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Abstract:
Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual
disability, developmental delays, microcephaly, and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding
for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog
Ube3b and show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO)
neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in
hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning, altered social
interactions, and repetitive behaviors. We further demonstrate that Ube3b ubiquitinates the catalytic γ-subunit of calcineurin,
Ppp3cc, the overexpression of which phenocopies Ube3b loss with regard to dendritic spine density. This work provides
insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetically engineered mouse
model.
