Kamiya Atsushi, Tomoda Toshifumi, Chang Jennifer, Takaki Manabu, Zhan Caixin, Morita Masahiko, Cascio Matthew B, Elashvili Sarah, Koizumi Hiroyuki, Takanezawa Yasukazu, Dickerson Faith, Yolken Robert, Arai Hiroyuki, Sawa Akira
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hum Mol Genet. 2006 Nov 15;15(22):3313-23. doi: 10.1093/hmg/ddl407. Epub 2006 Oct 11.
Disrupted-In-Schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, because of the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1, proximal to the NDEL1 binding site, affect the interaction between DISC1 and NDEL1.
精神分裂症断裂基因1（DISC1）是主要精神疾病的一个独特易感基因，这是因为在一个苏格兰家系中其遗传变异与遗传性精神病发生了分离。遗传关联研究反复表明，在多个种族群体中，DISC1与精神分裂症和双相情感障碍均有关联。DISC1蛋白具有多种功能，动力蛋白运动复合体中的一部分DISC1对于PC12细胞中的神经突生长以及体内发育中的大脑皮质中正常的神经元迁移和树突分支形成是必需的。在此，我们表明，在分化的PC12细胞中，神经突生长需要DISC1与核分布元件样蛋白（NDEL1/NUDEL）之间的特异性相互作用。在动力蛋白运动复合体的几个组分中，在PC12细胞分化过程中神经突生长时，DISC1和NDEL1会选择性上调。DISC1的NDEL1结合位点被缩小至第13外显子的一小部分，对应于DISC1的第802 - 835位氨基酸。我们证明，靠近NDEL1结合位点的DISC1遗传变异会影响DISC1与NDEL1之间的相互作用。
