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）：本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联。生长因子是有效的神经调质，在突触中起着不同的作用。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。鉴于其指导突触组织的重要性，重要的是要定义突触生长因子信号传导耦合到突触和神经元活动的分子和细胞机制。BMP/TGFβ家族成员是进化上保守的突触结构和功能调节因子。特别地，BMP/TGFβ途径在果蝇NMJ处具有神经营养途径活性。BMP途径突变体在NMJ形态和功能上显示出明显的缺陷。值得注意的是，不同的配体库独立地调节这些突触特征。我们表明，突触前池调节突触的结构和功能，而突触后池指导整体增长的NMJ终端。了解这些信息通道是如何在内源性突触分离是必不可少的，以了解不同的突触功能是如何独立控制。我们的切入点，这项工作是新的神经元跨膜蛋白Criminal。我们已经证明，Criminal能够区分突触前和突触后BMP池。criteria结合一种名为Gbb的BMP同源物，并将其运输到突触前致密核心囊泡（DCV）。如果没有CRYSTALINE，Gbb不再存在于DCV中，也不会通过突触前活动释放。在缺乏Crystaline的情况下，不能区分突触前和突触后配体库，并且NMJ的特征在于以突触前突触组织线索为代价的异常营养信号传导。在这个建议中，我们建立在我们的新的初步发现，以确定活动诱导的突触前BMP信号在突触结构和功能中的作用。首先，我们定义了突触前和突触后信号的分子身份。因为Crimine是标记突触前池的关键，我们将从生物化学的角度定义Crimine在BMP信号转导中的作用。其次，我们将阐明如何活动依赖性BMP信号直接突触组织。我们测试的假设，卷曲介导的突触前GBB信号是一个本地和急性线索指导线索驱动突触组织。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，一种新的BMP受体转导的活动依赖性信号。我们将建立受体在通路中的作用，并表征非经典活性依赖性BMP级联的新型下游成分。