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: 8657126
• 负责人: Heather Broihier
• 金额: $ 19.61万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657126
• 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(由申请人提供)：模型突触中依赖活性的BMP/转化生长因子释放的机制分析细胞如何使广泛使用的细胞间信号通路的信号输出多样化？一些保守的生长因子通路在整个生命过程中调节细胞之间的通讯。然而，值得注意的是，这些通路的信号结果与发育和细胞环境密切相关。我们将研究BMP/转化生长因子途径的信号特异性。这一途径在果蝇的NMJ中发挥着许多独立的功能。特别是，它调节NMJ的形态生长和神经递质的释放。我们提出的证据表明，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，在这个模型中，单程跨膜蛋白Crimpy是BMP的分选受体，用于调节分泌途径中致密核心小泡的BMP。我们认为(1)BMP活性依赖的重新释放促进了神经传递；(2)Crimpy定义了神经元来源的配位体。BMP/TGFβ家族成员在哺乳动物神经元中是突触定位的，并受到活性依赖性释放的影响。然而，负责它们定位于致密核心囊泡的细胞机制是不透明的。CrimPy将代表在任何系统中发现的第一个BMP/TGF？致密核心囊泡分选受体。鉴于临床上对识别选择性靶向生长因子信号通路突触功能的工具的兴趣，从机制上理解Crimpy及其哺乳动物同源物将是非常有意义的。