Molecular Mechanisms Regulating Axon Guidance Receptor Activity

调节轴突引导受体活性的分子机制

基本信息

项目摘要

DESCRIPTION (provided by applicant): As the nervous system develops, axons are guided along specific pathways to find their targets and make functional connections. The precise pattern of connections is essential for proper nervous system function. Axon migrations are directed by guidance cues in the extracellular environment. On the surface of migrating axons, receptors detect the cues and produce signals that control cytoskeletal dynamics to direct where an axon extends. Several classes of guidance cues and receptors have been identified, including the UNC-6/netrin cue and the UNC-40/DCC receptor. The molecular mechanisms that determine the directional response when a receptor is ligated by a guidance cue are not well understood. To explore the molecular basis of axon responses, we preformed a genetic screen in C. elegans for mutations that suppress axon guidance defects caused by a specific unc-6 missense allele, rh46. Our results indicate that we uncovered mutations that enhance UNC-40 signaling when UNC-40 is ligated by UNC-6. One mutation is a loss-of-function allele of clec-38, which encodes a protein with a transmembrane and extracellular C-type lectin-like domains. Our preliminary results indicate that clec-38 negatively regulates UNC-40 signaling in several different neurons. In one case, loss of clec- 38 function causes the failure of a neuron cell body to migrate and the precocious UNC-6-dependent formation of its axon. We also uncovered a missense mutation within the unc-40 ectodomain sequence that in combination with unc-6(rh46) causes new axons migration patterns. This response is suppressed when unc- 6(rh46) is replaced with unc-6(rh46ur282) or unc-6(rh46ur301), alleles that have second site mutations that suppress the original rh46 mutation. These intragenic mutations were also recovered from the screen. These observations indicate an interaction between UNC-6 and the UNC-40 ectodomain in vivo and they suggest that the ligated confirmation of the receptor influences the nature of the axon response. We propose to further study the molecular mechanisms through which the UNC-40 signals are regulated. We plan to further characterize CLEC-38, determine other components that regulate UNC- 40 signaling, genetically dissect the signaling which controls the UNC-40 axon response, and extend our genetic screening. PUBLIC HEALTH RELEVANCE: Neurons must make the proper connections in order for a nervous system to function. Understanding the molecular mechanisms that enable molecules to direct neurons to their targets could provide new insights into disorders that affect the wiring of the nervous system and could also prove useful for developing therapeutic agents to treat nerves damaged by injuries or disease.
描述(申请人提供):随着神经系统的发展,轴突被引导沿着特定的路径找到它们的目标并建立功能连接。准确的连接模式对神经系统的正常功能至关重要。轴突的迁移是由细胞外环境中的引导线索指导的。在迁移的轴突表面,受体检测信号,并产生信号,控制细胞骨架动力学,指示轴突延伸到哪里。已经确定了几类指导信号和受体,包括UNC-6/netrin信号和UNC-40/DCC受体。当受体被引导信号连接时,决定定向反应的分子机制还不是很清楚。为了探索轴突反应的分子基础,我们在线虫中进行了基因筛查,寻找抑制特定UNC-6错义等位基因Rh46引起的轴突引导缺陷的突变。我们的结果表明,当UNC-40被UNC-6连接时,我们发现了增强UNC-40信号的突变。一个突变是CLEC-38的功能缺失等位基因,它编码一种具有跨膜和细胞外C型凝集素样结构域的蛋白质。我们的初步结果表明,CLEC-38在几个不同的神经元中负向调节UNC-40信号。在一种情况下,CLEC-38功能的丧失导致神经元细胞体无法迁移,并导致其轴突的早熟形成依赖于UNC-6。我们还在UNC-40胞外结构域序列中发现了一个错义突变,与UNC-6(Rh46)结合会导致新的轴突迁移模式。当UNC-6(Rh46)被UNC-6(Rh46ur282)或UNC-6(Rh46ur301)取代时,这种反应被抑制,这些等位基因具有抑制原始Rh46突变的第二位点突变。这些基因内突变也是从筛查中恢复的。这些观察表明UNC-6和UNC-40胞外结构域在体内存在相互作用,它们表明受体的连接确认影响了轴突反应的性质。我们建议进一步研究UNC-40信号调控的分子机制。我们计划进一步确定CLEC-38的特征,确定调控UNC-40信号的其他成分,从基因上剖析控制UNC-40轴突反应的信号,并扩大我们的基因筛查。与公共健康相关:神经元必须建立适当的连接,才能使神经系统发挥作用。了解使分子能够将神经元定向到其靶点的分子机制,可以为影响神经系统连接的疾病提供新的见解,也可能被证明有助于开发治疗因损伤或疾病而受损的神经的治疗剂。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

WILLIAM G WADSWORTH其他文献

WILLIAM G WADSWORTH的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('WILLIAM G WADSWORTH', 18)}}的其他基金

Molecular Mechanisms Regulating Axon Guidance Receptor Activity
调节轴突引导受体活性的分子机制
  • 批准号:
    8055875
  • 财政年份:
    2009
  • 资助金额:
    $ 33.44万
  • 项目类别:
Molecular Mechanisms Regulating Axon Guidance Receptor Activity
调节轴突引导受体活性的分子机制
  • 批准号:
    7679878
  • 财政年份:
    2009
  • 资助金额:
    $ 33.44万
  • 项目类别:
Molecular Mechanisms Regulating Axon Guidance Receptor Activity
调节轴突引导受体活性的分子机制
  • 批准号:
    8704538
  • 财政年份:
    2009
  • 资助金额:
    $ 33.44万
  • 项目类别:
Molecular Mechanisms Regulating Axon Guidance Receptor Activity
调节轴突引导受体活性的分子机制
  • 批准号:
    7761277
  • 财政年份:
    2009
  • 资助金额:
    $ 33.44万
  • 项目类别:
Molecular Mechanisms Regulating Axon Guidance Receptor Activity
调节轴突引导受体活性的分子机制
  • 批准号:
    8432479
  • 财政年份:
    2009
  • 资助金额:
    $ 33.44万
  • 项目类别:
EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C ELEGANS
线虫的细胞外基质和轴突引导
  • 批准号:
    2703040
  • 财政年份:
    1995
  • 资助金额:
    $ 33.44万
  • 项目类别:
Extracellular Matrix and Axonal Guidance in C. elegans
线虫的细胞外基质和轴突引导
  • 批准号:
    7812488
  • 财政年份:
    1995
  • 资助金额:
    $ 33.44万
  • 项目类别:
EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C ELEGANS
线虫的细胞外基质和轴突引导
  • 批准号:
    2271766
  • 财政年份:
    1995
  • 资助金额:
    $ 33.44万
  • 项目类别:
EXTRACELLULAR MATRIX AND AXONAL GUIDANCE IN C. ELEGANS
线虫的细胞外基质和轴突引导
  • 批准号:
    6539795
  • 财政年份:
    1995
  • 资助金额:
    $ 33.44万
  • 项目类别:
Extracellular Matrix and Axonal Guidance in C. elegans
线虫的细胞外基质和轴突引导
  • 批准号:
    7416580
  • 财政年份:
    1995
  • 资助金额:
    $ 33.44万
  • 项目类别:

相似海外基金

How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
  • 批准号:
    23K00129
  • 财政年份:
    2023
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
  • 批准号:
    2883985
  • 财政年份:
    2023
  • 资助金额:
    $ 33.44万
  • 项目类别:
    Studentship
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了