Mesoderm Specification in C. elegans

秀丽隐杆线虫中胚层规范

• 批准号: 0416922
• 负责人: Morris Maduro
• 金额: --
• 依托单位: University of California-Riverside
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0416922&HistoricalAwards=false
• 关键词: Mesoderm; Specification; C.; elegans

A central problem in developmental biology is to account for how tissue and cell type diversity arises during embryonic development in the generation of the three fundamental germ layers in animals (endoderm, mesoderm and ectoderm). The nematode, C. elegans, has been an excellent model system in which to explore mechanisms of cell fate specification and to elucidate the molecular players involved. In early mbryogenesis, the C. elegans mesendodermal precursor EMS is specified by the activation of the GATA-like transcription factors MED-1 and -2. The MEDs function with the conserved Wnt signaling pathway to specify either mesoderm (MS) or endoderm (E) fate in the EMS daughter cells. While much is known about endoderm, very little is known about how the more complex mesoderm lineage is specified. The laboratory of Dr. Maduro is interested in elucidating the mesodermal regulatory gene network and understanding how the Wnt pathway restricts activation of MED target genes to the MS cell. They have determined the novel binding site of MED-1 and used this site to identify 19 new candidate target genes, many of which have been confirmed to be expressed in mesoderm or endoderm. This proposal aims to characterize these target genes and study their regulation by MED-1 and the Wnt pathway. First, they will complete the expression analysis of the candidate MED-1 targets, and with emphasis on the predicted transcription factors, their developmental roles will be assessed genetically. Second, they will analyze the structure-function properties of MED-1 to learn more about how this novel regulator functions in mesoderm specification. Third, they will characterize the basis for differential mesodermal vs. endodermal activation of MED target genes that are regulated through an apparently novel Wnt-based mechanism. As homologs of candidate MED target genes function in mesoderm in other systems, and as the Wnt pathway functions in developmentally important processes throughout metazoa (including cancer in humans), this work promises to reveal new principles about early embryonic development and gene regulation that are widely applicable.Broader impacts: This is the first grant for a beginning investigator of Hispanic descent. The work proposed will be central to the research training of two female PhD candidates at UC Riverside (UCR). Undergraduates drawn from UCR's ethnically-diverse student body will participate in the project. Dr. Maduro will integrate education and research by teaching graduate and undergraduate courses in developmental biology.

发育生物学的一个中心问题是如何解释在动物的三个基本生殖层(内胚层、中胚层和外胚层)的胚胎发育过程中，组织和细胞类型的多样性是如何产生的。线虫，线虫，已经成为一个很好的模型系统，在其中探索细胞命运指定的机制，并阐明其中涉及的分子参与者。在早期胚胎发生中，线虫中胚层前体EMS是通过激活GATA样转录因子MED-1和MED-2来特异性的。MEDS通过保守的Wnt信号通路决定EMS子代细胞中中胚层(MS)或内胚层(E)的命运。虽然关于内胚层的了解很多，但对更复杂的中胚层谱系是如何确定的却知之甚少。马杜罗博士的实验室感兴趣的是阐明中胚层调控基因网络，并了解Wnt通路如何将MED靶基因的激活限制在MS细胞中。他们已经确定了MED-1的新结合位点，并利用该结合位点鉴定了19个新的候选靶基因，其中许多已被证实在中胚层或内胚层中表达。本研究旨在确定这些靶基因的特征，并研究MED-1和Wnt途径对它们的调控作用。首先，他们将完成候选MED-1靶标的表达分析，并将重点放在预测的转录因子上，从基因上评估它们的发育作用。其次，他们将分析MED-1的结构-功能特性，以更多地了解这种新型调节因子如何在中胚层规范中发挥作用。第三，他们将描述MED靶基因中胚层和内胚层不同激活的基础，这些基因是通过一种明显新的基于Wnt的机制来调节的。由于候选MED靶基因的同源基因在其他系统的中胚层中发挥作用，并且Wnt通路在整个后生动物(包括人类中的癌症)的发育重要过程中发挥作用，这项工作有望揭示有关早期胚胎发育和基因调控的新原理，这些原理被广泛应用。广泛的影响：这是对西班牙裔后裔的初步研究人员的第一笔拨款。拟议的工作将是加州大学河滨分校(UCR)两名女性博士生研究培训的核心。从UCR不同种族的学生群体中抽取的本科生将参与该项目。马杜罗博士将通过教授发育生物学的研究生和本科生课程，将教育和研究结合起来。