KIF5C deficiency causes abnormal cortical neuronal migration, dendritic branching, and spine morphology in mice.

Abstract

Listen

Translate article

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. 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. 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. These results suggested a critical role for Kif5c in cortical development, providing insights into underlying pathogenic factors of kinesins in MCD. 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.