Abstract
ABSTRACTWnts are secreted proteins that regulate cell fate during development of all metazoans. Wnt proteins were proposed to spread over several cells to activate signaling directly at a distance. In the Drosophila wing epithelium, an extracellular gradient of the Wnt1 homolog Wingless (Wg) was observed extending over several cells away from producing cells. Surprisingly, however, it was also shown that a membrane-tethered Neurotactin-Wg fusion protein (NRT-Wg) can largely replace endogenous Wg, leading to proper patterning of the wing. Therefore, the functional range of Wg and whether Wg spreading is required for correct tissue patterning remains controversial. Here, by capturing secreted Wg on cells away from the source, we show that Wg acts over a distance of up to 11 cell diameters to induce signaling. Furthermore, cells located outside the reach of extracellular Wg depend on the Frizzled2 receptor to maintain signaling. Frizzled2 expression is increased in the absence of Wg secretion and is required to maintain signaling and cell survival in NRT-wg wing discs. Together, these results provide insight into the mechanisms by which robust Wnt signaling is achieved in proliferating tissues.
Highlights
Wnts are lipid-modified secreted proteins conserved in all metazoans and play a pivotal role in development and many diseases (Nusse and Clevers, 2017; Zhan et al, 2017)
We show that cells that have moved out of the range of a functional Wg gradient require the Fz2 receptor to maintain the expression of low-threshold Wg target genes, which is important for the survival of cells in NRT-wg discs
In order to control for the effect of cell proliferation on the accuracy of determining the Wg range, we induced the expression of Fz2 only at mid-third-instar larval stage and reduced the growth rate by keeping larvae at 18°C after the heat shock
Summary
Wnts are lipid-modified secreted proteins conserved in all metazoans and play a pivotal role in development and many diseases (Nusse and Clevers, 2017; Zhan et al, 2017). Studies of Wnt protein carriers, e.g. exosomes and other vesicles, lipoprotein particles and proteinaceous co-factors The long-range morphogen model for Wnt proteins has been challenged by recent studies, showing that juxtacrine Wnt signaling to the neighboring cell via a membranetethered Wnt protein is sufficient for proper tissue patterning in Drosophila (Alexandre et al, 2014). A primarily shortrange distribution of Wnt proteins is observed in the mouse intestinal crypts, mediated by Wnt-membrane association and cell division (Boutros and Niehrs, 2016; Farin et al, 2016), and Wnts are found on the surface of cytonemes and filopodia (Huang and Kornberg, 2015; Mattes et al, 2018; Stanganello et al, 2015; Stanganello and Scholpp, 2016)
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