Sex-specific perturbations of neuronal development caused by mutations in the autism risk gene DDX3X

ABSTRACT DDX3X is an X-linked RNA helicases that escapes X chromosome inactivation and is expressed at higher levels in female brains. Mutations in DDX3X are associated with intellectual disability (ID) and autism spectrum disorder (ASD) and are predominantly identified in females. Using cellular and mouse models, we show that Ddx3x mediates sexual dimorphisms in brain development at a molecular, cellular, and behavioral level. During cortical neuronal development, Ddx3x sustains a female-biased signature of enhanced ribosomal biogenesis and mRNA translation. Female neurons display higher levels of ribosomal proteins and larger nucleoli, and these sex dimorphisms are obliterated by Ddx3x loss. Ddx3x regulates dendritic outgrowth in a sex- and dose-dependent manner in both female and male neurons, and dendritic spine development only in female neurons. Further, ablating Ddx3x conditionally in forebrain neurons is sufficient to yield sex-specific changes in developmental outcomes and motor function. Together, these findings pose Ddx3x as a mediator of sexual differentiation during neurodevelopment and open new avenues to understand sex differences in health and disease.