A central problem in metazoan development is how cells are specified to develop along one particular pathway. I propose to analyze two developmental controls in the nematode, Caenorhabditis elegans: specification of cell type (sperm or oocyte) and regulation of cell proliferation (choice between mitosis and meiosis in the germ line). During the first period of this grant, my lab identified genes central to both controls. In addition, we proposed a model for the genetic control of germ-line sex determination that provides an intellectual framework for many of the experiments presented here. In the next five years, I plan an intensive genetic analysis of sex determination in the germ-line tissue of this nematode. Most, and perhaps all, genes central to the sperm/oocyte decision will be identified, and a genetic and phenotypic characterization of mutants will be used to study the function of the sex determination control genes. In addition, a molecular analysis of sex determination control will be initiated by cloning the fem-3 gene. This locus was selected because the properties of fem-3 mutants suggest that it is central to sex determination in all tissues. Once cloned, fem-3 gene structure and expression will be examined in wild-type and mutant animals. A genetic analysis of the germ-line choice between continued mitoses and entry into meiosis is also planned. Genes central to this decision will be identified by mutation, and the function of each gene will be studied by genetic and phenotypic characterization of mutant strains. For analysis of gene function in individual tissues during development several techniques will be used. Microinjection and in situ hybridization will be employed to introduce and localize fem-3 transcripts to explore the cellular basis of that control. Blastomere injections and genetic mosaics will be used to study the tissue specificity of genes not yet clone.d The health relatedness of this work derives from its contribution to an understanding of mechanisms of control over cell growth and differentiation. Defects in such controls may lead to congenital defects or cancer in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031816-07
Application #
3280144
Study Section
Genetics Study Section (GEN)
Project Start
1983-04-01
Project End
1991-03-31
Budget Start
1989-04-01
Budget End
1990-03-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Graduate Schools
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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