Department of Physiology and Cellular Biophysics, Columbia University, 630 West, 168th Street, New York, NY 10032, USA.
Mol Cell Neurosci. 2013 May;54:84-92. doi: 10.1016/j.mcn.2013.01.006. Epub 2013 Feb 6.
A balanced chromosomal translocation segregating with schizophrenia and affective disorders in a large Scottish family disrupting DISC1 implicated this gene as a susceptibility gene for major mental illness. Here we study neurons derived from a genetically engineered mouse strain with a truncating lesion disrupting the endogenous Disc1 ortholog. We provide a detailed account of the consequences of this mutation on axonal and dendritic morphogenesis as well as dendritic spine development in cultured hippocampal and cortical neurons. We show that the mutation has distinct effects on these two types of neurons, supporting a cell-type specific role of Disc1 in establishing structural connections among neurons. Moreover, using a validated antibody we provide evidence indicating that Disc1 localizes primarily to Golgi apparatus-related vesicles. Our results support the notion that in vitro cultures derived from Disc1(Tm1Kara) mice provide a valuable model for future mechanistic analysis of the cellular and biochemical effects of this mutation, and can thus serve as a platform for drug discovery efforts.
一个平衡的染色体易位与苏格兰大家庭中的精神分裂症和情感障碍分离，该易位使 DISC1 基因受到干扰，表明该基因是导致主要精神疾病的易感基因。在这里，我们研究了一种基因工程小鼠品系衍生的神经元，该品系的截断性病变破坏了内源性 Disc1 同源物。我们详细描述了这种突变对培养的海马和皮质神经元中的轴突和树突形态发生以及树突棘发育的影响。我们表明，该突变对这两种类型的神经元具有不同的影响，支持 Disc1 在神经元之间建立结构连接中的细胞类型特异性作用。此外，使用经过验证的抗体，我们提供了证据表明 Disc1 主要定位于与高尔基体相关的囊泡。我们的结果支持这样一种观点，即源自 Disc1(Tm1Kara) 小鼠的体外培养物为该突变的细胞和生化效应的未来机制分析提供了有价值的模型，因此可以作为药物发现工作的平台。
