| The interactions between signaling pathways are of critical importance to development and maintenance of adult tissues. As two examples, the Writ and NF-kappaB signaling pathways both have important functions during development and adulthood across the animal kingdom. Despite their widespread roles, interactions between these two well-conserved signaling families have not been reported. Here, I will describe the characterization of wntD, a divergent member of the Drosophila Wnt gene family. Using gain of function and loss of function genetics, including the construction of a wntD knockout, I will illustrate the role of wntD in acting as a feedback inhibitor of Dorsal, a member of the NF-kappaB family of transcription factors. This function will be demonstrated in the early embryo, where wntD overexpression blocks Dorsal nuclear translocation and activity independently of the inhibitor Cactus, a homolog of IkappaB. Conversely, wntD loss of function mutant embryos exhibit expanded Dorsal activation, illustrating a physiological role for endogenous WntD in Dorsal regulation. Further, I will present evidence that the role of WntD in inhibiting Dorsal is conserved during the adult immune response to infection. wntD mutants show an elevated immune response, with increased activation of known immunity genes; however, they die prematurely in response to Listeria monocytogenes infection. I will present a model in which hyperactivation of Dorsal target genes in wntD mutants is deleterious to a fly's viability, and will examine some candidate mediators of this effect that were identified with microarray analysis. Furthermore, I will begin to characterize the expression and regulation of one such candidate, CG32185. Last, the results of a genome-wide enhancer/suppressor screen for modifiers of the wntD overexpression phenotype will be presented. Candidate modifying loci will be described, with the aim of identifying components of the WntD signal transduction pathway. |
