Madencioglu Deniz A, Çalışkan Gürsel, Yuanxiang Pingan, Rehberg Kati, Demiray Yunus E, Kul Emre, Engler Alexander, Hayani Hussam, Bergado-Acosta Jorge R, Kummer Anne, Müller Iris, Song Inseon, Dityatev Alexander, Kähne Thilo, Kreutz Michael R, Stork Oliver
Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
Center for Behavioral Brain Sciences, 39102Magdeburg, Germany.
iScience. 2021 Jul 19;24(8):102868. doi: 10.1016/j.isci.2021.102868. eCollection 2021 Aug 20.
Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification.
短染色体片段的重复和缺失越来越被认为是罕见神经发育疾病的病因。该基因编码一种对神经元发育很重要的蛋白激酶，是12号染色体上一个与智力残疾、自闭症和癫痫相关的微重复区域的一部分。我们构建了一种条件性转基因小鼠，其迁移后前脑神经元中的Ndr2表达增加，以研究这种河马通路激酶基因剂量增加对脑回路和认知功能的影响。我们的分析显示，海马苔藓纤维的终末区域和突触传递减少，海马网络活动改变，以及苔藓纤维依赖行为存在缺陷。双皮质素表达降低和蛋白质相互作用组分析表明，转基因Ndr2干扰了齿状回颗粒细胞的成熟。总之，我们的数据表明，Ndr2表达增加可能在基因扩增时对智力残疾的发展起关键作用。
