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 in neural cells induces ribonucleoprotein (RNP) granules, which are RNA-protein assemblies 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 that DDX3X-ID mutants impair RNP interactions.  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 identify key DDX3X translational targets relevant for progenitor proliferation.  Aim 3 characterizes 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 RNA regulation required for normal brain development and the mechanism by which aberrations can lead to ID.