The coordination of miRNAs in axon guidance
miRNA 在轴突引导中的协调
基本信息
- 批准号:10437232
- 负责人:
- 金额:$ 45.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:3&apos Untranslated RegionsAxonBindingBrainChickensCollaborationsComplexCuesDefectDevelopmentDown-RegulationEctopic ExpressionEmbryoFloorGene ExpressionGenesGenetic TranscriptionIn VitroMediatingMessenger RNAMicroRNAsModelingMolecularMusNTN1 geneNervous system structureNeurodevelopmental DisorderNeuronsPatternPhenotypePlayProtein BiosynthesisProteinsRegulationRepressionRoleSHH geneSemaphorinsSpinalSpinal CordStudy modelsTestingTranslationsUntranslated RNAUntranslated RegionsVertebratesaxon guidancedesigndevelopmental diseaseexperimental studyin vivoloss of functionmRNA Transcript Degradationnervous system disorderneural circuitneural networkneuron developmentnovelprotein expressionreceptorreceptor expressionresponsespatiotemporal
项目摘要
Proper axon outgrowth and pathfinding is essential for establishing precise neural networks during
development. Defects in axon guidance are implicated in a variety of neurological disorders.
Spatiotemporal regulation of guidance receptor expression facilitates differential responses of neurons to
guidance cues in order to form accurate neuronal wiring. In vertebrates, levels of the guidance receptor
Robo1 are low in precrossing and high in postcrossing commissural axons (CAs), functioning as a
‘molecular switch’ to regulate sensitivity to Slit repulsion and guide CA midline crossing. However, the
mechanism underlying the fine-tuned spatiotemporal regulation of Robo1 expression remains largely
unknown. MicroRNAs (miRNAs) regulate target gene expression by binding specifically to the three prime
untranslated region (3’UTR) of target mRNAs, thus repressing translation and/or inducing
mRNA degradation. Our recent studies indicate that the chicken Robo1 (cRobo1) 3’UTR is required
for regulation of protein expression in the developing spinal cord, and miR-92 represses cRobo1
expression to regulate Slit sensitivity thereby controlling CA projection and midline crossing.
Interestingly, miR-219a, another highly conserved miRNA, also suppresses cRobo1 expression. Ectopic
expression of miR-219a in postcrossing commissural neurons results in stalling of CAs in the floor plate.
Therefore, we propose that both miR-92 and miR-219a function as negative regulators of Robo1
expression in CAs by targeting its mRNA at the 3’UTR to control Slit/Robo1-mediated CA projection
and midline crossing. To test this hypothesis, we will first determine whether endogenous
miR-219a specifically regulates cRobo1 expression in commissural neurons of embryonic chicken
spinal cords during midline crossing (Aim 1): we will (1) determine the temporospatial expression
patterns of miR-219a and cRobo1 in commissural neurons, (2) examine the activity of endogenous
miR-219a in precrossing commissural neurons of chicken spinal cords, and (3) untangle the
mechanisms underlying miR-219a-mediated repression of cRobo1. Secondly, we will focus on
studying the functional importance of miR-219a in Slit/Robo1-mediated CA outgrowth and turning in
vitro and CA projection and pathfinding in vivo (Aim 2). Finally, we will investigate the collaboration of
miR-92 and miR-219a in repression of cRobo1 expression in Slit/Robo1-mediated spinal CA guidance
(Aim 3): we will examine the collaboration of miR-92 and miR-219a in (1) suppression of cRobo1
expression by targeting its 3’UTR, (2) regulation of cRobo1 local protein synthesis in CAs, (3) Slit/
cRobo1-mediated CA guidance. These proposed experiments will provide a novel model that specific
miRNAs collaboratively suppress Robo1 expression, thereby modulating Slit sensitivity to
control Slit/Robo1-mediated CA guidance during embryonic spinal cord development.
