The goal of this project is to understand the molecular basis for how intercellular signals control cell-type determination during animal development. During vulval induction in the nematode Caenorhabditis elegans, a single gonadal cell induces three of six multipotent epithelial precursor cells to proliferate and generate differentiated vulval cells. Genetic analyses have defined genes necessary for this inductive process. Three such genes encode nematode homologs of mammalian proto-oncogenes involved in signalling, and act in a common pathway. The predicted lin-3 gene product, which contains a single epidermal growth factor [EGF] repeat, is a candidate for the inductive signal. the let-23 gene product, a transmembrane tyrosine kinase of the EGF-receptor family, is a candidate for the receptor for the inductive signal. the let-60 gene product, a ras protein, acts as a switch that controls cell type in response to lin-3 and let-23. This study will use classical genetics, molecular cloning, transgenic nematodes, and biochemical methods to understand the function of these proto-oncogenes in intercellular signalling, and to identify novel components of this signalling pathway.
The specific aims of this proposal are to test the hypotheses that lin-3 encodes the inductive signal and let- 23 encodes its receptor; to characterize the negative regulation of the let -23 receptor by studying genes, as well as domains of let-23, that modulate the activity of this receptor; to identify genes that couple the let-23 tyrosine kinase and let-60 ras, and to identify genes that act after the let-60 ras protein to activate vulval differentiation. Nematode vulval induction provides an excellent opportunity to study, in the context of a developing animal, the action of gene products whose mutant forms result in cell transformation and cancer. The strong conservation of these gene products and this signal transduction pathway throughout evolution makes it likely that novel gene products identified by these studies of vulval induction will help elucidate how intercellular signalling works during mammalian development.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetics Study Section (GEN)
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California Institute of Technology
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Green, Jennifer L; Inoue, Takao; Sternberg, Paul W (2008) Opposing Wnt pathways orient cell polarity during organogenesis. Cell 134:646-56
Gonzalez-Serricchio, Aidyl S; Sternberg, Paul W (2006) Visualization of C. elegans transgenic arrays by GFP. BMC Genet 7:36
Gupta, Bhagwati P; Liu, Jing; Hwang, Byung J et al. (2006) sli-3 negatively regulates the LET-23/epidermal growth factor receptor-mediated vulval induction pathway in Caenorhabditis elegans. Genetics 174:1315-26
Gupta, Bhagwati P; Wang, Minqin; Sternberg, Paul W (2003) The C. elegans LIM homeobox gene lin-11 specifies multiple cell fates during vulval development. Development 130:2589-601
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Wang, M; Sternberg, P W (2000) Patterning of the C. elegans 1 degrees vulval lineage by RAS and Wnt pathways. Development 127:5047-58
Shim, J; Sternberg, P W; Lee, J (2000) Distinct and redundant functions of mu1 medium chains of the AP-1 clathrin-associated protein complex in the nematode Caenorhabditis elegans. Mol Biol Cell 11:2743-56
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