CELL SIGNALING IN C. ELEGANS LARVAL DEVELOPMENT

描述(改编自研究人员摘要)：转化生长因子β途径游戏 在人类发育和疾病中的重要作用；转化生长因子β基因突变 途径导致癌症和疾病中不受控制的细胞生长和转移 如遗传性出血性毛细血管扩张症2型。 秀丽在神经内分泌事件中发挥作用，该事件控制着 专门的幼虫形式，称为达尔，除了控制其他 行为和表型。这些基因是：daf7(一种转化生长因子β配体)、daf1和 Daf4(受体激酶)，daf8和daf14(Smad转录因子)。这个 Daf3基因，也是Smad，突变为Dauer缺陷表型，并遗传 分析表明，这个基因受到其他五个基因的负调控。 基因。 他们的目的是：1)研究基因daf5的功能。有缺陷的达尔 Daf5的表型和上位性关系表明，它和daf3一样，可能 受转化生长因子β途径的负调控。他们将决定 Daf5的表达模式，以识别其功能所在的细胞，并且它们 将测试daf5的表达或亚细胞定位是否 受控制Dauer的其他基因控制。2)描述新的抑制子 Daf7的达尔构成表型。他们手中有85个抑制者； 对这些抑制子的一个子集的分析揭示了四个新的基因座 控制达尔队形。他们将确定其他抑制者中的哪些是 也是新基因的等位基因，并测试所有新的基因座在 由转化生长因子β途径控制的事件。他们将确定新的基因座是否 控制daf3和daf5的表达或亚细胞定位。这些 分析将为这些新的 基因发挥作用。然后他们将选择两个基因座进行克隆，这将允许 以研究这些基因在达尔形成和转化生长因子β中的作用 路径。3)为了鉴定表达Daf1受体激酶的细胞， 并通过激光消融来测试这些细胞的功能。他们还将使用纸巾 表达daf4、daf8、daf14和daf3的特异性启动子和细胞类型特异性启动子 来检验这些基因在哪里发挥作用的假说。他们将研究 组织培养体系中受体与Smad的生化关系 以检验监管关系的假设。这些目标的实现 将使他们能够阐明转化生长因子β途径在控制 神经内分泌调节线虫发育中的事件，并将导致 识别参与这一途径的新基因。参与其中 转化生长因子β和神经内分泌信号在重要发育过程中的作用 疾病表明了对人类健康的重要影响。

DESCRIPTION (adapted from investigator's abstract): TGF Beta pathways play important roles in human development and disease; mutations in TGF Beta pathways cause uncontrolled cell growth and metastasis in cancers, and diseases such as hereditary hemorrhagic telangiectasis type 2. A TGF Beta pathway in C. elegans functions in a neuroendocrine event that controls the development of a specialized larval form called dauer, in addition to controlling other behaviors and phenotypes. These genes are: daf7 (a TGF Beta ligand), daf1 and daf4 (receptor kinases), and daf8 and daf14 (Smad transcription factors). The daf3 gene, also a Smad, mutates to a dauer defective phenotype, and genetic analysis suggests that this gene is negatively regulated by the other five genes. Their aims are: 1) To study the function of the gene daf5. The dauer defective phenotype and epistasis relationships of daf5 suggests that it, like daf3, may be negatively regulated by the TGF Beta pathway. They will determine the expression pattern of daf5 to identify cells in which it functions, and they will test whether the expression or subcellular localization of daf5 is regulated by other genes that control dauer. 2) To characterize new suppressors of the dauer constitutive phenotype of daf7. They have 85 suppressors in hand; analysis of a subset of these suppressors has revealed four new loci that control dauer formation. They will determine which of the other suppressors are also alleles of new genes, and test all of the new loci for function in the events controlled by the TGF Beta pathway. They will determine if the new loci control the expression or subcellular localization of daf3 and daf5. These analyses will suggest models for the molecular mechanism by which these new genes function. They will then select two loci for cloning, which will allow them to study the function of these genes in dauer formation and the TGF Beta pathway. 3) To identify cells in which the daf1 receptor kinase is expressed, and test these cells for function by laser ablation. They will also use tissue specific and cell type specific promoters to express daf4, daf8, daf14 and daf3 to test hypotheses for where these genes function. They will study the biochemical relationships of the receptors and Smads in a tissue culture system to test hypotheses for regulatory relationships. The achievement of these aims will allow them to elucidate the function of a TGF Beta pathway in controlling neuroendocrine mediated events in C. elegans development, and will result in the identification new genes that participate in this pathway. The involvement of TGFBeta and neuroendocrine signaling in important developmental processes and diseases suggests important implications for human health.