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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.

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Fig. 1: Ube3b is expressed in developing and mature murine central nervous system and associates with postsynaptic densities.
Fig. 2: Ube3b loss in neurons leads to dramatic impairment of neurite branching.
Fig. 3: Ube3b deletion in neurons induces morphological aberrances in dendritic spines in vivo.
Fig. 4: Synaptic transmission is altered in Ube3b cKO autaptic neurons.
Fig. 5: Ube3b cKO male mice show loss of spatial memory and increased sociability.
Fig. 6: Proteomic screen identifies Ppp3cc as a Ube3b substrate.

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Acknowledgements

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). We would like to acknowledge Nils Brose for his help with project administration and insightful remarks regarding the conceptualization. We thank Fritz Benseler, Klaus-Peter Hellman, Bernd Hesse-Niessen, Ivonne Thanhäuser, Dayana Warnecke, Christiane Harenberg, Maik Schlieper, Dörte Hesse, Stefan Paul Koch, Jutta Schüler, Olaf Ninnemann, Claudia Pallasch, Rike Dannenberg, and Denis Lajkó and animal facilities of Max Planck Institute of Experimental Medicine and of Charité University Hospital. We acknowledge Alex Knebel, Thimo Kurz, Carlos Henrique Vieira e Vieira, Matthias Selbach, Hannelore Ehrenreich, Ahmed Mansouri, and Judith Stegmüller for their feedback.

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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 26, 1980–1995 (2021). https://doi.org/10.1038/s41380-020-0714-8

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