Abstract
The potent activity of Wnt/Wingless (Wg) signals necessitates sophisticated mechanisms that spatially and temporally regulate their distribution and range of action. The two main receptor components for Wg - Arrow (Arr) and Frizzled 2 (Fz2) - are transcriptionally downregulated by Wg signaling, thus forming gradients that oppose that of Wg. Here, we analyze the relevance of this transcriptional regulation for the formation of the Wg gradient in the Drosophila wing disc by combining in vivo receptor overexpression with an in silico model of Wg receptor interactions. Our experiments show that ubiquitous upregulation of Arr and Fz2 has no significant effects on Wg output, whereas clonal overexpression of these receptors leads to signaling discontinuities that have detrimental phenotypic consequences. These findings are supported by our in silico model for Wg diffusion and signal transduction, which suggests that abrupt changes in receptor levels causes discontinuities in Wg signaling. Furthermore, we identify a 200 bp regulatory element in the arr locus that can account for the Arr gradient, and we show that this is indirectly negatively controlled by Wg activity. Finally, we analyze the role of Frizzled 3 (Fz3) in this system and find that its expression, which is induced by Wg, contributes to the establishment of the Arr and Fz2 gradients through counteracting canonical signaling. Taken together, our results provide a model in which the regulatory network of Wg and the three receptor components account for the range and shape of this prototypical morphogen system.
Highlights
Communication between the cells in a tissue depends on extracellular signaling molecules
Transcriptional downregulation of Arr and Frizzled 2 (Fz2) by Wg signaling In the Drosophila melanogaster wing imaginal disc, the expression pattern of Arr and the inferred Wg protein gradient are inverse (Fig. 1A-C) – low Arr levels close to the Wg source are contrasted by high Arr levels at sites of little or no Wg
Modeling Wg receptor interactions To formalize, and systematically study, the mechanisms of Wg-receptor interaction, we developed an in silico model that reproduces the negative regulation of Arr and Fz2 by Wg in cells of the wing pouch (Fig. 2)
Summary
Communication between the cells in a tissue depends on extracellular signaling molecules. The vast majority of these are produced by defined subsets of cells. This restricted production provides spatial information that is needed for the signals to orchestrate patterning and growth. The signaling output is dependent on the range of action and level of activity of the secreted signaling protein – determinants that depend on the biochemical nature of the signal and on the receptor systems that are employed by the receiving cells. Mechanisms that precisely and tightly control Wnt signal reception and transduction, both spatially and temporally, are absolutely necessary – Wnt signaling is crucial in many developmental processes, and improper activation of the canonical signaling cascade
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