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

基本信息

批准号：
10606602
负责人：
Heather Broihier
金额：
$ 40.25万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10606602
关键词：
Address Adhesions Adhesives Architecture Biochemical Bone Morphogenetic Proteins Brain Diseases Calcium Channel Clinical Coupling Critical Pathways Data Defect Development Drosophila genus Extracellular Domain Extracellular Matrix Family Foundations Genetic Transcription Genetic study Glutamates Growth Factor Human Impairment Individual Integral Membrane Protein Light Link Maintenance Membrane Mental disorders Molecular Motor Mutation Nervous System Neurodevelopmental Disorder Neurons Neurotransmitter Receptor Neurotransmitters Nociception Pathway interactions Phenotype Positioning Attribute Proteins Publishing Regulation Research Role Sensory Side Signal Pathway Signal Transduction Signaling Protein Site Structure Synapses Synaptic Cleft Synaptic Receptors Synaptic plasticity System Testing Transforming Growth Factor beta Work autocrine density extracellular in vivo innovation insight interest mutant neurotransmission neurotransmitter release novel postsynaptic presynaptic protein degradation restraint synaptic function synaptogenesis

项目摘要

Project Summary The vast majority of our understanding regarding the function of classical developmental signaling pathways comes from studies outside the nervous system. We are interested in the overarching question of how evolutionarily conserved signaling pathways are customized for signaling at synapses. There are significant unanswered questions regarding how these pathways interface with synaptic activity as well as how they signal in the dense microenvironment of the synaptic cleft. Our identification of Crimpy and α2δ-3 as two novel components of a synaptic Bone Morphogenetic Protein (BMP) signaling pathway provides key insights into both questions, positioning us to explore innovative hypotheses directed at understanding how growth factors organize synapses. Our published studies indicate that autocrine BMP signaling assembles multiple principal features of the presynaptic compartment. Here, we build on novel findings relating to the regulation and function of this pathway. We provide evidence that autocrine BMP signaling maintains trans-synaptic adhesion and alignment of the pre- and postsynaptic compartments. Shedding light on these phenotypes, we identified the ECM protein SPARC as a putative BMP downstream effector. Lastly, we present novel preliminary data that the ability of this pathway to nucleate new presynaptic active zones is impeded by a transmembrane protein in the LRIG family.

项目概要我们对经典发展功能的绝大多数理解我们感兴趣的是信号通路来自神经系统之外的研究。在进化上如何保守的信号通路这一首要问题中为突触信号定制有一些重要的未解答的问题。关于这些通路如何与突触活动相互作用以及它们如何发出信号在突触间隙的致密微环境中，我们识别了 Crimpy 和 α2δ-3 作为突触骨形态发生蛋白 (BMP) 的两个新成分信号通路为这两个问题提供了关键见解，使我们能够探索旨在了解生长因子如何组织的创新假设我们发表的研究表明自分泌 BMP 信号组装。在这里，我们以新颖的方式构建突触前室的多个主要特征。我们提供了与该途径的调节和功能相关的发现。自分泌 BMP 信号维持跨突触粘附和前突触对齐和突触后区室揭示了这些表型，我们确定了 ECM 蛋白 SPARC 作为假定的 BMP 下游效应子最后，我们提出了新的方案。初步数据表明该途径使新的突触前活性物质成核的能力区域受到 LRIG 家族中的跨膜蛋白的阻碍。