DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1
DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1
复制标题
DOI：
10.1093/hmg/ddl407
复制
发表时间：
2006-11-15
影响因子：
3.5
通讯作者：
Sawa, Akira
中科院分区：
文献类型：
--
作者：
Kamiya, Atsushi;Tomoda, Toshifumi;Sawa, Akira
精神分裂症-1中断基因(DISC1)是一种独特的主要精神疾病易感基因，因为它的基因变异与遗传性精神病在苏格兰家系中是分离的。基因关联研究重复地表明，DISC1参与了几个民族的精神分裂症和双相情感障碍。DISC1蛋白是多功能的，在体内，动力蛋白运动复合体中的DISC1池对于PC12细胞的轴突生长以及发育中的大脑皮层中适当的神经元迁移和树突分枝是必要的。在这里，我们证明了DISC1和核分布元件样蛋白(NDEL1/Nudel)之间的特定相互作用对于分化PC12细胞的轴突生长是必要的。在动力蛋白运动复合体的几个成分中，DISC1和NDEL1在PC12细胞分化的突起生长过程中选择性上调。DISC1的NDEL1结合位点被缩小到外显子13的一小部分，对应于DISC1的802-835个氨基酸。我们证明了位于NDEL1结合位点附近的DISC1的遗传变异影响了DISC1和NDEL1之间的相互作用。
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.