适当的轴突生长和寻路对于建立精确的神经网络至关重要,
发展轴突导向缺陷与多种神经系统疾病有关。
引导受体表达的时空调节促进神经元对
以形成准确的神经元布线。在脊椎动物中,
Robo 1在交叉前低而在交叉后高的连合轴突(CA)中,作为一个神经元,
“分子开关”调节对Slit排斥的敏感性并引导CA中线交叉。但
Robo 1表达的微调时空调控机制在很大程度上仍然存在
未知microRNAs(miRNAs)通过特异性结合三个引物来调节靶基因的表达。
靶mRNA的非翻译区(3 'UTR),从而抑制翻译和/或诱导
mRNA降解。我们最近的研究表明,鸡Robo 1(cRobo 1)3 'UTR是必需的,
调节发育中脊髓的蛋白表达,miR-92抑制cRobo 1
表达以调节Slit敏感性,从而控制CA投射和中线穿越。
有趣的是,另一种高度保守的miRNA miR-219 a也抑制cRobo 1的表达。异位
miR-219 a在交叉后连合神经元中的表达导致底板中CA的停滞。
因此,我们认为miR-92和miR-219 a都是Robo 1的负调控因子,
通过在3 'UTR处靶向其mRNA以控制Slit/Robo 1介导的CA投射来在CA中表达
和中线交叉。为了检验这一假设,我们将首先确定是否内源性
miR-219 a特异性调控鸡胚连合神经元cRobo 1的表达
脊髓中线穿越(目标1):我们将(1)确定时空表达
miR-219 a和cRobo 1在连合神经元中的模式,(2)检查内源性miR-219 a和cRobo 1的活性。
miR-219 a在鸡脊髓交叉前连合神经元中的表达,以及(3)解开
miR-219 a介导的cRobo 1抑制的潜在机制。第二,我们会专注于
研究miR-219 a在Slit/Robo 1介导的CA生长和转化中的功能重要性
体外和CA投射和体内寻路(Aim 2)。最后,我们将调查
miR-92和miR-219 a在Slit/Robo 1介导的脊髓CA引导中抑制cRobo 1表达
(Aim 3):我们将研究miR-92和miR-219 a在(1)抑制cRobo 1
通过靶向其3 'UTR表达,(2)调节CA中cRobo 1局部蛋白质合成,(3)Slit/
cRobo 1介导的CA引导。这些拟议的实验将提供一种新的模型,
miRNAs协同抑制Robo 1表达,从而调节Slit敏感性,
胚胎脊髓发育过程中Slit/Robo 1介导的CA指导。
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 }}
Guofa Liu其他文献
Guofa Liu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('Guofa Liu', 18)}}的其他基金
MicroRNA regulation of guidance receptors in axonal pathfinding
轴突寻路中引导受体的微小RNA调节
- 批准号:
9892213 - 财政年份:2019
- 资助金额:
$ 45.15万 - 项目类别:
Modulation of Microtubule Dynamics in Axon Guidance
轴突引导中微管动力学的调节
- 批准号:
8732123 - 财政年份:2014
- 资助金额:
$ 45.15万 - 项目类别:
相似海外基金
Impact of alternative polyadenylation of 3'-untranslated regions in the PI3K/AKT cascade on microRNA
PI3K/AKT 级联中 3-非翻译区的替代多聚腺苷酸化对 microRNA 的影响
- 批准号:
573541-2022 - 财政年份:2022
- 资助金额:
$ 45.15万 - 项目类别:
University Undergraduate Student Research Awards
How do untranslated regions of cannabinoid receptor type 1 mRNA determine receptor subcellular localisation and function?
1 型大麻素受体 mRNA 的非翻译区如何决定受体亚细胞定位和功能?
- 批准号:
2744317 - 财政年份:2022
- 资助金额:
$ 45.15万 - 项目类别:
Studentship
MICA:Synthetic untranslated regions for direct delivery of therapeutic mRNAs
MICA:用于直接递送治疗性 mRNA 的合成非翻译区
- 批准号:
MR/V010948/1 - 财政年份:2021
- 资助金额:
$ 45.15万 - 项目类别:
Research Grant
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10019570 - 财政年份:2019
- 资助金额:
$ 45.15万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10223370 - 财政年份:2019
- 资助金额:
$ 45.15万 - 项目类别:
Translational Control by 5'-untranslated regions
5-非翻译区域的翻译控制
- 批准号:
10455108 - 财政年份:2019
- 资助金额:
$ 45.15万 - 项目类别:
Synergistic microRNA-binding sites, and 3' untranslated regions: a dialogue of silence
协同的 microRNA 结合位点和 3 非翻译区:沉默的对话
- 批准号:
255762 - 财政年份:2012
- 资助金额:
$ 45.15万 - 项目类别:
Operating Grants
Analysis of long untranslated regions in Nipah virus genome
尼帕病毒基因组长非翻译区分析
- 批准号:
20790351 - 财政年份:2008
- 资助金额:
$ 45.15万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Search for mRNA elements involved in the compatibility between 5' untranslated regions and coding regions in chloroplast translation
寻找参与叶绿体翻译中 5 非翻译区和编码区之间兼容性的 mRNA 元件
- 批准号:
19370021 - 财政年份:2007
- 资助金额:
$ 45.15万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Post-transcriptional Regulation of PPAR-g Expression by 5'-Untranslated Regions
5-非翻译区对 PPAR-g 表达的转录后调控
- 批准号:
7131841 - 财政年份:2006
- 资助金额:
$ 45.15万 - 项目类别: