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

描述（由申请人提供）：转化生长因子β（TGF β）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剂。线虫C.在秀丽隐杆线虫中，TGF β相关的信号传导途径，dbl-1途径，控制身体大小和雄性尾部形态发生。对该途径的研究以前在鉴定保守的信号传导组分方面富有成效，包括Smad信号转导物SMA-2、SMA-3和SMA-4。Smad蛋白是细胞质组分，其直接受活化的TGF β受体调节以易位到细胞核中并产生转录应答。鉴于TGF β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组分的调节。为了鉴定dbl-1途径的其他组分，特别是赋予特异性途径应答的那些组分，对影响体型的其他突变进行了正向遗传筛选。这个筛选鉴定出了几个新基因，包括sma-20。对sma-20突变体表型的初步分析表明，它在dbl-1信号传导中发挥着空间和时间特异性作用。为了表征sma-20在体型调节、雄性尾部发育和TGF β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的完全丧失功能（空）表型;（2）定位克隆sma-20;（3）分析sma-20的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TGF β超家族配体及其受体，Smads和Schnurri通过遥远的动物门是保守的，因此研究遗传上易于处理的模式生物中的新组分也应该提供对它们在其他生物中的功能的了解。

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.