Linking an activity-dependent BMP pathway to synapse structure and function

将活动依赖性 BMP 通路与突触结构和功能联系起来

• 批准号: 9078715
• 负责人: Heather Broihier
• 金额: $ 34.67万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9078715
• 关键词: Acute; Adult; Architecture; Automobile Driving; Axon; Binding; Biology; Brain Diseases; Cells; Characteristics; Clinical; Coupling; Cues; Data; Defect; Dense Core Vesicle; Development; Discrimination; Docking; Drosophila genus; Employee Strikes; Exhibits; Family member; Foundations; Growth; Homeostasis; Homologous Gene; Human; Integral Membrane Protein; Ligands; Link; Mediating; Membrane; Mental disorders; Molecular; Morphology; Neuromodulator; Neuromuscular Junction; Neurons; Pathway interactions; Peripheral; Phenocopy; Play; Process; Proteolysis; RNA interference screen; Regulation; Research; Role; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Structure; Synapses; System; Testing; Transforming Growth Factor beta; Vesicle; Work; base; bone morphogenetic protein receptors; in vivo; mutant; nervous system disorder; neurotransmitter release; neurotrophic factor; novel; postsynaptic; presynaptic; public health relevance; receptor; synaptic function; trafficking

 DESCRIPTION (provided by applicant): This proposal examines how a growth factor signaling pathway is linked to synapse structure and function. Growth factors are potent neuromodulators and play diverse roles at synapses. They regulate fundamental features of synaptic biology including baseline transmitter release, synapse morphology, and plasticity. Given their importance directing synapse organization, it is important to define the molecular and cellular mechanisms coupling synaptic growth factor signaling to synapses and neuronal activity. BMP/TGFβ family members are evolutionarily conserved regulators of synapse structure and function. In particular, a BMP/TGFβ pathway has neurotrophic pathway activity at the Drosophila NMJ. BMP pathway mutants display striking defects in NMJ morphology and function. Remarkably, distinct ligand pools independently regulate these synaptic features. We demonstrate that the presynaptic pool regulates synaptic structure and function, while the postsynaptic pool directs overall growth of the NMJ terminal. Understanding how these information channels are separated at an endogenous synapse is essential to understand how distinct synaptic features are independently controlled. Our entry point to this work is the novel neuronal transmembrane protein Crimpy. We have demonstrated that Crimpy enables discrimination between pre- and postsynaptic BMP pools. Crimpy binds a BMP homolog called Gbb and traffics it to presynaptic dense core vesicles (DCVs). Without Crimpy, Gbb is no longer found in DCVs and is not released by presynaptic activity. In the absence of Crimpy, pre- and postsynaptic ligand pools cannot be distinguished, and the NMJs are characterized by aberrant trophic signaling at the expense of the presynaptic synapse-organizing cue. In this proposal, we build on our novel preliminary findings to define the role of activity-induced presynaptic BMP signaling in synapse structure and function. First, we define the molecular identity of the pre- and postsynaptic signals. Because Crimpy is key for marking the presynaptic pool, we will define biochemically the role of Crimpy in BMP signal transduction. Second, we will elucidate how activity-dependent BMP signals direct synapse organization. We test the hypothesis that the Crimpy-mediated presynaptic Gbb signal is a local and acute cue instructive cue driving synapse organization. And third, we will define the downstream signaling cascade. We have exciting preliminary evidence that a novel BMP receptor transduces the activity-dependent signal. We will establish the receptor's role in the pathway and characterize novel downstream components of a non-canonical activity-dependent BMP cascade.

 描述（由申请人提供）：该提案研究了生长因子信号通路如何与突触结构和功能相关。生长因子是有效的神经调节剂，在突触中发挥多种作用。它们调节突触生物学的基本特征，包括基线递质释放、突触形态和可塑性。鉴于它们对指导突触组织的重要性，定义将突触生长因子信号传导与突触和神经元活动耦合的分子和细胞机制非常重要。 BMP/TGFβ 家族成员是进化上保守的突触结构和功能调节剂。特别是，BMP/TGFβ 通路在果蝇 NMJ 处具有神经营养通路活性。 BMP 通路突变体在 NMJ 形态和功能上表现出显着的缺陷。值得注意的是，不同的配体池独立调节这些突触特征。我们证明突触前池调节突触结构和功能，而突触后池指导 NMJ 末端的整体生长。了解这些信息通道如何在内源性突触处分离对于了解如何独立控制不同的突触特征至关重要。我们这项工作的切入点是新型神经元跨膜蛋白 Crimpy。我们已经证明 Crimpy 能够区分突触前和突触后 BMP 池。 Crimpy 结合名为 Gbb 的 BMP 同源物，并将其运输至突触前致密核心囊泡 (DCV)。没有 Crimpy，DCV 中就不再存在 Gbb，并且突触前活动也不会释放 Gbb。在没有 Crimpy 的情况下，无法区分突触前和突触后配体池，并且 NMJ 的特点是异常的营养信号传导，而牺牲了突触前突触组织线索。在本提案中，我们基于新的初步发现来定义活动诱导的突触前 BMP 信号在突触结构和功能中的作用。首先，我们定义突触前和突触后信号的分子特性。由于 Crimpy 是标记突触前池的关键，因此我们将从生化角度定义 Crimpy 在 BMP 信号转导中的作用。其次，我们将阐明活动依赖性 BMP 如何向直接突触组织发出信号。我们测试了这样的假设：Crimpy 介导的突触前 Gbb 信号是驱动突触组织的局部且敏锐的指导性线索。第三，我们将定义下游信令级联。我们有令人兴奋的初步证据表明一种新型 BMP 受体可以转导活性依赖性信号。我们将确定受体在该通路中的作用，并表征非规范活性依赖性 BMP 级联的新型下游成分。