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（TGFβ）相关配体调节细胞分化和功能的许多方面，并且信号传导途径的组分充当涉及人类癌症的肿瘤抑制因子。在线虫秀丽隐杆线虫中，TGFbeta 相关信号通路（dbl-1 通路）控制体型大小和雄性尾部形态发生。此前对该通路的研究在识别保守信号成分方面取得了丰硕成果，包括 Smad 信号转导器 SMA-2、SMA-3 和 SMA-4。 Smad 蛋白是细胞质成分，受激活的 TGFbeta 受体直接调节，易位到细胞核并产生转录反应。鉴于 TGFbeta 反应的多样性和细胞类型特异性，这种简单的 Smad 信号传导机制必须需要其他信号传导成分的调节。为了确定 dbl-1 途径的其他成分，特别是那些赋予特定途径反应的成分，对影响体型的其他突变进行了正向遗传筛选。该筛选鉴定了几个新基因，包括 sma-20。对 sma-20 突变体表型的初步分析表明，它在 dbl-1 信号传导中发挥空间和时间上的特定作用。为了表征 sma-20 在体型调节、雄性尾部发育和 TGFbeta 相关信号转导中的作用，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 功能完全丧失（空）表型； (2)作图并定位克隆sma-20； (3) 分析 sma-20 细胞和时间作用焦点。这些实验将为纽约市立大学皇后学院的一名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、Smads 和 Schnurri 在遥远的动物门中是保守的，因此研究遗传易处理的模型生物体中的新成分也应该可以深入了解它们在其他生物体中的功能。