Accurate mitotic division of neural stem cell/progenitor cells (NSPCs) is crucial for the coordinated generation of progenitors and neurons in the developing cortex. Here, we investigated the pivotal role of Kif23, an N-kinesin motor protein, in embryonic mouse NSPCs. We found that Kif23 is highly expressed in the mitotic NSPCs within the embryonic cortex of both mouse and human. Knockdown (KD) of Kif23 led to precocious neurogenesis, attributed to an accelerated cell cycle exit, likely resulting from disrupted mitotic spindle orientation and impaired cytokinesis. Kif23 KD induced upregulation of the γ-H2AX-p53-p21 signaling pathway, ultimately culminating in cytokinetic failure. Additionally, Kif23 depletion perturbed the apical surface structure of NSPCs and disrupted the proper localization of apical junctional proteins. Importantly, we demonstrated the successful rescue of Kif23 KD-induced phenotypes by introducing wild-type human KIF23 , but not by a variant of KIF23 with a microcephaly-associated mutation. Our findings underscore the critical role of Kif23 in cortical development and provide novel insights into the intricate molecular mechanisms underlying pathogenesis of microcephaly.

Graphical abstract