Toll Pathway Signal Transduction in Pattern Formation and Innate Immunity

We are interested in how information regulating gene expression is encoded, transmitted, and interpreted. In addressing this question, we focus on a signaling pathway, conserved from insects to humans, that has evolved a rich array of variations adaptive to diverse functions in development and defense. We are investigating both mechanism and adaptations in the fruit fly, where we can readily generate mutations that disrupt pathway function, monitor and manipulate gene activity, and map out regulatory circuitry using molecular, biochemical, and bioinformatic techniques.

The Toll signal transduction pathway establishes the dorsoventral axis of the fly embryo.  Localized activation of the transmembrane receptor Toll leads to the graded nuclear translocation of the transcription factor Dorsal. By activation of ventral-specific loci and repression of dorsal-specific loci, the Dorsal gradient establishes subdivides the dorsoventral axis. Dorsal protein is initially present throughout the embryonic cytoplasm, bound to an inhibitor, Cactus, that blocks nuclear translocation. Following fertilization, localized cleavage of the ligand Spätzle activates Toll in a graded ventral to dorsal pattern over the embryo surface. Signaling by activated Toll triggers degradation of Cactus, freeing Dorsal protein to direct gene expression.

Toll  also functions as part of the innate immune response to microbial infection. Upon exposure to a fungal pathogen, wild-type flies express an array of genes encoding anti-microbial peptides, including Drosomycin, a potent anti-fungal agent. The transcription factor activated by Toll in this setting is the Drosophila Immunity Factor (DIF), which, like Dorsal, 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.

The Research link at the top of the page provides an overview of our current research efforts in this area.