The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

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.

• Authors: Mateusz C Ambrozkiewicz, Ekaterina Borisova, Manuela Schwark, Silvia Ripamonti, Theres Schaub, Alina Smorodchenko, A Ioana Weber, Hong Jun Rhee, Bekir Altas, Rüstem Yilmaz, Susanne Mueller, Lars Piepkorn, Stephen T Horan, Rachel Straussberg, Sami Zaqout, Olaf Jahn, Ekrem Dere, Marta Rosário, Philipp Boehm-Sturm, Guntram Borck, Katrin I Willig, JeongSeop Rhee, Victor Tarabykin, Hiroshi Kawabe
• Journal: Molecular psychiatry (Mol Psychiatry) Vol. 26 Issue 6 Pg. 1980-1995 (06 2021) ISSN: 1476-5578 [Electronic] England
• PMID: 32249816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020. The Author(s), under exclusive licence to Springer Nature Limited.

Chemical References

• Ubiquitin-Protein Ligases
• Calcineurin

Topics

• Animals
• Calcineurin
• Dendritic Spines
• Eye Abnormalities
• Facies
• Intellectual Disability (genetics)
• Limb Deformities, Congenital
• Mice
• Mice, Knockout
• Microcephaly (genetics)
• Mutation (genetics)
• Synapses
• Ubiquitin-Protein Ligases (genetics)