MELK is Required for G2/M Phase Progression in Cortical Progenitors: Insights from Rare ASD-Associated Variants

Maternal embryonic leucine zipper kinase (MELK) is a cell cycle regulator, yet its role in embryonic cortical development remains unclear. We identified ultra-rare, predicted loss-of-function MELK variants in ASD individuals, prompting this functional investigation. Published human single-cell transcriptomics showed that MELK expression is enriched in neural progenitors and correlates with the G2/M phase. Using in utero electroporation in mouse cortex, we found that Melk knockdown reduced the proportion of progenitors in G2/M phase. Knockdown also caused impaired multipolar-to-bipolar transition and shorter leading processes. Complementing these findings, transcriptomic analysis of FACS-sorted Melk-knockdown cortical cells revealed downregulation of G2/M-related genes and cytoskeletal regulators linked to neuronal morphogenesis. Together, these findings identify MELK as a critical regulator of both G2/M phase progression and neuronal morphogenesis during cortical development, providing a mechanistic link to neurodevelopmental conditions.