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Exploring the Neurodevelopmental Bases of DDX3X Syndrome

Poster Presentation
Friday, May 3, 2019: 11:30 AM-1:30 PM
Room: 710 (Palais des congres de Montreal)
D. Ung1,2,3, A. Boitnott1,2,3, D. Mendonca1,2,3, K. Niblo1,2 and S. De Rubeis1,2,3, (1)Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, (2)Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, (3)Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
Background:

DDX3X syndrome is a recently identified rare genetic disorder associated with autism spectrum disorder (ASD) and intellectual disability (ID). Affected individuals present with ID, behavioral problems including ASD, low body weight, movement disorder, hypotonia and brain anomalies such as cortical malformations. DDX3X syndrome is caused by mutations in the X-linked gene DDX3X and most patients are females with de novo mutations. DDX3X is a RNA helicase and it has been studied in non-neuronal cells, where it has been found to regulate mRNA translation. Local mRNA translation at synapses is essential for learning and memory and is altered in mouse models for ASD and/ID. To date, the exact functions of DDX3X in neurons and at synapses are poorly known.

Objectives: The objective of the study is to understanding the molecular and cellular functions of DDX3X during neurodevelopment, particularly corticogenesis and synaptogenesis.

Methods:

We have generated a novel conditional knockout mouse recapitulating DDX3X deficiency. To study the effect of DDX3X deficiency on corticogenesis, we study cortical lamination with layer-specific markers. To dissect the molecular complexes and mechanisms mediating DDX3X-dependent translation, we apply biochemical methods to purified synapses (synaptosomes) from mouse cortices.To study synaptogenesis, we use the novel mouse model we have generated to assess synapse morphology and density in single-embryo mouse neuronal cultures modeling the genetics of DDX3X syndrome.

Results: We found that Ddx3xnull male mice (Ddx3x-/y) die in utero, compatible with the dearth of boys affected by DDX3X syndrome. Ddx3x-deficient females (Ddx3x+/-) are viable and have reduced DDX3X protein expression in the cortex compared to control littermate. DDX3X is expressed at synapses from cortex at a critical window for synaptogenesis and expression is sex-specific. DDX3X is also expressed in glutamatergic projection neurons in the developing cortex and we are beginning to characterize cortical connections in Ddx3x-deficient mice.

Conclusions:

We have generated a mouse model with construct validity for DDX3X syndrome that shows initial evidence for face validity. We are using this model to understand the molecular and cellular neurobiology underlying DDX3X syndrome.

See more of: Molecular Neuroscience
See more of: Molecular Neuroscience