A Goldilocks Effect for Ube3a in Regulating Social Behavior Via Altered Gene Expression in Idic15 Autism and Angelman Syndrome

Background: Increases of Ube3a gene dosage cause autism (maternal isodicentric chromosome 15 [idic15], maternal Ube3a triplication), while maternal Ube3a loss causes Angelman syndrome. In mature neurons, Ube3a is expressed exclusively from the maternal allele. In neurons, paternal Ube3aexpression is repressed. Ube3a acts as an E3 ubiquitin ligase but also, independently, as a transcriptional co-activator.

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.