| Autor: |
Ambrozkiewicz, Mateusz C., Borisova, Ekaterina, Schwark, Manuela, Ripamonti, Silvia, Schaub, Theres, Smorodchenko, Alina, Weber, A. Ioana, Rhee, Hong Jun, Altas, Bekir, Yilmaz, Rüstem, Mueller, Susanne, Piepkorn, Lars, Horan, Stephen T., Straussberg, Rachel, Zaqout, Sami, Jahn, Olaf, Dere, Ekrem, Rosário, Marta, Boehm-Sturm, Philipp, Borck, Guntram, Willig, Katrin I., Rhee, JeongSeop, Tarabykin, Victor, Kawabe, Hiroshi |
| Zdroj: |
Molecular Psychiatry; June 2021, Vol. 26 Issue: 6 p1980-1995, 16p |
| Abstrakt: |
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 Ube3band show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3bknockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3bKO 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 Ube3bloss 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. |
| Databáze: |
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