How do cells communicate to control growth and differentiation? To approach this fundamental problem of metazoan development, we propose to analyze the genetic control of a single cell-cell interaction in the nematode Caenorhabditis elegans: regulation of germline proliferation by the somatic distal tip cell (DTC). During the past few years, we have laid the groundwork for the experiments proposed: genetic and molecular analyses of the g1p-1 gene, which mediates the DTC/germline interaction, and discovery of two new genes, 1ag-1 and 1ag-2, which are essential to interactions mediated by g1p-1 and its homologue, 1in-12. During the next five years, we propose to investigate the mechanism by which the DTC, g1p-1, and 1ag genes control germline proliferation. First, we plan to delineate the functional domains of the g1p-1 protein. To this end, we will elucidate the sequence changes in known EMS-induced g1p-1 mutations and assay the effects of site-directed g1p-1 mutants on germline growth. In parallel we will characterize the g1p-1 protein and locate it within the germ line. Second, we plan to investigate the roles of the 1ag genes and analyze genetically their functional relationship(s) with g1p-1 and 1in-12. We will also clone both 1ag genes and obtain their DNA sequences in an attempt to gain insight into their biochemical functions(s). Third, we will examine the architecture of wild-type and mutant gonads by electron microscopy to learn about the cellular basis of the DTC control over germline growth. Fourth, we will try novel mutagenesis schemes to identify other genes involved in the DTC/germline interaction. Finally, we will explore the role of g1p-1 in embryonic induction and investigate the functional redundancy of g1p-1 and 1in-12. The health relatedness of this work derives from its contribution to the understanding of controls over cell growth and differentiation. The g1p-1 gene is a member of a small gene family with members found also in frogs and man. Defects in g1p-1-like controls in man might lead to congenital defects or cancer.
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