MELK Downregulation in NPCs Disrupts Cortical Neurogenesis via G2/M Dysregulation: Autism Implications

Abstract Maternal Embryonic Leucine Zipper Kinase (MELK) regulates cell cycle progression, but its role in neurodevelopmental disorders is unclear. We identified loss-of-function MELK variants in autism spectrum disorder (ASD) patients, suggesting MELK haploinsufficiency contributes to ASD pathogenesis. Single-cell analysis revealed preferential MELK expression in proliferating neural progenitors during neurodevelopment, correlating with the expression of G2/M-phase regulators. In vivo MELK knockdown induced neuronal mislocalization and premature cell cycle exit without concomitant differentiation. Additionally, MELK deficiency impaired neuronal polarity transition. Our findings establish MELK as a critical regulator of G2/M progression and neuronal maturation during cortical neurogenesis, providing mechanistic insights into ASD etiology.