Aberrant cortical development is driven by impaired cell cycle and translational control in aDDX3Xsyndrome model

Mutations in the RNA helicase,DDX3X, are a leading cause of Intellectual Disability and present asDDX3Xsyndrome, a neurodevelopmental disorder associated with cortical malformations and autism. Yet the cellular and molecular mechanisms by whichDDX3Xcontrols cortical development are largely unknown. Here, using a mouse model ofDdx3xloss-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 highly sensitive toDdx3xdosage; CompleteDdx3xloss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition,Ddx3xloss is sexually dimorphic, as its paralog,Ddx3y,compensates forDdx3xin 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 profilingin vivoto 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 ofDDX3Xsyndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.