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

• 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
• 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

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.

项目摘要 我们对经典发育的功能的绝大多数理解 信号通路来自神经系统以外的研究。我们很感兴趣 在进化上如何保守的信号通路这一首要问题上 为突触发出信号而定制的。有一些重大的悬而未决的问题 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 在突触裂隙的密集微环境中。我们对Crimpy和 突触性骨形态发生蛋白的两种新成分α-2、δ-3 信号通路提供了对这两个问题的关键见解，使我们能够探索 旨在理解增长因素如何组织的创新假说 突触。我们已发表的研究表明，自分泌BMP信号组装 突触前脑室的多种主要特征。在这里，我们以小说为基础 与这一途径的调节和功能有关的发现。我们提供证据证明 自分泌BMP信号维持前突触的跨突触黏附和排列 和突触后间隔。在这些表型上，我们发现了 ECM蛋白SPARC可能是BMP下游效应因子。最后，我们介绍了小说 初步数据表明，这一通路形成新的突触前活性的能力 Zones受到LRIG家族中一种跨膜蛋白的阻碍。