Wrd promotes active zone stability through dephosphorylation of Coracle

WRD通过Coracle的去磷酸化促进活动区的稳定性 摘要 活动区(AZs)是位于神经末梢的特殊的膜间隔， 协调神经递质的释放。AZ在结构上是塑料的，因为它们的数量，大小， 位置和强度都可以通过发育线索和神经来动态改变 活动。这种形式的结构神经可塑性可能在学习和记忆中发挥关键作用， 它的功能障碍可能会导致认知障碍。然而，我们对此知之甚少 调控AZ支架动力学的分子机制。我们发现突触PP2A/WRD 磷酸酶促进果蝇NMJ中AZ的稳定性，并且是光诱导AZ所必需的 成体阶段感光突触的重塑和味觉学习。通过一个 用比较蛋白质组学的方法，我们鉴定了Coracle(Cora，哺乳动物同源物被称为 蛋白4.1)，一种组织细胞间连接和膜蛋白的枢纽蛋白，作为一种 关键的WRD特定底物，可以调节AZ支架的动力学。这项建议 回答以下两个问题：第一，Coracle在突触中的作用是什么 发展与稳定？第二，Coracle的去磷酸化是如何通过 WRD/PP2A改变突触前终末的冠状突触活动？在目标1中，我们将定义一个 发育和成熟时突触定位CORA在AZ动态调节中的新作用 突触，以及学习和记忆。在目标2中，我们将定义WRD如何调解 CORA去磷酸化影响CORA介导的调节突触稳定性的作用 认知功能。

Wrd promotes active zone stability through dephosphorylation of Coracle Abstract Active zones (AZs) are specialized membrane compartments at the nerve terminal that orchestrate the release of neurotransmitters. AZs are structurally plastic as their number, size, location and strength can each be dynamically modified by developmental cues and neural activities. This form of structural neuroplasticity may play key roles in learning and memory, and its dysfunction may cause cognitive impairment. However, we know very little about the molecular mechanisms that regulate AZ scaffold dynamics. We found that synaptic PP2A/Wrd phosphatase promotes AZ stability at the Drosophila NMJs, and is required for light-induced AZ remodeling at the photoreceptor synapses and taste learning at the adult stage. Through a comparative proteomic approach, we identified Coracle (Cora, mammalian homologue is called protein 4.1), a hub protein that organizes intercellular junctions and membrane proteins, as a key Wrd-specific substrate that could mediate the AZ scaffold dynamics. This proposal addresses the following two questions: First, what are the roles of Coracle in synaptic development and stabilization? Second, how does the dephosphorylation of Coracle by Wrd/PP2A alter the action of Coracle at the presynaptic terminal? In Aim 1, we will define a novel role of synaptically localized Cora in regulating AZ dynamics at the developing and mature synapses, as well as learning and memory. In Aim 2, we will define how Wrd-mediated dephosphorylation of Cora affects Cora-mediated action in regulating synaptic stability and cognitive function.