Body size control genes & TGF-beta signaling C. elegans

体型控制基因

• 批准号: 6898122
• 负责人: CATHY SAVAGE-DUNN
• 金额: $ 21.59万
• 依托单位: QUEENS COLLEGE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898122
• 关键词: Caenorhabditis elegans; biological signal transduction; body physical characteristic; developmental genetics; gene expression; genetic regulation; helminth genetics; male; phenotype; polymerase chain reaction; transcription factor; transforming growth factors

DESCRIPTION (provided by applicant): Transforming growth factor beta (TGFbeta) related ligands regulate many aspects of cell differentiation and function, and components of the signaling pathway act as tumor suppressors involved in human cancers. In the nematode C. elegans, a TGFbeta-related signaling pathway, the dbl-1 pathway, controls body size and male tail morphogenesis. Studies of this pathway have previously been fruitful in identifying conserved signaling components, including the Smad signal transducers SMA-2, SMA-3, and SMA-4. Smad proteins are cytoplasmic components that are directly regulated by activated TGFbeta receptors to translocate into the nucleus and generate transcriptional responses. Given the diversity and cell type specificity of TGFbeta responses, this simple Smad signaling mechanism must require modulation by other signaling components. To identify additional components of the dbl-1 pathway and in particular those that confer specific pathway responses, a forward genetic screen for additional mutations affecting body size was performed. This screen identified several new genes, including sma-20. Preliminary analysis of sma-20 mutant phenotypes suggests that it plays spatially and temporally specific roles in dbl-1 signaling. To characterize the roles of sma-20 in body size regulation, male tail development, and TGFbeta-related signal transduction, we propose to use genetic, molecular, and phenotypic analyses of sma-20. Our goals are to (1) determine the complete loss of function (null) phenotype of sma-20; (2) map and positionally clone sma-20; and (3) analyze sma-20 cellular and temporal focus of action. These experiments will provide educational and scientific training opportunities for a graduate student and one or more undergraduate students at Queens College, CUNY. Since TGFbeta superfamily ligands and their receptors, the Smads, and Schnurri are conserved through distant animal phyla, studying new components in a genetically tractable model organism should provide insight into their functions in other organisms as well.

描述（由申请人提供）：转化生长因子β（TGFBETA）相关的配体调节细胞分化和功能的许多方面，信号通路的成分充当涉及人类癌症的肿瘤抑制器。在线虫C.秀丽隐杆线虫中，与TGFBETA相关的信号通路，DBL-1途径控制体大小和男性尾巴形态发生。对该途径的研究以前在鉴定保守的信号传导组件（包括SMAD信号传感器SMA-2，SMA-3和SMA-4）方面富有成果。 SMAD蛋白是细胞质成分，由活化的TGFBETA受体直接调节以转移到细胞核中并产生转录反应。鉴于TGFBETA响应的多样性和细胞类型特异性，这种简单的SMAD信号机制必须需要其他信号传导组件进行调节。为了鉴定DBL-1途径的其他组件，尤其是那些赋予特定途径响应的组件，进行了前向遗传筛选，以实现影响身体大小的其他突变。该屏幕确定了几个新基因，包括SMA-20。 SMA-20突变表型的初步分析表明，它在DBL-1信号传导中扮演了空间和时间上特定的作用。为了表征SMA-20在体型调节，男性尾巴发育和与TGFBETA相关的信号转导中的作用，我们建议使用SMA-20的遗传，分子和表型分析。我们的目标是（1）确定SMA-20的功能（NULL）表型的完全丧失； （2）地图和位置克隆SMA-20； （3）分析SMA-20细胞和时间的作用重点。这些实验将为CUNY皇后学院的研究生和一名或多名本科生提供教育和科学培训机会。由于TGFBETA超家族配体及其受体，因此Smads和Schnurri是通过遥远的动物门来保存的，研究了遗传障碍模型生物体中的新成分也应提供对其在其他生物体中的功能的见解。