PTEN (phosphatase and tensin homolog, deleted on chromosome ten) is an important tumor suppressor gene in human. Somatic mutations in PTEN are found in advanced forms of brain, endometrial, prostate and skin cancers. Germline mutations in PTEN when heterozygous are associated with tumor predisposing diseases, and when homozygous cause lethality. Since PTEN affects many types of cells, it is likely to control fundamental cellular processes. However, the effects of PTEN mutations vary from cell to cell. This disparity can be explained by that different pathways operating in these cells affect the outcome of PTEN mutations. In C. elegans, the PTEN homolog
daf-18 has known roles in aging and dauer formation (Refs. 1-4), but is dispensable for the survival of the organism under the standard lab condition. We therefore set out to find synthetic lethal genes that function with
daf-18. Using in situ hybridization, we preliminarily determined that
daf-18 is robustly expressed in the germline of adult animals. Based on this observation, we focused on two phenotypes, sterile (Ste) and embryonic lethality (Emb) in our screen. We used
daf-18(
nr2037) and
rrf-3(
pk1426);
daf-18(
nr2037) animals to screen the chromosome I feeding library (Ref. 5) for RNAi clones that exhibit P0 Ste and/or F1 Emb. These clones were re-screened using controls, N2 and
rrf-3, as well as information available in the Ahringer Lab database. At the time of writing, we are down to several candidate clones with which RNAi treatment causes highly penetrant Ste or Emb phenotypes in the
daf-18 mutants, but not in wild-type animals. We are examining (a) the cell lineage of the affected animals, (b) the interactions between other genes in the
daf-2 insulin receptor-like pathway and genes identified to interact with
daf-18, and (c) the interactions between genes related to the identified genes and
daf-18. C. elegans appears to be a powerful system to uncover redundant pathways functioning with PTEN. Identification of these pathways could help explain the cell-type specificity of PTEN effects in human, thereby enabling more effective treatment of PTEN-related diseases. References: (1) Ogg S, Ruvkun G. Mol Cell. 1998 2:887-93. (2) Gil EB et al. Proc Natl Acad Sci U S A. 1999 96:2925-30. (3) Mihaylova VT et al. Proc Natl Acad Sci U S A. 1999 96:7427-32. (4) Rouault JP et al. Curr Biol. 1999 9:329-32. (5) Fraser AG et al. Nature. 2000 408:325-30.