): Cell junctions like adherens, septate and tight junctions, play an important role in the control of cell proliferation, intercellular barrier formation, cellular differentiation, and morphogenesis. These junctions are composed of proteins that play both structural and/or signaling roles. Characterization of Neurexin IV (NRX IV), a septate junction associated protein in Drosophila, has established its role in blood-nerve barrier formation, and morphogenesis. T h e present data show that NRX IV is also required for cellular differentiation and control of cell proliferation. The absence of NRX IV presumably causes aggressive tumors through the constitutive activation of specific proteins in one or more of the signaling pathways (e.g. hedgehog, wingless, Ras etc.). The applicants will test this hypothesis using mitotic recombination and immunocytochemical staining techniques using a variety of markers implicated in these signaling pathways. They will also determine if a human homologue of NRX IV, which maps near the BRCA1 gene, is implicated in breast and ovarian cancer. Several lines of evidence suggest that other genes than BRCA1 are involved in breast, ovarian, and prostate cancer and map to this region. The proposed studies will determine if molecular alterations in human NRX IV can be identified in breast and ovarian cancer cell lines as well as in freshly isolated tumors. Through a yeast two hybrid screen, the principal investigator has identified an intracellular ligand of NRX IV which contains 4 PDZ domains. Mutational analysis of the gene encoding this protein, discs lost (dlt), suggest that it may also play a role in the control of cell proliferation: in the absence of DLT protein, severely reduced proliferation of imaginal cells was observed. The principal investigator therefore proposes to carry out experiments which will define more precisely the role of this apically localized protein in signaling by attempting to answer the following questions: Where is the protein precisely localized? Is the maternal contribution important? Is cell polarity affected in mutant cells? What are the consequences of over expressing the protein? The P.I. will also define the signaling pathway that may be affected in dlt mutants causing lack of cell proliferation. In summary, the proposed experiments should clarify the role of two important novel proteins in cell signaling and tumorigenesis.
