Genetic analysis of a microRNA pathway regulating neural tube closure

调节神经管闭合的 microRNA 通路的遗传分析

基本信息

批准号：
9564399
负责人：
Jianfu Chen
金额：
$ 31.09万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9564399
关键词：
3&apos Untranslated Regions Affect Apoptotic Behavior Binding Biological Birth Cell Proliferation Cell Survival Cell physiology Chemicals Complex Congenital Abnormality Cyclin D1 Data Defect Development Embryo Exhibits Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Goals Human Image Individual Knock-out Lead Mediating Messenger RNA Methods MicroRNAs Molecular Morphogenesis Mus Mutant Strains Mice Neural Tube Closure Neural Tube Defects Neural tube Pathway interactions Phenotype Process RNA-Binding Proteins Regulator Genes Repression Role Testing Tissues Untranslated RNA cell behavior embryo culture genetic analysis genetic approach improved inhibitor/antagonist insight loss of function mouse model mutant neural plate neural precursor cell neuromechanism neuroregulation novel premature prevent public health relevance spatiotemporal time use trait

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to establish a novel mechanism whereby microRNA (miRNA) miR-302/367 regulates neural tube closure (NTC). Disruption of NTC leads to neural tube defect (NTD), which is the second most common birth defect in humans affecting 1 to 1,000 births. However, the regulators and mechanisms that control NTC at post-transcriptional gene regulation levels remain largely unknown. We have created the first miRNA mouse model of NTD. We found that depletion of miR-302/367 leads to NTD and embryonic lethality. Neural precursor cells (NPCs) exhibit reduced proliferation, premature differentiation, and decreased survival in the mutant embryos. Importantly, we have identified individual miRNA targets with potent roles in specific cellular behaviors that are affected in mutant embryos. In addition, we found that miR-302/367 is associated with an RNA binding protein Lin41 to regulate gene expression; depletion of Lin41 also leads to NTD. These preliminary data lead to a novel hypothesis that miR-302/367 interacts with Lin41 to coordinately control multiple neural precursor cell (NPC) behaviors by regulating different miRNA targets during neural tube closure (NTC). In this project, we will determine miR-302/367 functions and their action mechanisms during neural tube closure. Three specific aims will be pursued: 1) Determine the developmental and cellular basis of neural tube defect (NTD) in miR-302/367 mutant mice; 2) Test whether individual genes that we have identified as targets of miR-302 mediate specific cellular behaviors during neural tube closure; 3) Test the hypothesis that miR-302 functions together with Lin41 to regulate gene expression and NPC behaviors during neural tube closure. Together, these studies will improve our understanding of genetic factors associated with NTD and provide novel insights into mechanisms underlying neural tube closure and neural tube defect (NTD).

描述（由适用提供）：该提案的总体目标是建立一种新的机制，microRNA（miRNA）miR-302/367调节神经管闭合（NTC）。 NTC的破坏会导致神经元管缺陷（NTD），这是影响1至1,000个出生的人类中第二常见的先天缺陷。但是，在转录后基因调控水平上控制NTC的调节剂和机制在很大程度上尚不清楚。我们创建了NTD的第一个miRNA小鼠模型。我们发现miR-302/367的耗竭导致NTD和胚胎致死性。神经前体细胞（NPC）暴露于突变胚胎中的增殖，过早分化和增加的生存率。重要的是，我们已经确定了在突变胚胎中受影响的特定细胞行为中潜在作用的单个miRNA靶标。此外，我们发现miR-302/367与RNA结合蛋白LIN41有关以调节基因表达。 LIN41的耗竭也导致NTD。这些初步数据导致了一个新的假设，即miR-302/367与LIN41相互作用，以协调控制多个神经元前体细胞（NPC）行为，通过控制神经元管闭合（NTC）期间的不同miRNA靶标。在这个项目中，我们将确定miR-302/367功能及其在神经管闭合过程中的作用机制。将追求三个具体目标：1）确定miR-302/367突变小鼠中神经管缺陷（NTD）的发育和细胞基础； 2）测试我们已确定为神经管闭合期间的miR-302特定细胞行为的靶标的单个基因； 3）测试miR-302与LIN41一起发挥作用以调节神经管闭合期间基因表达和NPC行为的假设。总之，这些研究将提高我们对与NTD相关的遗传因素的理解，并为神经管闭合和神经管缺陷（NTD）提供的机制提供新的见解。