I am currently an Assistant Professor of Microbiology and Molecular Genetics at Harvard Medical School (tenure track). My laboratory occupies approximately 1000 sq. ft of space in the Molecular Medicine Unit of the Beth Israel Hospital. I am committed to an academic research career with 90% of my time devoted to research activities and 10% of my time spent in the graduate teaching programs of Harvard Medical School. I have previously demonstrated that signaling by Wnts (a family of secreted proteins related to the Wnt1 proto-oncogene) are important for body plan formation in vertebrate embryos. Although a large body of prior experimental evidence implicates Wnts in a variety of developmental processes, little is known about the reception or transduction of Wnt signals. My long term career goal is to define the signal transduction pathways, especially those relevant to Wnts, which are required for early vertebrate development. To achieve this goal, I plan to acquire new experimental skills and knowledge of signal transduction and the structure/functional studies of proteins by expanding my interactions with a number of Harvard faculty, by participating in seminars, journal clubs and workshops specialized in these fields and by intensifying my studies of Dishevelled, a novel protein involved in the Wnt signaling pathway both in Drosophila and in vertebrates. My preliminary experiments indicate that a maternally expressed Xenopus homolog of Dishevelled (Xdsh) participates in the reception of Wnt signals and plays a crucial role in early development. It is proposed to analyze expression of Xdsh mRNA and protein by in situ hybridization and immunocytochemistry. The developmental function of Xdsh will be investigated by destroying the Xdsh mRNA with antisense oligonucleotides. Over- and underexpression techniques will be utilized to determine the role of Xdsh in dorsoventral patterning and during neural tissue development. Antibodies to Xdsh and cDNA expression cloning will be used to identify proteins that physically interact with Xdsh in embryonic cells. These experiments should lead to better understanding of the molecular basis of Wnt signal transduction during vertebrate development and its involvement in breast tumor formation.
