Abstract
Dorsal-ventral patterning of the Drosophila embryo depends on the NFκB superfamily transcription factor Dorsal (Dl). Toll receptor activation signals for degradation of the IκB inhibitor Cactus (Cact), leading to a ventral-to-dorsal nuclear Dl gradient. Cact is critical for Dl nuclear import, as it binds to and prevents Dl from entering the nuclei. Quantitative analysis of cact mutants revealed an additional Cact function to promote Dl nuclear translocation in ventral regions of the embryo. To investigate this dual Cact role, we developed a predictive model based on a reaction-diffusion regulatory network. This network distinguishes non-uniform Toll-dependent Dl nuclear import and Cact degradation, from the Toll-independent processes of Cact degradation and reversible nuclear-cytoplasmic Dl flow. In addition, it incorporates translational control of Cact levels by Dl. Our model successfully reproduces wild-type data and emulates the Dl nuclear gradient in mutant dl and cact allelic combinations. Our results indicate that the dual role of Cact depends on the dynamics of Dl-Cact trimers along the dorsal-ventral axis: In the absence of Toll activation, free Dl-Cact trimers retain Dl in the cytoplasm, limiting the flow of Dl into the nucleus; in ventral-lateral regions, Dl-Cact trimers are recruited by Toll activation into predominant signaling complexes and promote Dl nuclear translocation. Simulations suggest that the balance between Toll-dependent and Toll-independent processes are key to this dynamics and reproduce the full assortment of Cact effects. Considering the high evolutionary conservation of these pathways, our analysis should contribute to understanding NFκB/c-Rel activation in other contexts such as in the vertebrate immune system and disease.
Highlights
In a developing organism, tissues are often patterned by long-range and spatially graded signaling factors called morphogens, which carry the positional information necessary to control gene expression
A reaction-diffusion model that distinguishes two routes for Dorsal nuclear localization highlights the distinctive contribution of Tollactivated versus free Dl flow to the nuclear Dl (nDl) gradient
In order to investigate how these different Dl nuclear entry modes impact the nuclear Dl gradient, we built a model that discriminates between these two routes
Summary
Tissues are often patterned by long-range and spatially graded signaling factors called morphogens, which carry the positional information necessary to control gene expression. Morphogens act in a concentration-dependent manner to activate or repress target genes [1,2,3,4]. In the Drosophila syncytial blastoderm, dorsal-ventral (DV) patterning depends on the nuclear localization gradient of Dorsal (Dl), an NFκB superfamily transcription factor homologous to mammalian c-Rel. Dl acts in a concentration-dependent manner to activate or repress target genes, defining three main territories of the embryo DV axis: the ventral mesoderm, lateral neuroectoderm, and dorsal ectoderm [5]. A ventral-to-dorsal activity gradient of the Toll cell surface receptor provides the activating signal for DV patterning. Activated Toll receptors on the ventral and lateral regions of the embryo lead to Cact phosphorylation followed by ubiquitination and degradation, resulting in dissociation of the Dl-Cact complex and Dl nuclear import. The amount of Dl in the nuclei is key to defining ventral, lateral and dorsal territories of the embryo
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
