PT  - JOURNAL ARTICLE
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
TI  - Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome
AID  - 10.1101/2021.01.22.427482
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.22.427482
4099  - http://biorxiv.org/content/early/2021/02/08/2021.01.22.427482.short
4100  - http://biorxiv.org/content/early/2021/02/08/2021.01.22.427482.full
AB  - 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.