GABAergic Neuron Differentiation in C. elegans

线虫中的 GABA 能神经元分化

基本信息

  • 批准号:
    6949633
  • 负责人:
  • 金额:
    $ 30.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-07-18 至 2008-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Chemical synapses are ultrastructurally distinct subcellular entities that mediate the information flow from neurons to their targets. In the presynaptic terminals, synaptic vesicles are arranged orderly around the electron-dense active zones. Recent studies have revealed multiple pathways controlling presynaptic differentiation. A focus of this lab is to take a genetic approach in the nematode C. elegans to identify genes that regulate synapse formation. The rpm-1 gene (for regulator of presynaptic morphology) encodes a large evolutionarily conserved protein that contains multiple functional domains including a Ring-finger E3 ubiquitin ligase domain. Loss of function in rpm-1 results in diverse synaptic defects, ranging from failure to form stable synapses to disorganized presynaptic terminals. Through genetic screens, we have identified a MAP kinase module whose activity is inhibited by rpm-1. This MAP kinase module is composed of DLK-1, a MAP kinase kinase kinase; MKK-4, a MAP kinase kinase; and PMK-3, a p38-like MAP kinase. Loss of function in any one of the kinases suppresses the synaptic defects in rpm-1 mutants, whereas elevating the MAP kinase signaling in wild type animals causes abnormal synapses resembling those of rpm-1 mutants. DLK-1 is localized to presynaptic regions, and its abundance appears to be elevated in rpm-1 mutants. Based on these data, we hypothesize that during synapse formation RPM-1 functions to down-regulate the MAP kinase pathway, possibly by targeting DLK-1 for degradation. The main goals of this renewal application are to define the biochemical interactions between the MAP kinases (in particular DLK-1) and RPM-1, and to identify additional components of this MAP kinase pathway and other genes that may interact with RPM- 1. RPM-1 is localized to a distinct subsynaptic domain. Additional experiments are proposed to examine how its synaptic localization is regulated. The outcome of this application will advance our understanding of the regulatory network in synapse formation. Synapse integrity is detrimental to the function of the brain, hence the health of a human being. This study will contribute to the understanding of the basic mechanisms that maintain healthy synapses, and may also provide insights into the pathogenesis of synapse dysfunction.
描述(由申请人提供): 化学突触是介导从神经元到其靶点的信息流的超微结构不同的亚细胞实体。在突触前终末,突触囊泡有序地排列在电子致密的活动区周围。最近的研究揭示了多种途径控制突触前分化。本实验室的一个重点是在线虫C. elegans来鉴定调节突触形成的基因。rpm-1基因(突触前形态的调节因子)编码一个进化上保守的大蛋白,该蛋白含有多个功能结构域,包括环指E3泛素连接酶结构域。rpm-1功能的丧失导致了不同的突触缺陷,从不能形成稳定的突触到突触前末梢的紊乱。通过遗传筛选,我们已经确定了一个MAP激酶模块,其活性被rpm-1抑制。该MAP激酶模块由DLK-1(MAP激酶)、MKK-4(MAP激酶激酶)和PMK-3(p38样MAP激酶)组成。任何一种激酶的功能丧失都会抑制rpm-1突变体中的突触缺陷,而野生型动物中MAP激酶信号传导的升高会导致类似于rpm-1突变体的异常突触。DLK-1定位于突触前区域,并且其丰度似乎在rpm-1突变体中升高。基于这些数据,我们假设在突触形成期间RPM-1可能通过靶向DLK-1降解而下调MAP激酶通路。该更新申请的主要目标是定义MAP激酶(特别是DLK-1)和RPM-1之间的生物化学相互作用,并鉴定该MAP激酶途径的其他组分和可能与RPM- 1相互作用的其他基因。RPM-1定位于不同的突触下结构域。提出了额外的实验来研究其突触定位是如何调节的。这一应用的结果将促进我们对突触形成中的调节网络的理解。突触的完整性对大脑的功能有害,因此对人类的健康有害。这项研究将有助于理解维持健康突触的基本机制,也可能为突触功能障碍的发病机制提供见解。

项目成果

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Yishi Jin其他文献

Yishi Jin的其他文献

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{{ truncateString('Yishi Jin', 18)}}的其他基金

2023 Central Nervous System Injury and Repair Gordon Research Conference and Seminar
2023中枢神经系统损伤与修复戈登研究会议暨研讨会
  • 批准号:
    10753737
  • 财政年份:
    2023
  • 资助金额:
    $ 30.48万
  • 项目类别:
Molecular genetics of axon and synapse development and maintenance
轴突和突触发育和维持的分子遗传学
  • 批准号:
    10610882
  • 财政年份:
    2022
  • 资助金额:
    $ 30.48万
  • 项目类别:
Molecular genetics of axon and synapse development and maintenance
轴突和突触发育和维持的分子遗传学
  • 批准号:
    10456448
  • 财政年份:
    2022
  • 资助金额:
    $ 30.48万
  • 项目类别:
GABAergic Neuron Differentiation in C.elegans
线虫中 GABA 能神经元的分化
  • 批准号:
    10442930
  • 财政年份:
    2021
  • 资助金额:
    $ 30.48万
  • 项目类别:
ORGANIZATION OF PRESYNAPTIC ACTIVE ZONE BASED ON TOMOGRAPHIC RECONSTRUCTION
基于断层重建的突触前活动区组织
  • 批准号:
    8169634
  • 财政年份:
    2010
  • 资助金额:
    $ 30.48万
  • 项目类别:
ORGANIZATION OF PRESYNAPTIC ACTIVE ZONE BASED ON TOMOGRAPHIC RECONSTRUCTION
基于断层重建的突触前活动区组织
  • 批准号:
    7957647
  • 财政年份:
    2009
  • 资助金额:
    $ 30.48万
  • 项目类别:
ORGANIZATION OF PRESYNAPTIC ACTIVE ZONE BASED ON TOMOGRAPHIC RECONSTRUCTION
基于断层重建的突触前活动区组织
  • 批准号:
    7722482
  • 财政年份:
    2008
  • 资助金额:
    $ 30.48万
  • 项目类别:
Neuroscience Graduate Training Program
神经科学研究生培训计划
  • 批准号:
    8474567
  • 财政年份:
    2008
  • 资助金额:
    $ 30.48万
  • 项目类别:
Neuroscience Graduate Training Program
神经科学研究生培训计划
  • 批准号:
    8089291
  • 财政年份:
    2008
  • 资助金额:
    $ 30.48万
  • 项目类别:
Neuroscience Graduate Training Program
神经科学研究生培训计划
  • 批准号:
    8293164
  • 财政年份:
    2008
  • 资助金额:
    $ 30.48万
  • 项目类别:
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