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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：此提案考试如何将增长因子信号通路与突触结构和功能联系起来。生长因子是潜在的神经调节剂，并在突触中扮演不同的角色。它们调节突触生物学的基本特征，包括基线发射机释放，突触形态和可塑性。鉴于它们的重要性指导突触组织，必须定义分子和细胞机制将突触生长因子信号传导与突触和神经元活性耦合。 BMP/TGFβ家族成员是突触结构和功能的进化配置的调节剂。特别是，BMP/TGFβ途径在果蝇NMJ上具有神经营养途径活性。 BMP途径突变体在NMJ的形态和功能中显示出惊人的缺陷。值得注意的是，不同的配体池独立调节这些合成特征。我们证明，突触前池调节突触结构和功能，而突触后池则指导NMJ末端的总体生长。了解这些信息通道如何在内源性突触下分离，这对于了解如何独立控制独立的突触特征至关重要。我们对这项工作的切入点是新型神经跨膜蛋白crimpy。我们已经证明，Crimpy可以歧视突触前和后BMP池。 Crimpy结合了一个称为GBB的BMP同源物，并将其运输到突触前密集的核心蔬菜（DCV）。没有Crimpy，GBB不再在DCV中找到，也不会因突触前活动而释放。在没有Crrimpy的情况下，无法区分突触前和后配体池，NMJ的特征是异常的营养信号传导，以突触前突触 - 组织 - 组织提示为代价。在此提案中，我们建立在新的初步发现的基础上，以定义活动引起的突触前BMP信号在突触结构和功能中的作用。首先，我们定义了前和突触后信号的分子身份。由于Crimpy是标记突触前池的关键，因此我们将在生化上定义Crimpy在BMP信号转导中的作用。其次，我们将阐明依赖活动的BMP信号直接突触组织。我们检验了以下假设：Crimpy介导的突触前GBB信号是局部和急性提示的提示提示驱动突触组织。第三，我们将定义下游信号级联。我们有令人兴奋的初步证据表明，新型BMP受体会导致活性依赖性信号。我们将确定受体在途径中的作用，并表征非依赖活性依赖性BMP级联的新型下游成分。