Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.
International Max Planck Research School for Neurosciences, Georg-August-Universität Göttingen, Griesebachstr. 5, 37077, Göttingen, Germany.
Mol Psychiatry. 2021 Jun;26(6):1980-1995. doi: 10.1038/s41380-020-0714-8. Epub 2020 Apr 6.
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.
考夫曼眼脑面综合征（KOS）是一种严重的常染色体隐性疾病，其特征为智力障碍、发育迟缓、小头畸形和特征性的发育异常。UBE3B 基因的双等位基因突变，该基因编码一种泛素连接酶 E3B，是 KOS 的致病原因。在本报告中，我们描述了其鼠类同源物 Ube3b 的神经元功能，并表明 Ube3b 以细胞自主的方式调节树突分支。此外，Ube3b 敲除（KO）神经元表现出树突棘密度增加和形态异常、突触生理学改变以及海马回路活动变化。背侧前脑特异性 Ube3b KO 动物表现出空间学习能力受损、社交互动改变和重复行为。我们进一步证明 Ube3b 泛素化钙调神经磷酸酶的催化 γ 亚基 Ppp3cc，其过表达在树突棘密度方面模拟了 Ube3b 的缺失。这项工作为基因工程小鼠模型中智力障碍样表型的分子病理学提供了见解。
