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Published on: May 12, 2015
KIF5C deficiency causes abnormal cortical neuronal migration, dendritic branching, and spine morphology in mice
Wanxing Li1, Tianling Cheng2, Xinran Dong3
1Division of Neonatology, Children's Hospital of Fudan University, 201102, Shanghai, People's Republic of China.
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.
Insights
KIF5C gene mutations cause early-onset malformations of cortical development (MCD). KIF5C deficiency disrupts neuronal migration and development, offering insights into MCD pathogenesis.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Malformations of cortical development (MCD) are common causes of neurodevelopmental delay and epilepsy.
- KIF5C mutations are increasingly linked to early-onset MCD, but mechanisms are unclear.
Purpose of the Study:
- To investigate the role of KIF5C in early cortical development.
- To elucidate the molecular mechanisms underlying KIF5C mutation-related MCD.
Main Methods:
- Examined KIF5C expression in mouse and human cortical neurons and organoids.
- Assessed neuronal migration, dendritic branching, and spine growth after KIF5C knockdown in vitro and in vivo.
- Performed RNA sequencing to analyze transcriptome changes post-KIF5C knockdown.
Main Results:
- High KIF5C expression observed in developing neurons.
- KIF5C deficiency impaired cortical neuronal migration, dendritic branching, and spine growth.
- KIF5C knockdown altered expression of genes critical for cortical development.
Conclusions:
- KIF5C plays a crucial role in mammalian cortical development.
- KIF5C deficiency contributes to MCD through aberrant neuronal development.
- Findings provide new perspectives on the pathology of kinesin-related MCD.
