ANALYSIS OF GERM LINE SEX DETERMINATION IN C ELEGANS

生殖系发育是所有后生动物的基础，包括四个 关键过程：1)决定进入减数分裂途径，2) 减数分裂前期进展，3)性别决定，4) 配子发生。这项拟议的研究检查了生殖系在 线虫通过对三个基因的遗传和分子研究 控制这些进程(GLD-1、GLD-2和FOG-2)。GLD-1缺失突变体 有显著的肿瘤表型(在整个 生殖系)，具有新的来源(进入减数分裂途径的生殖细胞 未能通过减数分裂前期并重新进入细胞周期)。 GLD-1抑癌基因在生殖系中具有多重作用 发展。它不仅是减数分裂进程所必需的 前期，但也用于两性人的雄性决定 生殖系和卵子发生。GLD-2，一个具有肿瘤生殖系的新基因座 表型，也影响体细胞性别决定。雾2号和GLD-1号一样， 对于两性生殖系中的男性性别决定是必要的。 对这三个相关基因的拟议研究提供了一个重要的 我们描述生殖系发展的长期目标的起点 作为一种分子遗传途径。 GLD-1的分析：一个主要目标是确定GLD-1的结构 GLD-1产品(S)，定义了不同 生殖系功能，并检查时空模式 表情。第二个目标是确定体细胞性腺的作用。 GLP-1基因与肿瘤表型有关。第三个目标是 了解GLD-1的多种功能是如何在 通过识别作为靶标或行为的基因来进行生殖系开发 协助或调节GLD-1。 分析GLD-2：了解受控过程的范围 GLD-2，将对该基因座进行详细的遗传分析。这个 肿瘤表型的细胞基础，以及 体细胞性腺和GLP-1基因在肿瘤形成中的作用，将被确定。 FOG-2分析：FOG-2产品的结构和时间 表达的空间模式将被确定。我们之前已经 认为FOG-2通过负向促进雄性生殖系发育 调节tra-2受体。FOG-2对tra-2的调节将是 使用酵母双杂交系统进行了遗传测试。 这项拟议的工作与健康有关有两个方面。第一，研究 关于在简单的、可实验获取的后生动物中的生殖系发育 Celegans等系统提供了有关 包括人类在内的所有动物的发育过程。第二， GLD-1和GLD-2基因为生殖系肿瘤提供了有用的体内模型 可能适用于人类癌症的形成。

Germline development is fundamental to all metazoans and includes four crucial processes: 1) the decision to enter the meiotic pathway, 2) progression through meiotic prophase, 3) sex determination, and 4) gametogenesis. The proposed research examines germline development in C elegans through a genetic and molecular study of three genes which control these processes (gld-1, gld-2, and fog-2). gld-1 null mutants have a striking tumorous phenotype (proliferation throughout the germline), with a novel origin (germ cells that enter the meiotic pathway fail to progress through meiotic prophase and re-enter the cell cycle). The gld-1 tumor suppressor locus has multiple roles in germline development. It is required not only for progression through meiotic prophase, but also for male sex determination in the hermaphrodite germline, and oogenesis. gld-2, a new locus with a tumorous germline phenotype, also affects somatic sex determination. fog-2, like gld-1, is necessary for male sex determination in the hermaphrodite germline. Proposed studies of these three interrelated genes provide an important starting point for our long-term goal of describing germline development as a molecular-genetic pathway. Analysis of gld-1: One major aim is to determine the structure of the gld-1 products(s), define domains that are necessary for different germline functions, and examine temporal and spatial patterns of expression. The second aim is to determine the role of the somatic gonad and the glp-1 gene in the tumorous phenotype. The third aim is to understand how the multiple functions of gld-1 are coordinated in germline development by identifying genes that are targets, or that act to assist or regulate gld-1. Analysis of gld-2: To understand the range of processes controlled by gld-2, a detailed genetic analysis of the locus will be performed. The cellular basis of the tumorous phenotype, as well as the roles of the somatic gonad and the glp-1 gene in tumor formation, will be determined. Analysis of fog-2: The structure of the fog-2 product and the temporal and spatial pattern of expression will be determined. We have previously proposed that fog-2 promotes male germline development by negatively regulating the tra-2 receptor. Regulation of tra-2 by fog-2 will be tested genetically and using the yeast two-hybrid system. The health relatedness of the proposed work is two-fold. First, research on germline development in simple, experimentally accessible, metazoan systems such as C elegans provides fundamental information about developmental processes in all animals, including humans. Second, the gld-1 and gld-2 genes provide a useful in vivo model for germline tumor formation that may be applicable to human cancer.