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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031816-11
Application #
3280147
Study Section
Genetics Study Section (GEN)
Project Start
1983-04-01
Project End
1995-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
11
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Kadyk, L C; Kimble, J (1998) Genetic regulation of entry into meiosis in Caenorhabditis elegans. Development 125:1803-13
Kadyk, L C; Lambie, E J; Kimble, J (1997) glp-3 is required for mitosis and meiosis in the Caenorhabditis elegans germ line. Genetics 145:111-21
Francis, R; Barton, M K; Kimble, J et al. (1995) gld-1, a tumor suppressor gene required for oocyte development in Caenorhabditis elegans. Genetics 139:579-606
Ellis, R E; Kimble, J (1995) The fog-3 gene and regulation of cell fate in the germ line of Caenorhabditis elegans. Genetics 139:561-77
Ellis, R E; Kimble, J (1994) Control of germ cell differentiation in Caenorhabditis elegans. Ciba Found Symp 182:179-88;discussion 189-92
Henderson, S T; Gao, D; Lambie, E J et al. (1994) lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans. Development 120:2913-24
Maine, E M; Kimble, J (1993) Suppressors of glp-1, a gene required for cell communication during development in Caenorhabditis elegans, define a set of interacting genes. Genetics 135:1011-22
Lissemore, J L; Currie, P D; Turk, C M et al. (1993) Intragenic dominant suppressors of glp-1, a gene essential for cell-signaling in Caenorhabditis elegans, support a role for cdc10/SWI6/ankyrin motifs in GLP-1 function. Genetics 135:1023-34
Ahringer, J; Rosenquist, T A; Lawson, D N et al. (1992) The Caenorhabditis elegans sex determining gene fem-3 is regulated post-transcriptionally. EMBO J 11:2303-10
Kodoyianni, V; Maine, E M; Kimble, J (1992) Molecular basis of loss-of-function mutations in the glp-1 gene of Caenorhabditis elegans. Mol Biol Cell 3:1199-213

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