A Feed-Forward Circuit Linking Wingless, Fat-Dachsous Signaling, and the Warts-Hippo Pathway to Drosophila Wing Growth

Abstract

The secreted morphogen Wingless promotes Drosophila wing growth by fueling a wave front of Fat-Dachsous signaling that recruits new cells into the wing primordium.

Abstract

During development, the Drosophila wing primordium undergoes a dramatic increase in cell number and mass under the control of the long-range morphogens Wingless (Wg, a Wnt) and Decapentaplegic (Dpp, a BMP). This process depends in part on the capacity of wing cells to recruit neighboring, non-wing cells into the wing primordium. Wing cells are defined by activity of the selector gene vestigial ( vg) and recruitment entails the production of a vg-dependent “feed-forward signal” that acts together with morphogen to induce vg expression in neighboring non-wing cells. Here, we identify the protocadherins Fat (Ft) and Dachsous (Ds), the Warts-Hippo tumor suppressor pathway, and the transcriptional co-activator Yorkie (Yki, a YES associated protein, or YAP) as components of the feed-forward signaling mechanism, and we show how this mechanism promotes wing growth in response to Wg. We find that vg generates the feed-forward signal by creating a steep differential in Ft-Ds signaling between wing and non-wing cells. This differential down-regulates Warts-Hippo pathway activity in non-wing cells, leading to a burst of Yki activity and the induction of vg in response to Wg. We posit that Wg propels wing growth at least in part by fueling a wave front of Ft-Ds signaling that propagates vg expression from one cell to the next.

Author Summary

Under normal conditions, animals and their various body parts grow until they achieve a genetically predetermined size and shape—a process governed by secreted organizer proteins called morphogens. How morphogens control growth remains unknown. In Drosophila, wings develop at the larval stage from wing primordia. Recently, we discovered that the morphogen Wingless promotes growth of the Drosophila wing by inducing the recruitment of neighboring cells into the wing primordium. Wing cells are defined by the expression of the “selector” gene vestigial. Recruitment depends on the capacity of wing cells to send a short-range, feed-forward signal that allows Wingless to activate vestigial in adjacent non-wing cells. Here, we identify the molecular components and circuitry of the recruitment process. We define the protocadherins Fat and Dachsous as a bidirectional ligand-receptor system that is controlled by vestigial to generate the feed-forward signal. Further, we show that the signal is transduced by the conserved Warts-Hippo tumor suppressor pathway via activation of its transcriptional effector Yorkie. Finally, we propose that Wingless propels wing growth by fueling a wave front of Fat-Dachsous signaling and Yorkie activity that propagates vestigial expression from one cell to the next.