FMR1 与 DISC1 基因相互作用,调控谷氨酸能突触发生。

IF 3 Q2 PSYCHIATRY
Takato Honda, Kazuki Kurita, Yuko Arai, Himani Pandey, Akira Sawa, Katsuo Furukubo-Tokunaga
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引用次数: 0

摘要

突触的发育和功能被认为是多种神经精神疾病的关键机制。过去几年的研究表明,脆性 X 精神发育迟滞 1(FMR1)基因突变与智力障碍、自闭症谱系障碍和精神分裂症等多种精神疾病有关。在这项研究中,我们利用果蝇研究了一组风险因子基因之间的遗传相互作用,发现人类 FMR1 基因的果蝇同源基因 dfmr1 在突触发育过程中与 DISC1 存在功能性相互作用。我们发现,DISC1在dfmr1缺失杂合背景下的过表达会导致幼虫神经肌肉接头处的突触改变,这种改变与野生型背景下的突触改变不同。dfmr1 缺失改变了 DISC1 在突触形成中的过表达表型,抑制了突触束的形成。dfmr1突变抑制了DISC1介导的突触后谷氨酸受体表达和突触前运动神经元中ELKS/CAST蛋白Bruchpilot的表达,进一步从分子上支持了这两个基因之间的相互作用。此外,DISC1 在 dfmr1null 杂合背景下的过表达会导致 MAP1 家族蛋白 Futsch 的下调。因此,这些结果表明,在发育中的谷氨酸能突触中,FMR1 和 DISC1 控制着一种有趣的交汇机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
FMR1 genetically interacts with DISC1 to regulate glutamatergic synaptogenesis.

Synaptic development and functions have been hypothesized as crucial mechanisms of diverse neuropsychiatric disorders. Studies in past years suggest that mutations in the fragile X mental retardation 1 (FMR1) are associated with diverse mental disorders including intellectual disability, autistic spectrum disorder, and schizophrenia. In this study, we have examined genetical interactions between a select set of risk factor genes using fruit flies to find that dfmr1, the Drosophila homolog of the human FMR1 gene, exhibits functional interactions with DISC1 in synaptic development. We show that DISC1 overexpression in the dfmr1null heterozygous background causes synaptic alterations at the larval neuromuscular junctions that are distinct from those in the wild-type background. Loss of dfmr1 modifies the DISC1 overexpression phenotype in synaptic formation, suppressing the formation of synapse boutons. Interaction between the two genes was further supported molecularly by the results that dfmr1 mutations suppress the DISC1-mediated upregulations of the postsynaptic expression of a glutamate receptor and the expression of ELKS/CAST protein, Bruchpilot, in presynaptic motoneurons. Moreover, DISC1 overexpression in the dfmr1null heterozygous background causes downregulation of a MAP1 family protein, Futsch. These results thus suggest an intriguing converging mechanism controlled by FMR1 and DISC1 in the developing glutamatergic synapses.

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