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Transcriptional Regulation of Cell Differentiation in C. elegans by Tailless

Tailless 对线虫细胞分化的转录调控

基本信息

批准号：
8687856
负责人：
Bruce Wightman
金额：
$ 28.57万
依托单位：
MUHLENBERG COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687856
关键词：
Affect Automobile Driving Binding Sites Blood Vessels Caenorhabditis elegans Cell Count Cell Differentiation process Cell Nucleus Cell Separation Cell division Cells Complement Development Embryo Evaluation Event Excision Feedback Future Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Transcription Globin Gonadal structure Heat-Shock Response Human Hybrids In Vitro Indium Individual Invertebrates Investigation Knowledge Larva Link Lobular Neoplasia Malignant Neoplasms Mediator of activation protein Methods Modeling Molecular Molecular Genetics Morphogenesis Nematoda Neurodegenerative Disorders Nuclear Receptors Organogenesis Pathway interactions Play RNA Interference Regulation Regulator Genes Regulatory Pathway Research Personnel Role Sampling Signal Pathway Signal Transduction Specific qualifier value Stem Cell Development Stem cells System Testing Time Tissue-Specific Gene Expression Tissues Transcriptional Regulation Transgenes Uterus Vertebrates Work Yeasts aortic valve disorder base cell type gene function human disease in vivo intercellular communication interest mutant nerve stem cell neurodevelopment notch protein novel promoter public health relevance response sex sex determination transcription factor transcription factor USF transcriptome sequencing tumor progression

项目摘要

DESCRIPTION (provided by applicant): The nhr-67/tailless gene of C. elegans encodes a nuclear receptor transcription factor that plays a central role in regulating cell differentiation,and ultimately organogenesis. The human version of the nhr-67 gene, Tlx, has been shown to be a key regulator of neural stem cell identity. When the Tlx gene is compromised in vertebrates, neural stem cells cannot be maintained as dividing stem cells. Therefore, an understanding of how Tlx regulates other genes is central to understanding neural stem cells, and an important first step in identifying potential candidates for therapy in neurodegenerative disease. Towards this end, the Wightman Lab is studying the regulatory pathways both upstream and downstream of nhr-67, using the differentiation of uterine cells as a model. Among the most interesting targets of nhr-67 are the cell-cell signaling receptor Notch (lin-12) and its cognate signal delta (lag-2). In humans, Notch has been linked to developmental mechanisms associated with aortic valve disease and cancer. While Notch is also known to function in vertebrate and invertebrate neural development, this study is among the first to link Tlx function to Notch regulation. This study seeks to advance understanding of Tlx-based regulatory systems by identifying both genes that are upstream of nhr-67 and those that are downstream targets of nhr-67 function. The first major aim, to determine the upstream regulators of nhr-67 transcription in the ventral uterus, will evaluate candidate upstream transcription factors (bHLH heterodimers, LAG-1 mediator of Notch response, SEX-1 nuclear receptor) through a combination of in vitro and in vivo approaches. The bHLH transcription factor, HLH-2, which has a well-defined role in early ventral uterine development, will be evaluated in vivo as a candidate direct activator of nhr-67 expression. The study will investigate how a Notch- based feedback loop sets transcriptional levels of nhr-67, and test the hypothesis that the sex-1 embryonic sex determination function is complemented by a later function in sex-specific organogenesis. The second major aim, to evaluate the downstream mediators of nhr-67 function in the ventral uterus, will identify and study potential effectors of NHR-67 for differentiation events. This aspect of the project will clarify the role of Notch regulation as a key feature of nhr-67 function, examine the relationship between nhr-67 and a globin gene, glb-12, and identify unanticipated new targets using a new nuclei purification and differential expression strategy, combined with an established cell-sorting strategy. Successful completion of the differential expression strategy will demonstrate how a method by which other researchers can study gene expression in a small number of cells. These molecular and genetic strategies will provide a better understanding of the regulatory events that govern important developmental events. The targets identified by this study will provide important candidates for future investigations of the molecular pathways that control specification of neural stem cells and organogenesis.

描述（由申请人提供）：C.线虫编码一种核受体转录因子，该因子在调节细胞分化和最终器官发生中起核心作用。人类版本的nhr-67基因Tlx已被证明是神经干细胞身份的关键调节因子。当Tlx基因在脊椎动物中受损时，神经干细胞不能维持为分裂干细胞。因此，了解Tlx如何调节其他基因是理解神经干细胞的核心，也是确定神经退行性疾病治疗潜在候选者的重要第一步。为此，Wightman实验室正在研究nhr-67上游和下游的调控途径，使用子宫细胞的分化作为模型。nhr-67最令人感兴趣的靶点是细胞-细胞信号受体Notch（lin-12）及其同源信号delta（lag-2）。在人类中，Notch与主动脉瓣疾病和癌症相关的发育机制有关。虽然Notch也已知在脊椎动物和无脊椎动物神经发育中起作用，但这项研究是第一个将Tlx功能与Notch调节联系起来的研究。本研究旨在通过识别nhr-67上游的基因和nhr-67功能的下游靶基因来促进对Tlx调控系统的理解。第一个主要目的是确定腹侧子宫中nhr-67转录的上游调节因子，将通过体外和体内方法的组合评估候选上游转录因子（bHLH异源二聚体、LAG-1 Notch反应介体、SEX-1核受体）。bHLH转录因子HLH-2在早期腹侧子宫发育中具有明确的作用，将作为nhr-67表达的候选直接激活剂进行体内评估。该研究将研究基于Notch的反馈环如何设置nhr-67的转录水平，并测试性别-1胚胎性别决定功能由性别特异性器官发生中的后期功能补充的假设。第二个主要目的是评估腹侧子宫中nhr-67功能的下游介质，将识别和研究NHR-67对分化事件的潜在效应物。该项目的这一方面将阐明Notch调节作为nhr-67功能的关键特征的作用，研究nhr-67与珠蛋白基因glb-12之间的关系，并使用新的核纯化和差异表达策略结合已建立的细胞分选技术来鉴定未预料到的新靶点。战略差异表达策略的成功完成将展示其他研究人员如何在少量细胞中研究基因表达的方法。这些分子和遗传策略将提供一个更好的了解，管理重要的发育事件的监管事件。这项研究确定的目标将为未来研究控制神经干细胞和器官发生的分子途径提供重要的候选人。