DISC1 causes associative memory and neurodevelopmental defects in fruit flies.
DISC1 causes associative memory and neurodevelopmental defects in fruit flies.
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DOI：
10.1038/mp.2016.15
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发表时间：
2016-09
影响因子：
11
通讯作者：
Sawa A
中科院分区：
文献类型：
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作者：
Furukubo-Tokunaga K;Kurita K;Honjo K;Pandey H;Ando T;Takayama K;Arai Y;Mochizuki H;Ando M;Kamiya A;Sawa A
DISC1蛋白最初发现于一个患有多种精神障碍的苏格兰家庭，其特征在于它是一种细胞内支架蛋白，与神经发育中的多种结合伙伴相关。为了探索其在遗传上易于处理的系统中的功能，我们在果蝇（Drosophila melanogaster）中表达了人DISC1。在哺乳动物神经元中，DISC1定位于发育中的果蝇神经元的不同亚细胞结构域，包括细胞核、轴突和树突。DISC1的过度表达会损害联想记忆。用缺失/突变构建体进行的实验已经揭示了氨基末端结构域（46 - 290）对于记忆抑制的重要性，而羧基结构域（598 - 854）和氨基末端残基（1 - 45）（包括核定位信号（NLS 1））是不重要的。DISC1过表达还引起蘑菇体神经元的轴突和树突分支的抑制，其介导果蝇脑中的各种认知功能。缺失结构分析表明，蛋白质结构域598 - 854和349 - 402都是抑制轴突分支所必需的，而包括NLS 1的氨基末端结构域是不稳定的。相反，NLS 1是抑制树突状分支所必需的，这表明了一种涉及基因表达的机制。此外，结构域403 - 596也是抑制树突状分支所必需的。我们还发现，DISC1的过度表达抑制了神经肌肉接头发育中的神经元突触发生。缺失/突变实验已经揭示了蛋白质结构域403 - 596和349 - 402对于突触抑制的重要性，而包括NLS 1的氨基末端结构域是缺失的。最后，我们表明，DISC1功能相互作用与果蝇同源的Dysbindin（DTNBP1）通过直接的蛋白质-蛋白质相互作用，在发展中的突触。
Originally found in a Scottish family with diverse mental disorders, the DISC1 protein has been characterized as an intracellular scaffold protein that associates with diverse binding partners in neural development. To explore its functions in a genetically tractable system, we expressed the human DISC1 in fruit flies (Drosophila melanogaster). As in mammalian neurons, DISC1 is localized to diverse subcellular domains of developing fly neurons including the nuclei, axons and dendrites. Overexpression of DISC1 impairs associative memory. Experiments with deletion/mutation constructs have revealed the importance of amino terminal domain (46–290) for memory suppression whereas carboxyl domain (598–854) and the amino terminal residues (1–45) including the nuclear localization signal (NLS1) are dispensable. DISC1 overexpression also causes suppression of axonal and dendritic branching of mushroom body neurons, which mediate a variety of cognitive functions in the fly brain. Analyses with deletion constructs reveal that protein domains 598–854 and 349–402 are both required for the suppression of axonal branching while amino-terminal domains including NLS1 are dispensable. In contrast, NLS1 was required for the suppression of dendritic branching, suggesting a mechanism involving gene expression. Moreover, domain 403–596 is also required for the suppression of dendritic branching. We also show that overexpression of DISC1 suppresses glutamatergic synaptogenesis in developing neuromuscular junctions. Deletion/mutation experiments have revealed the importance of protein domains 403–596 and 349–402 for synaptic suppression, while amino terminal domains including NLS1 are dispensable. Finally, we show that DISC1 functionally interacts with the fly homolog of Dysbindin (DTNBP1) via direct protein-protein interaction in developing synapses.