The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.
Author | Ambrozkiewicz, Mateusz C |
Author | Borisova, Ekaterina |
Author | Schwark, Manuela |
Author | Ripamonti, Silvia |
Author | Schaub, Theres |
Author | Smorodchenko, Alina |
Author | Weber, A Ioana |
Author | Rhee, Hong Jun |
Author | Altas, Bekir |
Author | Yilmaz, Rüstem |
Author | Mueller, Susanne |
Author | Piepkorn, Lars |
Author | Horan, Stephen T |
Author | Straussberg, Rachel |
Author | Zaqout, Sami |
Author | Jahn, Olaf |
Author | Dere, Ekrem |
Author | Rosário, Marta |
Author | Boehm-Sturm, Philipp |
Author | Borck, Guntram |
Author | Willig, Katrin I |
Author | Rhee, JeongSeop |
Author | Tarabykin, Victor |
Author | Kawabe, Hiroshi |
Available date | 2020-12-24T08:15:01Z |
Publication Date | 2020-04-01 |
Publication Name | Molecular Psychiatry |
Identifier | http://dx.doi.org/10.1038/s41380-020-0714-8 |
Citation | Ambrozkiewicz, M.C., Borisova, E., Schwark, M. et al. The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0714-8 |
ISSN | 1359-4184 |
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. |
Sponsor | This work was supported by the German Research Foundation (SPP1365/KA3423/1-1 and KA3423/3-1, HK; DFG TA 303/4-2, VT), and the Russian Scientific Foundation (19-14-00345, VT), JSPS KAKENHI Grant Numbers 15K21769 (HK), The Mother and Child Health Foundation (HK), the Uehara Memorial Foundation (HK), and the Fritz Thyssen Foundation (HK). Funding to SM and PBS was provided by the German Federal Ministry of Education and Research (BMBF, Center for Stroke Research Berlin 01EO1301), the BMBF under the ERA-NET NEURON scheme (01EW1811), and the German Research Foundation (DFG, Project 428869206 and EXC NeuroCure). |
Language | en |
Publisher | Springer Nature |
Subject | Kaufman oculocerebrofacial syndrome Ube3b synapse |
Type | Article |
ESSN | 1476-5578 |
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