Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan.
Hum Mol Genet. 2011 Dec 1;20(23):4666-83. doi: 10.1093/hmg/ddr400. Epub 2011 Sep 8.
Disrupted-In-Schizophrenia 1 (DISC1) is a promising candidate gene for susceptibility to psychiatric disorders, including schizophrenia. DISC1 appears to be involved in neurogenesis, neuronal migration, axon/dendrite formation and synapse formation; during these processes, DISC1 acts as a scaffold protein by interacting with various partners. However, the lack of Disc1 knockout mice and a well-characterized antibody to DISC1 has made it difficult to determine the exact role of DISC1 in vivo. In this study, we generated mice lacking exons 2 and 3 of the Disc1 gene and prepared specific antibodies to the N- and C-termini of DISC1. The Disc1 mutant mice are viable and fertile, and no gross phenotypes, such as disorganization of the brain's cytoarchitecture, were observed. Western blot analysis revealed that the DISC1-specific antibodies recognize a protein with an apparent molecular mass of ~100 kDa in brain extracts from wild-type mice but not in brain extracts from DISC1 mutant mice. Immunochemical studies demonstrated that DISC1 is mainly localized to the vicinity of the Golgi apparatus in hippocampal neurons and astrocytes. A deficiency of full-length Disc1 induced a threshold shift in the induction of long-term potentiation in the dentate gyrus. The Disc1 mutant mice displayed abnormal emotional behavior as assessed by the elevated plus-maze and cliff-avoidance tests, thereby suggesting that a deficiency of full-length DISC1 may result in lower anxiety and/or higher impulsivity. Based on these results, we suggest that full-length Disc1-deficient mice and DISC1-specific antibodies are powerful tools for dissecting the pathophysiological functions of DISC1.
精神分裂症相关蛋白 1（DISC1）是一种有希望的精神疾病易感性候选基因，包括精神分裂症。DISC1 似乎参与神经发生、神经元迁移、轴突/树突形成和突触形成；在这些过程中，DISC1 通过与各种伴侣相互作用充当支架蛋白。然而，缺乏 Disc1 基因敲除小鼠和特征明确的 DISC1 抗体使得难以确定 DISC1 在体内的确切作用。在这项研究中，我们生成了缺乏 Disc1 基因外显子 2 和 3 的小鼠，并制备了针对 DISC1 的 N-和 C-末端的特异性抗体。Disc1 突变小鼠具有活力和繁殖力，没有观察到大脑细胞结构紊乱等明显的表型。Western blot 分析显示，DISC1 特异性抗体可识别野生型小鼠脑提取物中一种表观分子量约为 100 kDa 的蛋白，但不能识别 Disc1 突变小鼠脑提取物中的蛋白。免疫化学研究表明，DISC1 主要定位于海马神经元和星形胶质细胞的高尔基体附近。全长 Disc1 的缺失会导致齿状回长时程增强诱导的阈值偏移。Disc1 突变小鼠在高架十字迷宫和悬崖回避测试中表现出异常的情绪行为，这表明全长 DISC1 的缺失可能导致较低的焦虑和/或较高的冲动性。基于这些结果，我们认为全长 Disc1 缺失小鼠和 DISC1 特异性抗体是解析 DISC1 病理生理功能的有力工具。
