We are interested in how biological information regulating gene expression is encoded, transmitted, and interpreted. In addressing this question, we focus on Toll signaling, a pathway for transducing information within cells that is conserved from insects to humans and that has diverse roles in development and innate immunity. Our studies focus on the fruit fly Drosophila melanogaster, with which we can readily generate mutations that disrupt pathway activity; monitor and manipulate gene activity; and map out signaling modules and regulatory circuitry using molecular, biochemical, and bioinformatic techniques. In this way, we have defined the structure and organization of a trimeric signaling complex, elucidated function-specific evolutionary adaptations, and identified novel pathway functions and effectors.
The signal transduction pathway defined by the Toll transmembrane receptor is a critical component of the Drosophila innate immune response to microbial infection. Upon exposure to a fungal pathogen, wild-type fruit flies express an array of genes encoding antimicrobial peptides, including Drosomycin, a potent anti-fungal agent. The transcription factor activated by Toll in this setting is the Drosophila Immunity Factor (DIF), which belongs to the NF-kB protein family. In mammals, Toll-like receptors (TLR’s) activate NF-kB as a critical step in innate immune response to infection. Furthermore, aberrant Toll signaling underlies a number of debilitating inflammatory disorders. The function of Toll in innate immunity is thus broadly conserved and of interest from both a fundamental and clinical perspective.
In Drosophila, Toll signaling also establishes the dorsoventral axis of the embryo. Localized activation of the transmembrane receptor Toll leads to the graded nuclear translocation of the transcription factor Dorsal, another NF-kB family member. By activation of ventral-specific loci and repression of dorsal-specific loci, the Dorsal gradient establishes subdivides the dorsoventral axis.
The same signaling pathway is used in immunity and development. Prior to signaling, the target NF-kB protein, either DIF or Dorsal, is bound in the cytoplasm by an inhibitor, Cactus, that blocks nuclear translocation. Following generation of the active Toll ligand Spätzle by upstream signals, Toll transduces signals leading to degradation of Cactus, freeing the NF-kB protein to direct gene expression.
Currently, our studies of Toll signaling are centered on three research areas:
Steven Wasserman received his Ph.D. from MIT and was a postdoctoral fellow at UC Berkeley. He has been the recipient of a Lucille P. Markey Scholarship in Biomedical Sciences, a David and Lucile Packard Fellowship in Science and Engineering, and a Distinguished Teaching Award from the UCSD Academic Senate.