The deficiency of KIF2C leads to abnormal distribution of cortical neurons and behavioral deficits in mice.

The microtubule-depolymerizing kinesin family member 2C (KIF2C) is highly expressed in neurological tumors and has been implicated in central nervous system (CNS) and psychiatric conditions, but its functions in the CNS remain unclear. To investigate the role of KIF2C in vivo, we generated global Kif2c knockout mice. Kif2c knockout leads to cortical structural abnormalities, selective reduction of deep-layer TBR1 immunoreactivity, and impairments in motor coordination and spatial learning. Single-cell RNA sequencing reveals altered deep-layer neuronal composition, marked by decreased layer 5 intratelencephalic neurons and a relative increase in extratelencephalic projection neurons. Furthermore, Kif2c deficiency drives disorganization of synapse-related gene expression and correlates with widespread expression changes in key developmental signaling pathways. Overall, this study indicates that KIF2C may regulate microtubule dynamics to control deep-layer cortical neuron number and organization and modulate neuronal projections and signaling pathways. This work provides a foundation for understanding the role of KIF2C in neural development.