A Goldilocks Effect for Ube3a in Regulating Social Behavior Via Altered Gene Expression in Idic15 Autism and Angelman Syndrome
Objectives: Whether excess Ube3a in the neuronal synapse, cytoplasm, or nucleus causes autism is unknown. Furthermore, clinically, Idic15-associated autism and Angelman syndrome appear to have diametrically opposite social behavioral features. Can this idea be reinforced through studies of this behavior in mouse models of the disorders?
Methods: To clarify, we engineered a nuclear importing peptide signal to the C-terminus of Ube3a. We also examined the effects of changes in Ube3a gene dosage on transcription and social behavior.
Results: Mice with just a single added copy of nuclear-imported Ube3a displayed the full autism-type behavioral deficits in social interaction and communication generated by two copies of non-targeted Ube3a that models idic15. In contrast, mice with a deleted maternal Ube3a displayed increased social behavior, consistent with the reported increased social laughter, smiling, and interaction of individuals with Angelman syndrome. Ube3adose-dependently altered cortical mRNAs mirroring its effects on social behavior. Direct protein-protein interactions between products of the Ube3a-regulated and all known autism deleted, duplicated, or mutated (missense) genes, identified pivotal Ube3a-regulated genes in an autism protein-interaction network.
Conclusions: By comparing idic15 autism and Angelman, we uncover a Goldilocks effect for Ube3a in controlling cortical gene expression and social behavior. Furthermore, by targeting Ube3a to the nucleus, we link dysregulated gene expression to autism.