How Ephexin Signaling Promotes Neuronal Stability

Ephexin 信号如何促进神经元稳定性

• 批准号: 8231539
• 负责人: CARL ANDREW FRANK
• 金额: $ 23.44万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8231539
• 关键词: Binding; Calcium Channel; Cell membrane; Couples; Data; Disease; Drosophila genus; Eph Family Receptors; EphA Receptors; Ephrins; Financial compensation; Gene Expression; Gene Proteins; Genetic; Genetic Epistasis; Guanine; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Homologous Gene; Laboratories; Lead; Ligands; Mentors; Nerve; Nervous system structure; Neurons; Neurophysiology - biologic function; P-Q type voltage-dependent calcium channel; Pathway interactions; Phase; Postdoctoral Fellow; Progress Reports; Publishing; Recruitment Activity; Regulation; Research; Role; Signal Pathway; Signal Transduction; Synapses; System; Testing; Training; Transgenic Organisms; Work; ephexin; graduate student; member; mutant; nervous system disorder; neurotransmission; neurotransmitter release; presynaptic; relating to nervous system; research study; rho; rho GTP-Binding Proteins; synaptic function

OBJECTIVE: The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function, in particular by modulating the strength of synaptic connections. This project aims to clarify the mechanisms of synaptic homeostatic signaling. BACKGROUND/RATIONALE: We published a study demonstrating a role in synaptic homeostasis for an Ephexin signaling system. Ephexin is a Rho-type guanine exchange factor (GEF). Drosophila Ephexin is required presynaptically for synaptic homestasis and localizes in proximity of other components of the nerve terminal. Downstream of Ephexin GEF function, Rho-type GTPases are important for executing homeostatic compensation, in particular Cdc42. Upstream of Ephexin, the Drosophila Eph receptor (Eph) binds Ephexin and Eph mutants have impaired synaptic homeostasis. Components of this signaling system show strong genetic interactions with each other and with CaV2.1 calcium channel mutants. We postulate that this presynaptic signaling system couples homeostatic retrograde signaling at the synaptic plasma membrane to the modulation of presynaptic CaV2.1 function and neurotransmitter release. R00 PHASE DESIGN: Candidate molecules already known in other systems to regulate calcium channel function and Eph/Ephexin/GTP signaling will be tested for roles in synaptic homeostasis. Molecules that do show a role in homeostasis will be placed into the context of our presynaptic signaling system. This work will utilize a combination of approaches for the three-year R00 phase: electrophysiological analysis of synaptic function, genetic mutant analyses, pharmacological inhibition of target molecules, analyses of gene expression and protein localization, transgenic rescue, and genetic epistasis and pathway analyses. TRAINEES: New recruited members of my laboratory will be trained in all aspects of this project. Over the course of three years, this may include a technician, two graduate students, and a postdoctoral fellow.

目的：几种神经系统疾病的原因和进展受到控制神经功能稳定性的因素的影响。 然而，对决定神经激发和抑制作用的机制知之甚少。 许多研究表明，稳态信号传导机制参与了神经功能的调节，特别是通过调节突触连接的强度。 该项目旨在阐明突触稳态信号传导的机制。 背景/理由：我们发表了一项研究，该研究表明在急剧信号系统的突触稳态中发挥了作用。 以埃菲素是一种鸟嘌呤交换因子（GEF）。 果蝇果蝇是突触前的突触寄居时需要的，并定位在神经末端其他成分的接近度中。 在以埃菲素GEF函数的下游，Rho-Type GTPases对于执行稳态补偿很重要，特别是CDC42。 果蝇果蝇受体（EPH）的上游结合以诸禁素和以etph突变体的突触稳态受损。 该信号系统的组成部分彼此显示强烈的遗传相互作用，并且与Cav2.1钙通道突变体相互作用。 我们假设该突触前信号系统伴侣在突触质膜处伴侣稳态逆行信号传导，以调节突触前CAV2.1功能和神经递质释放。 R00相设计：在其他系统中已知的候选分子调节钙通道功能和EPH/Ephexin/GTP信号传导将测试突触稳态中的作用。 确实在体内平衡中表现出作用的分子将放置在我们突触前信号系统的背景下。 这项工作将利用三年R00阶段的方法组合：突触功能的电生理分析，遗传突变分析，药理对靶分子的药理抑制作用，基因表达和蛋白质定位的分析，转基因救援，以及遗传性epistasis and Pathway分析。 学员：我的实验室的新招聘成员将在该项目的各个方面接受培训。 在三年的时间里，这可能包括一名技术人员，两名研究生和一个博士后研究员。

项目成果

Hierarchical microtubule organization controls axon caliber and transport and determines synaptic structure and stability.

• DOI: 10.1016/j.devcel.2015.02.003
• 发表时间: 2015-04-06
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Stephan R;Goellner B;Moreno E;Frank CA;Hugenschmidt T;Genoud C;Aberle H;Pielage J
• 通讯作者: Pielage J