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 i s to determine the role of the somatic gonad and the glp-1 gene in the tumorous phenotype.
The third aim i s 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.
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