Völker Linus A, Maar Barbara A, Pulido Guevara Barbara A, Bilkei-Gorzo Andras, Zimmer Andreas, Brönneke Hella, Dafinger Claudia, Bertsch Sabine, Wagener Jan-Robin, Schweizer Heiko, Schermer Bernhard, Benzing Thomas, Hoehne Martin
Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Institute of Molecular Psychiatry, Medical Faculty of the University of Bonn, Bonn, Germany.
Genes Brain Behav. 2018 Nov;17(8):e12516. doi: 10.1111/gbb.12516. Epub 2018 Sep 14.
Adhesion molecules of the immunoglobulin superfamily (IgSF) are essential for neuronal synapse development across evolution and control various aspects of synapse formation and maturation. Neph2, also known as Kirrel3, is an IgSF adhesion molecule implicated in synapse formation, synaptic transmission and ultrastructure. In humans, defects in the NEPH2 gene have been associated with neurodevelopmental disorders such as Jacobsen syndrome, intellectual disability, and autism-spectrum disorders. However, the precise role in development and function of the nervous system is still unclear. Here, we present the histomorphological and phenotypical analysis of a constitutive Neph2-knockout mouse line. Knockout mice display defects in auditory sensory processing, motor skills, and hyperactivity in the home-cage analysis. Olfactory, memory and metabolic testing did not differ from controls. Despite the wide-spread expression of Neph2 in various brain areas, no gross anatomic defects could be observed. Neph2 protein could be located at the cerebellar pinceaux. It interacted with the pinceau core component neurofascin and other synaptic proteins thus suggesting a possible role in cerebellar synapse formation and circuit assembly. Our results suggest that Neph2/Kirrel3 acts on the synaptic ultrastructural level and neuronal wiring rather than on ontogenetic events affecting macroscopic structure. Neph2-knockout mice may provide a valuable rodent model for research on autism spectrum diseases and neurodevelopmental disorders.
免疫球蛋白超家族（IgSF）的黏附分子对于整个进化过程中的神经元突触发育至关重要，并控制突触形成和成熟的各个方面。Neph2，也称为Kirrel3，是一种与突触形成、突触传递和超微结构有关的IgSF黏附分子。在人类中，NEPH2基因缺陷与诸如雅各布森综合征、智力障碍和自闭症谱系障碍等神经发育障碍有关。然而，其在神经系统发育和功能中的精确作用仍不清楚。在此，我们展示了一种组成型Neph2基因敲除小鼠品系的组织形态学和表型分析。基因敲除小鼠在听觉感觉处理、运动技能方面存在缺陷，并且在笼内分析中表现出多动。嗅觉、记忆和代谢测试与对照组无差异。尽管Neph2在各个脑区广泛表达，但未观察到明显的解剖学缺陷。Neph2蛋白可定位于小脑夹钳。它与夹钳核心成分神经束蛋白和其他突触蛋白相互作用，因此提示其在小脑突触形成和回路组装中可能发挥作用。我们的结果表明，Neph2/Kirrel3作用于突触超微结构水平和神经元连接，而非影响宏观结构的个体发生事件。Neph2基因敲除小鼠可能为自闭症谱系疾病和神经发育障碍的研究提供有价值的啮齿动物模型。
