TY - JOUR T1 - Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome JF - bioRxiv DO - 10.1101/2021.01.22.427482 SP - 2021.01.22.427482 AU - Andrea Boitnott AU - Dévina C Ung AU - Marta Garcia-Forn AU - Kristi Niblo AU - Danielle Mendonca AU - Michael Flores AU - Sylvia Maxwell AU - Jacob Ellegood AU - Lily R Qiu AU - Dorothy E Grice AU - Jason P Lerch AU - Mladen-Roko Rasin AU - Joseph D Buxbaum AU - Elodie Drapeau AU - Silvia De Rubeis Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/01/23/2021.01.22.427482.abstract N2 - Background Mutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis.Methods We generated a Ddx3x haploinsufficient mouse (Ddx3x+/−) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development.Results Ddx3x+/− mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex.Conclusions These data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.Competing Interest StatementThe authors have declared no competing interest. ER -