发表日期: 2024-03-15
• 关键词: progressive myoclonus epilepsy; channel-related gene; neuronal migration; spectrum; Mutation; cytoskeleton; arise

摘要

KCTD10 belongs to the KCTD (potassiumchannel tetramerization domain) family, many members of which are associated with neuropsychiatric disorders. However, the biological function underlying the association with brain disorders remains to be explored. Here, we reveal that Kctd10 is highly expressed in neuronal progenitors and layer V neurons throughout brain development. Kctd10 deficiency triggers abnormal proliferation and differentiation of neuronal progenitors, reduced deep - layer (especially layer V) neurons, increased upper - layer neurons, and lowered brain size. Mechanistically, we screened and identified a unique KCTD10-interacting protein, KCTD13, associated with neurodevelopmental disorders. KCTD10 mediated the ubiquitination- dependent degradation of KCTD13 and KCTD10 ablation resulted in a considerable increase of KCTD13 expression in the developing cortex. KCTD13 overexpression in neuronal progenitors led to reduced proliferation and abnormal cell distribution, mirroring KCTD10 deficiency. Notably, mice with brain- specific Kctd10 knockout exhibited obvious motor deficits. This study uncovers the physiological function of KCTD10 and provides unique insights into the pathogenesis of neurodevelopmental disorders.