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: 10378093
• 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/10378093
• 关键词: Address; Adhesions; Adhesives; Architecture; Biochemical Genetics; Bone Morphogenetic Proteins; Brain Diseases; Calcium Channel; Clinical; Coupling; Critical Pathways; Custom; 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 structure; 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; 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 绝大多数我们对经典发展功能的理解 信号通路来自神经系统以外的研究。我们感兴趣 在进化上保守的信号通路是如何 专门用来在突触上传递信号还有很多重要的问题没有得到解答 关于这些通路如何与突触活动连接以及它们如何发出信号， 在突触间隙的致密微环境中。我们对罪犯的识别， α2δ-3作为突触骨形态发生蛋白（BMP）的两个新组分 信号通路为这两个问题提供了关键的见解，使我们能够探索 旨在了解生长因子如何组织的创新假设 突触我们发表的研究表明，自分泌BMP信号组装 突触前区室的多个主要特征。在这里，我们建立在小说 有关这一途径的调节和功能的发现。我们提供的证据表明， 自分泌BMP信号传导维持跨突触的粘附和排列， 和突触后区室。为了揭示这些表型，我们确定了 ECM蛋白作为推定的BMP下游效应物。最后，我们介绍了小说 初步数据表明，这一途径的能力，以核新的突触前活性 区被LRIG家族中的跨膜蛋白阻碍。