Abstract: Mutations in the RNA helicase DDX3X are associated with a wide range of developmental deficits and brain malformations and account for 1-3% of Intellectual disability (ID) cases in females. Interestingly, expression of DDX3X mutants induces stress granule-like complexes, an RNA-protein assembly associated with neurological diseases. Our preliminary data indicate DDX3X regulates neural progenitor proliferation and their propensity to form neurons. However, the distinct requirements for DDX3X in neural progenitors and neurons have not been characterized nor the mechanisms by which ID-associated DDX3X mutations impair cortical development. Here, we test the hypothesis that DDX3X controls neural progenitor proliferation and fate decisions through regulation of translation and SG dynamics. Aim 1 uses mouse models to define the distinct consequences of Ddx3x depletion in progenitors and neurons during cortical development. Aim 2 employs translation-based assays to understand how DDX3X translational control impacts progenitor proliferation. Aim 3 seeks to characterize the nature of DDX3X ID-mutant granules and the protein interactome of WT DDX3X and ID-mutants. Upon completion, this proposal will enhance our understanding of post-transcriptional RNA regulation required for normal brain development and the mechanism by which aberrations can lead to ID.