Signaling pathways such as the MAP kinase pathway are used in many different tissues throughout metazoan development to control important cell fate decisions. Misinterpretation of a signal by a cell can lead to cancer or developmental defects. However, the mechanisms by which a signal directs downstream effectors to generate the ultimate fate of the cell remain largely mysterious. The long-term objective of this proposal is to gain a comprehensive knowledge of how the information from a cytoplasmic signal such as MAP kinase is interpreted through altered target gene expression to produce a specific cell fate. These studies focus on MAP kinase regulation of meiotic progression in the Caenorhabditis elegans germ line. Because MAP kinase mediates meiotic progression in many species, the results obtained from these studies will potentially be broadly applicable. By taking functional genomics approaches to identify genes acting downstream of the MAP kinase signaling pathway, followed by classical molecular analysis of key effeetors, comprehensive knowledge of the genetic and biochemical network responding to MAP kinase in a particular tissue will be attained. ? ? Specifically, DNA microarrays will be used to identify candidate transcriptional target genes downstream of MAP kinase signaling in the C. elegans germ line. The cis-acting regulatory sites in those genes will be defined through sequence identification algorithms and tested for MAP kinase responsiveness through transgenic analysis. Candidate immediate-early genes encoding transcription factors will then be examined for binding to the cis-acting sites identified in the target genes. The requirement for these downstream effectors, whether transcription factor or transcription target, in mediating MAP kinase dependent meiotic progression in vivo will be assessed using RNA-mediated interference and genetic analysis. Together these experiments should build toward a comprehensive understanding of the mechanisms used to produce a specific cell fate in response to a generally used signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM065682-05
Application #
7172689
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Haynes, Susan R
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
5
Fiscal Year
2007
Total Cost
$272,849
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chi, Woo; Reinke, Valerie (2009) DPL-1 (DP) acts in the germ line to coordinate ovulation and fertilization in C. elegans. Mech Dev 126:406-16
Wang, Guilin; Reinke, Valerie (2008) A C. elegans Piwi, PRG-1, regulates 21U-RNAs during spermatogenesis. Curr Biol 18:861-7
Kudron, Michelle M; Reinke, Valerie (2008) C. elegans nucleostemin is required for larval growth and germline stem cell division. PLoS Genet 4:e1000181
Lin, Baiqing; Reinke, Valerie (2008) The candidate MAP kinase phosphorylation substrate DPL-1 (DP) promotes expression of the MAP kinase phosphatase LIP-1 in C. elegans germ cells. Dev Biol 316:50-61
Leacock, Stefanie W; Reinke, Valerie (2008) MEG-1 and MEG-2 are embryo-specific P-granule components required for germline development in Caenorhabditis elegans. Genetics 178:295-306
Boag, Peter R; Atalay, Arzu; Robida, Stacey et al. (2008) Protection of specific maternal messenger RNAs by the P body protein CGH-1 (Dhh1/RCK) during Caenorhabditis elegans oogenesis. J Cell Biol 182:543-57
Spike, Caroline A; Bader, Jason; Reinke, Valerie et al. (2008) DEPS-1 promotes P-granule assembly and RNA interference in C. elegans germ cells. Development 135:983-93
Bender, Laurel B; Suh, Jinkyo; Carroll, Coleen R et al. (2006) MES-4: an autosome-associated histone methyltransferase that participates in silencing the X chromosomes in the C. elegans germ line. Development 133:3907-17
Chi, Woo; Reinke, Valerie (2006) Promotion of oogenesis and embryogenesis in the C. elegans gonad by EFL-1/DPL-1 (E2F) does not require LIN-35 (pRB). Development 133:3147-57
Leacock, Stefanie W; Reinke, Valerie (2006) Expression profiling of MAP kinase-mediated meiotic progression in Caenorhabditis elegans. PLoS Genet 2:e174

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