Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses.
Genetic interaction of DISC1 and Neurexin in the development of fruit fly glutamatergic synapses.
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DOI：
10.1038/s41537-017-0040-6
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发表时间：
2017-10-27
影响因子：
5.4
通讯作者：
Furukubo-Tokunaga K
中科院分区：
文献类型：
--
作者：
Pandey H;Bourahmoune K;Honda T;Honjo K;Kurita K;Sato T;Sawa A;Furukubo-Tokunaga K
DISC 1基因最初被发现在一个苏格兰家庭的（1;11）（q42.1; q14.3）染色体易位的断点，广泛的精神障碍，一直是一个重点的深入调查作为一个切入点，研究不同的精神功能障碍的分子机制。DISC 1功能的扰动导致动物模型中的行为变化，这与患者的精神状况有关。在这项工作中，我们表达了人类DISC 1基因在果蝇（果蝇），并进行了遗传筛选的精神病风险基因的突变，导致DISC 1突触表型在神经肌肉接头的修改。我们发现，DISC 1相互作用与dnrx 1，果蝇同源的人类神经毒素（NRXN 1）基因，在发育的神经元突触。虽然DISC 1的过表达抑制了靶肌肉上的总终扣面积，并刺激了野生型背景下的活动区密度，但dnrx 1活性的部分降低否定了DISC 1介导的突触改变。同样，DISC 1的过表达刺激谷氨酸受体成分DGLURIIA的表达，在野生型背景下，但不是在dnrx 1杂合子背景。此外，DISC 1引起的Discs大，果蝇PSD-95同源物，在dnrx 1杂合背景的错误定位。一系列结构域缺失的分析揭示了DISC 1蛋白的轴突定位对于有效抑制突触终扣中的DNRX 1的重要性。因此，这些结果表明，一个有趣的收敛机制控制的DISC 1和Neurexin的相互作用，在发展中的突触。果蝇模型揭示了一种潜在的新机制，通过这种机制，两个精神分裂症风险因子基因相互作用，改变突触连接。DISC 1基因改变以前曾与精神异常有关，尽管该基因尚未被正式确认为精神分裂症的危险因素。由筑波大学Katsuo Furukubo-Tokunaga领导的美日研究合作在果蝇突触中表达了人类DISC 1，以更好地了解基因破坏导致过度表达时发生的变化。研究小组发现，DISC 1的过表达影响了果蝇中与人类“neurexin”对应的表达，这是一种已知的精神分裂症和自闭症谱系障碍等疾病的危险因素。neurexin和DISC 1之间的相互作用也影响了其他突触改变基因。DISC 1和neurexin在精神疾病中的作用有待进一步研究。
Originally identified at the breakpoint of a (1;11)(q42.1; q14.3) chromosomal translocation in a Scottish family with a wide range of mental disorders, the DISC1 gene has been a focus of intensive investigations as an entry point to study the molecular mechanisms of diverse mental dysfunctions. Perturbations of the DISC1 functions lead to behavioral changes in animal models, which are relevant to psychiatric conditions in patients. In this work, we have expressed the human DISC1 gene in the fruit fly (Drosophila melanogaster) and performed a genetic screening for the mutations of psychiatric risk genes that cause modifications of DISC1 synaptic phenotypes at the neuromuscular junction. We found that DISC1 interacts with dnrx1, the Drosophila homolog of the human Neurexin (NRXN1) gene, in the development of glutamatergic synapses. While overexpression of DISC1 suppressed the total bouton area on the target muscles and stimulated active zone density in wild-type background, a partial reduction of the dnrx1 activity negated the DISC1–mediated synaptic alterations. Likewise, overexpression of DISC1 stimulated the expression of a glutamate receptor component, DGLURIIA, in wild-type background but not in the dnrx1 heterozygous background. In addition, DISC1 caused mislocalization of Discs large, the Drosophila PSD-95 homolog, in the dnrx1 heterozygous background. Analyses with a series of domain deletions have revealed the importance of axonal localization of the DISC1 protein for efficient suppression of DNRX1 in synaptic boutons. These results thus suggest an intriguing converging mechanism controlled by the interaction of DISC1 and Neurexin in the developing glutamatergic synapses. Fruit fly models uncover a potential new mechanism by which two schizophrenia risk factor genes interact to alter synaptic junctions. DISC1 gene alterations have previously been linked to psychiatric anomalies, although the gene has not been formally recognized as a schizophrenia risk factor. A US-Japan research collaboration led by the University of Tsukuba’s Katsuo Furukubo-Tokunaga expressed human DISC1 in fruit fly synapses to better understand the changes that take place when gene disruption leads to overexpression. The team found that overexpression of DISC1 affected the expression of the fruit fly counterpart to human ‘neurexin,’ a known risk factor for conditions including schizophrenia and autism spectrum disorders. The interaction between neurexin and DISC1 also influenced other synapse-altering genes. Further research is warranted to explore the roles of DISC1 and neurexin in psychiatric disease.
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影响因子：
5.3
作者：
Doll CA;Broadie K
通讯作者：
Broadie K
影响因子：
11
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
通讯作者：
Sawa A
影响因子：
4.7
作者：
Androschuk, Alaura;Al-Jabri, Basma;Bolduc, Francois V.
通讯作者：
Bolduc, Francois V.
影响因子：
11
作者：
Camargo, L. M.;Collura, V.;Brandon, N. J.
通讯作者：
Brandon, N. J.
影响因子：
15.9
作者：
Bemben, Michael A.;Shipman, Seth L.;Nicoll, Roger A.;Roche, Katherine W.
通讯作者：
Roche, Katherine W.