Aberrant cortical development is driven by impaired cell cycle and translational control in a <i>DDX3X</i> syndrome model.

Abstract

Mutations in the RNA helicase, <i>DDX3X</i>, are a leading cause of Intellectual Disability and present as <i>DDX3X</i> 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 <i>Ddx3x</i> 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 <i>Ddx3x</i> dosage; complete <i>Ddx3x</i> loss from neural progenitors causes microcephaly in females, whereas hemizygous males and heterozygous females show reduced neurogenesis without marked microcephaly. In addition, <i>Ddx3x</i> loss is sexually dimorphic, as its paralog, <i>Ddx3y</i>, compensates for <i>Ddx3x</i> 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 <i>in vivo</i> 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 <i>DDX3X</i> syndrome, implicating dysregulated progenitor cell cycle dynamics and translation as pathogenic mechanisms.