Mechanistic analysis of activity-dependent BMP/TGF-beta release at a model synaps

模型突触活性依赖性 BMP/TGF-β 释放的机制分析

• 批准号: 8569373
• 负责人: Heather Broihier
• 金额: $ 23.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8569373
• 关键词: Automobile Driving; Biochemical; Biological; Cell membrane; Cells; Chronic; Clinical; Communication; Coupling; Dense Core Vesicle; Development; Drosophila genus; Exocytosis; Family member; Feedback; Genetic; Growth; Growth Factor; Homeostasis; Homologous Gene; Integral Membrane Protein; Life; Ligands; Mammals; Maps; Mediating; Mission; Modeling; Molecular; Morphology; Motor Neurons; Muscle; Muscle Cells; Names; Neuromuscular Junction; Neurons; Outcome; Output; Pathway interactions; Physiological; Play; Proteins; Role; Route; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Source; Specificity; Synapses; System; Testing; Time; Transforming Growth Factor beta; Vesicle; autocrine; bone morphogenetic protein receptors; fly; interest; mutant; neurotransmission; neurotransmitter release; paracrine; postsynaptic; presynaptic; public health relevance; receptor; research study; response; synaptic function; tool; trafficking; trans-Golgi Network

DESCRIPTION (provided by applicant): Mechanistic analysis of activity-dependent BMP/TGF¿ release at a model synapse How do cells diversify signaling outputs of widely used intercellular signaling pathways? A handful of conserved growth factor pathways mediate communication between cells throughout life. Yet remarkably, the signaling outcomes of these pathways are finely tuned to developmental and cellular context. We will investigate signaling specificity of the BMP/TGF¿ pathway. This pathway serves a number of independent functions at the Drosophila NMJ. In particular, it regulates both NMJ morphological growth and neurotransmitter release. We present evidence that the cellular source of the BMP ligand Gbb discriminates between these two pathways. We propose a model in which the single-pass transmembrane protein Crimpy is a sorting receptor for the BMP for dense core vesicles in the regulated secretory pathway. We argue that (1) activity-dependent re- lease of the BMP promotes neurotransmission and (2) Crimpy defines the neuron-derived ligand pool. BMP/TGF¿ family members are synaptically localized and subject to activity-dependent release in mammalian neurons. However, the cellular mechanisms responsible for their localization to dense core vesicles are opaque. Crimpy would represent the first BMP/TGF¿ dense core vesicle sorting receptor identified in any system. Given clinical interest in identifying tools to selectively target synaptic functions of growth factor signaling pathways, a mechanistic understanding of Crimpy and its mammalian homologs will be of significant interest.

描述（通过应用程序提供）：在模型突触下释放活动依赖性BMP/TGF的机理分析如何多样化使用广泛使用细胞间信号通路的信号传导输出？一生中细胞之间的少数保守生长因子途径媒体通信。然而，值得注意的是，这些途径的信号传导结果可将其细微调整为发育和细胞环境。我们将研究BMP/TGF途径的信号传导特异性。该途径在果蝇NMJ上提供许多独立的功能。特别是，它调节NMJ形态生长和神经递质释放。我们提供了证据表明，BMP配体GBB的细胞来源区分这两种途径。我们提出了一个模型，其中单次跨膜蛋白Crimpy是在受调节秘密途径中致密核心蔬菜的BMP的分类受体。我们认为（1）BMP的活性依赖性重新释放会促进神经传递，并且（2）Crimpy定义了神经衍生的配体库。 bmp/tgf¿家庭成员是突触局部的，并且在哺乳动物神经元中受活动依赖性释放。但是，导致其定位到密集核蔬菜的细胞机制是不透明的。 Crimpy将代表任何系统中鉴定出的第一个BMP/TGF核心囊泡分类受体。鉴于鉴定有选择性靶向生长因子信号通路的突触功能的临床兴趣，对Crimpy及其哺乳动物同源物的机械理解将引起人们的重大关注。