Wanxing Li1, Tianling Cheng2, Xinran Dong3, Huiyao Chen3, Lin Yang4, Zilong Qiu5, Wenhao Zhou6,7,8. 1. Division of Neonatology, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. 2. Institute of Pediatrics, Children's Hospital, Institutes for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, 200032, Shanghai, People's Republic of China. 3. Center for Molecular Medicine of Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. 4. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. 5. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Chinese Academy of Sciences, 200032, Shanghai, People's Republic of China. 6. Division of Neonatology, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. zhouwenhao@fudan.edu.cn. 7. Key Laboratory of Birth Defects, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. zhouwenhao@fudan.edu.cn. 8. Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China. zhouwenhao@fudan.edu.cn.
Abstract
BACKGROUND: Malformation of cortical development (MCD) includes a variety of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. Most recently, clinical studies found that patients carrying KIF5C mutations present early-onset MCD; however, the underlying mechanisms remain elusive. METHODS: KIF5C expression level was examined in mouse primary cortical neurons and human ips-derived forebrain organoids. We studied the cortical neuronal migration, dendritic branching, and dendritic spine growth after knocking down the KIF5C gene by electroporation in vitro and in vivo. Then, we studied the transcriptome differences between the knockdown and control groups through RNA sequencing. RESULTS: We observed high KIF5C expression in neurons during the early developmental stage in mice and the human brain. Kif5c deficiency results in disturbed cortical neuronal migration, dendritic, and spine growth. Finally, we found that Kif5c knockdown affected several genes associated with cortical neuronal development in vitro. CONCLUSIONS: These results suggested a critical role for Kif5c in cortical development, providing insights into underlying pathogenic factors of kinesins in MCD. IMPACT: KIF5C mutation-related MCD might be caused by abnormal early cortical neuronal development. Kif5c deficiency led to abnormal cortical neuronal dendritic and spine growth and neuronal migration. Our findings explain how Kif5c deficiency is involved in the aberrant development of cortical neurons and provide a new perspective for the pathology of MCD.
BACKGROUND: Malformation of cortical development (MCD) includes a variety of developmental disorders that are common causes of neurodevelopmental delay and epilepsy. Most recently, clinical studies found that patients carrying KIF5C mutations present early-onset MCD; however, the underlying mechanisms remain elusive. METHODS: KIF5C expression level was examined in mouse primary cortical neurons and human ips-derived forebrain organoids. We studied the cortical neuronal migration, dendritic branching, and dendritic spine growth after knocking down the KIF5C gene by electroporation in vitro and in vivo. Then, we studied the transcriptome differences between the knockdown and control groups through RNA sequencing. RESULTS: We observed high KIF5C expression in neurons during the early developmental stage in mice and the human brain. Kif5c deficiency results in disturbed cortical neuronal migration, dendritic, and spine growth. Finally, we found that Kif5c knockdown affected several genes associated with cortical neuronal development in vitro. CONCLUSIONS: These results suggested a critical role for Kif5c in cortical development, providing insights into underlying pathogenic factors of kinesins in MCD. IMPACT: KIF5C mutation-related MCD might be caused by abnormal early cortical neuronal development. Kif5c deficiency led to abnormal cortical neuronal dendritic and spine growth and neuronal migration. Our findings explain how Kif5c deficiency is involved in the aberrant development of cortical neurons and provide a new perspective for the pathology of MCD.
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