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

描述（由申请人提供）：模型突触中活性依赖性BMP/TGF -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？少数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。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/TGF¿通路的信号特异性。这条通路在果蝇NMJ中有许多独立的功能。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，其中单遍跨膜蛋白Crimpy是BMP在调节分泌途径中致密核心囊泡的分选受体。我们认为(1)BMP的活性依赖性释放促进了神经传递；(2)Crimpy定义了神经元源性配体库。BMP/TGF家族成员在哺乳动物神经元中是突触定位的，并受活动依赖性释放的影响。然而，细胞机制负责他们定位密集的核心囊泡是不透明的。cripy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。鉴于临床对识别工具的兴趣，以选择性地靶向生长因子信号通路的突触功能，对Crimpy及其哺乳动物同源物的机制理解将具有重大意义。

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.