ANALYSIS OF GERM LINE SEX DETERMINATION IN C ELEGANS

生殖系发育是所有后生动物的基础， 关键过程：1）决定进入减数分裂途径，2） 通过减数分裂前期的进展，3）性别决定，和4） 配子发生 这项拟议中的研究检查了生殖系的发育， 通过对三个基因的遗传和分子研究， 控制这些过程（gld-1、gld-2和fog-2）。 gld-1缺失突变体 具有显著的肿瘤表型（在整个肿瘤细胞中增殖）， 生殖细胞），具有新的起源（进入减数分裂途径的生殖细胞 不能通过减数分裂前期并重新进入细胞周期）。 gld-1肿瘤抑制基因座在生殖系中具有多重作用 发展 它不仅是减数分裂过程中所必需的 前期，也用于雌雄同体的雄性性别决定 生殖系和卵子发生。 gld-2，一个具有肿瘤生殖系的新位点 表型，也影响体细胞性别决定。 fog-2和gld-1一样， 在雌雄同体的生殖细胞系中是男性性别决定所必需的。 对这三个相关基因的研究提供了一个重要的 这是我们描述生殖系发育的长期目标的起点 作为一种分子遗传途径。 gld-1的分析：一个主要目的是确定 gld-1产品，定义不同产品所需的域 生殖系功能，并检查时间和空间模式， 表情 第二个目的是确定体细胞性腺的作用 和肿瘤表型中的GLP-1基因。 第三个目标是 了解gld-1的多种功能如何协调， 通过鉴定作为靶基因的基因， 以辅助或调节GLD-1。 gld-2分析：了解gld-2控制的过程范围 gld-2，将对该基因座进行详细的遗传分析。 的 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。 分析雾-2：雾-2产品的结构和时间 并确定表达的空间模式。 我们先前已经 提出fog-2通过负作用促进雄性生殖细胞的发育， 调节TRA-2受体。 fog-2对tra-2的调节将是 基因测试和酵母双杂交系统。 拟议工作的健康相关性是双重的。 一是研究 关于简单、实验可及的多细胞动物的种系发育 系统，如C elegans提供了关于 包括人类在内的所有动物的发育过程。 二是 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.