A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development
A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development
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DOI：
10.1038/ncb1328
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发表时间：
2005-12-01
影响因子：
21.3
通讯作者：
Sawa, A
中科院分区：
文献类型：
--
作者：
Kamiya, A;Kubo, K;Sawa, A
精神分裂蛋白1 (DISC1)，最初在染色体易位的断点上被发现，与一种罕见的家族性精神分裂症有关，在其他人群中也与精神分裂症有遗传关系。精神分裂症涉及神经发育过程中出现的微妙的细胞结构异常，但潜在的分子机制尚不清楚。在这里，我们证明了DISC1是微管相关动力蛋白运动复合物的一个组成部分，对于维持中心体的复合物至关重要，因此有助于正常的微管动力学。羧基末端截断突变体DISC1 （mutDISC1）是由染色体易位引起的，通过自结合和DISC1-动力蛋白复合物从中心体分离，以显性负性方式重新分配野生型DISC1。因此，内源性DISC1的缺失或mutDISC1的表达都会在体外损害神经突的生长和体内大脑皮层的正常发育。这些结果表明，DISC1参与大脑皮层发育，并提示DISC1功能的丧失可能是精神分裂症神经发育障碍的基础。
Disrupted-In-Schizophrenia-1 (DISC1), originally identified at the breakpoint of a chromosomal translocation that is linked to a rare familial schizophrenia, has been genetically implicated in schizophrenia in other populations. Schizophrenia involves subtle cytoarchitectural abnormalities that arise during neurodevelopment, but the underlying molecular mechanisms are unclear. Here, we demonstrate that DISC1 is a component of the microtubule-associated dynein motor complex and is essential for maintaining the complex at the centrosome, hence contributing to normal microtubular dynamics. Carboxy-terminal-truncated mutant DISC1 (mutDISC1), which results from a chromosomal translocation, functions in a dominant-negative manner by redistributing wildtype DISC1 through self-association and by dissociating the DISC1-dynein complex from the centrosome. Consequently, either depletion of endogenous DISC1 or expression of mutDISC1 impairs neurite outgrowth in vitro and proper development of the cerebral cortex in vivo. These results indicate that DISC1 is involved in cerebral cortex development, and suggest that loss of DISCI function may underlie neurodevelopmental dysfunction in schizophrenia.