Over the past fifteen years since the cloning of the Drosophila melanogaster segment polarity gene wingless (wg), many genes that are involved in the signal transduction pathway downstream of Wg, or the vertebrate Wg homologue Wnt, have been identified. Research has also proposed the importance of this pathway in cancer development. However, just as Wg/Wnt researchers were beginning to think the pathway might be 'solved', two new members of the Wg pathway in Drosophila have been cloned. In this issue of Nature Cell Biology, Mariann Bienz and colleagues clone pygopus (Nature Cell Biol., 4, 367–373, 2002), and in a recent Cell publication (Cell, 109, 47–60, 2002), Konrad Basler and colleagues also cloned pygopus and another gene called legless (lgs).

Work by both these groups, and others, have previously shown that transduction of the Wg/Wnt signal is mediated by nuclear TCF/LEF-1, through association with Armadillo (Arm)/β-catenin. Basler et al. identified Lgs in a genetic screen for suppressors of an eye phenotype in Drosophila, which is generated by overexpression of wg. Embryos that lack Lgs have similar phenotypes to wg mutants, and genetic epistasis experiments indicate that Lgs functions downstream of Arm. Protein localization experiments show that Lgs is probably a nuclear protein. Surprisingly, when Lgs was cloned it, was shown to be the Drosophila homologue of Bcl-9, a known oncogene involved in the development of non-Hodgkins lymphoma. As Lgs is found in the nucleus, Basler and colleagues showed that both Lgs and human BLC-9 could bind Arm, which strongly suggests that Lgs functions in a nuclear complex with Arm.

M. BIENZ

A second gene was identified simultaneously by Basler et al. and by Bienz et al. Bienz identified Pygopus in a genetic screen for suppressors of an activated Arm phenotype in the fly eye, whereas Basler identified Pygopus as a binding partner of Lgs. However, both groups show that Drosophila embryos that are mutant for pygopus have a phenotype which is similar to a loss of wg (see image).

Through protein localization studies, Bienz et al. show that, in common with Lgs, Pygopus is also a nuclear protein and that it is found in a complex with Arm. Using epistasis studies, it became clear that Pygopus was also needed for TCF/LEF-1-mediated gene transcription. This lead Bienz et al. to conclude that Pygopus functions to mediate access of either TCF or Arm to chromatin, possibly through the PHD domain of Pygopus, which is also found in other proteins that function in chromatin complexes. Whereas results from the Basler lab indicate that Pygopus is not only found in a complex with Arm and TCF, but is also found in a complex with Lgs, and that the primary function of Lgs is to recruit Pygopus to Arm. They suggest that this enables recruitment of Pygopus and functions to affect gene transcription. Work in press at Development by Kenneth Cadigan and colleagues also identifies Pygopus as a member of the Wg pathway.

Whatever the actual mechanism of action for both Lgs and Pygopus, it is clear that the Wg/Wnt pathway is far from solved. Furthermore, even in these days of sequenced genomes, new members of the pathway, which could have important consequences in the understanding of signal transduction and cancer development, are still being identified.