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Mutations in the RNA helicase,  DDX3X , are a leading cause of Intellectual Disability and present as  DDX3X  syndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet, the cellular and molecular mechanisms by which DDX3X controls cortical development are largely unknown. Here, using a mouse model of  Ddx3x  loss-of-function we demonstrate that DDX3X directs translational and cell cycle control of neural progenitors, which underlies precise corticogenesis. First, we show brain development is sensitive to  Ddx3x  dosage; complete  Ddx3x  loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition,  Ddx3x  loss is sexually dimorphic, as its paralog,  Ddx3y , compensates for  Ddx3x  in the developing male neocortex. Using live imaging of progenitors, we show that DDX3X promotes neuronal generation by regulating both cell cycle duration and neurogenic divisions. Finally, we use ribosome profiling  in vivo  to discover the repertoire of translated transcripts in neural progenitors, including those which are DDX3X-dependent and essential for neurogenesis. Our study reveals invaluable new insights into the etiology of  DDX3X  syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.

Aberrant cortical development is driven by impaired cell cycle and translational control in a DDX3X syndrome model