Scribble Scaffolds a Signalosome for Active Forgetting.
Scribble Scaffolds a Signalosome for Active Forgetting.
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DOI：
10.1016/j.neuron.2016.05.010
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发表时间：
2016-06-15
期刊：
影响因子：
16.2
通讯作者：
Davis RL
中科院分区：
文献类型：
--
作者：
Cervantes-Sandoval I;Chakraborty M;MacMullen C;Davis RL
遗忘是大脑记忆管理系统的一部分，它通过删除未使用或不需要的记忆或抑制它们的表达，为新信息的编码和巩固提供平衡。最近的研究发现，小G蛋白Rac1是果蝇蘑菇体神经元（MBn）主动遗忘的关键参与者。我们随后发现，少数多巴胺能神经元（DAn），支配MBn介导的遗忘。在这里，我们表明，Scribble，一种主要以其作为细胞极性决定因素的作用而闻名的支架蛋白，协调了正常遗忘的细胞内信号。敲低MBn或DAn中的scribble表达会损害正常的记忆丧失。Scribble与MBn内的Rac1，Pak3和Cofilin在物理和遗传上相互作用，使调节遗忘的多巴胺能输入下游的遗忘信号体成核。这些结果将主动遗忘中不同的分子参与者结合到单一的信号通路中：多巴胺→多巴胺受体→Scribble→Rac→Cofilin。遗忘是大脑的一种调节良好的功能，可以适应不断变化的环境。这项研究表明，Scribble，最初被确定为细胞极性决定蛋白，通过支架遗忘信号体调节记忆丧失。
Forgetting, one part of the brain’s memory management system, provides balance to the encoding and consolidation of new information by removing unused or unwanted memories or by suppressing their expression. Recent studies identified the small G-protein, Rac1, as a key player in the Drosophila mushroom bodies neurons (MBn) for, active forgetting. We subsequently discovered that a few dopaminergic neurons (DAn) that innervate the MBn mediate forgetting. Here we show that Scribble, a scaffolding protein known primarily for its role as a cell polarity determinant, orchestrates the intracellular signaling for normal forgetting. Knocking down scribble expression in either MBn or DAn impairs normal memory loss. Scribble interacts physically and genetically with Rac1, Pak3 and Cofilin within MBn, nucleating a forgetting signalosome that is downstream of dopaminergic inputs that regulate forgetting. These results bind disparate molecular players in active forgetting into a single signaling pathway: Dopamine→Dopamine Receptor→Scribble→Rac→Cofilin. Forgetting is a well-regulated function of the brain that allows adaptation to an ever-changing environment. This study demonstrates that Scribble, identified originally as a cell polarity determinant protein, regulates memory loss by scaffolding a forgetting signalosome.