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：一些神经系统疾病的病因和进展受到控制神经功能稳定性的因素的影响。 然而，人们对决定神经兴奋和抑制的机制知之甚少。 许多研究表明，稳态信号机制参与神经功能的调节，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/基本原理：我们发表了一项研究，证明 Ephexin 信号系统在突触稳态中的作用。 Ephexin 是一种 Rho 型鸟嘌呤交换因子 (GEF)。 果蝇 Ephexin 是突触前维持突触稳态所必需的，并且位于神经末梢其他组件附近。 Ephexin GEF 功能的下游，Rho 型 GTPases 对于执行稳态补偿非常重要，特别是 Cdc42。 Ephexin 的上游，果蝇 Eph 受体 (Eph) 与 Ephexin 结合，Eph 突变体会​​损害突触稳态。 该信号系统的组成部分彼此之间以及与 CaV2.1 钙通道突变体之间表现出强烈的遗传相互作用。 我们假设这种突触前信号系统将突触质膜上的稳态逆行信号与突触前 CaV2.1 功能和神经递质释放的调节结合起来。 R00 相设计：将测试其他系统中已知的调节钙通道功能和 Eph/Ephexin/GTP 信号传导的候选分子在突触稳态中的作用。 确实在稳态中发挥作用的分子将被置于我们的突触前信号系统的背景下。 这项工作将在三年 R00 阶段采用多种方法：突触功能的电生理学分析、遗传突变分析、靶分子的药理学抑制、基因表达和蛋白质定位分析、转基因拯救以及遗传上位性和途径分析。 受训人员：我的实验室新招募的成员将接受该项目各个方面的培训。 在三年的时间里，这可能包括一名技术员、两名研究生和一名博士后。

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