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

基本信息

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
项目类别：
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

项目摘要

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）：活性依赖性 BMP/TGF 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介导细胞之间的通信，但不幸的是，这些通路的信号传导结果根据发育和细胞环境进行了微调。我们将研究 BMP/TGF 的信号传导特异性¿该途径在果蝇 NMJ 中具有许多独立的功能，特别是，它调节 NMJ 形态生长和神经递质释放，我们提供了 BMP 配体 Gbb 的细胞来源区分这两种途径的证据。其中单次跨膜蛋白 Crimpy 是调节分泌途径中致密核心囊泡的 BMP 的分选受体。我们认为 (1) 活性依赖性释放。 BMP 促进神经传递，并且 (2) Crimpy 定义了神经元衍生的配体库。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，然而，负责其定位到致密核心囊泡的细胞机制是不透明的。鉴于临床对选择性靶向生长因子信号通路突触功能的工具的兴趣，对 Crimpy 及其哺乳动物同源物的机制理解将具有重大意义。