SUMMARYCell competition is a conserved mechanism that regulates organ size and shares properties with the early stages of cancer. In Drosophila, wing cells with increased Myc or with optimum ribosome function become supercompetitors that kill their wild-type neighbors (called losers) up to several cell diameters away. Here, we report that modulating STAT activity levels regulates competitor status. Cells lacking STAT become losers that are killed by neighboring wild-type cells. By contrast, cells with hyper-activated STAT become supercompetitors that kill losers located at a distance in a manner that is dependent on hid but independent of Myc, Yorkie, Wingless signaling, and of ribosome biogenesis. These results indicate that STAT, Wingless and Myc are major parallel regulators of cell competition, which may converge on signals that non-autonomously kill losers. As hyper-activated STATs are causal to tumorigenesis and stem cell niche occupancy, our results have therapeutic implications for cancer and regenerative medicine.

SUMMARY JAK/STAT signaling is localized to the wing hinge, but its function is not known. Here we show that the Drosophila STAT Stat92E is downstream of Homothorax and is required for hinge development by cell-autonomously regulating hinge-specific factors. Within the hinge, Stat92E activity becomes restricted to gap domain cells that lack Nubbin and Teashirt. While gap domain cells lacking Stat92E have significantly reduced proliferation, increased JAK/STAT signaling there does not expand this domain. Thus, this pathway is necessary but not sufficient for gap domain growth. We show that reduced Wingless (Wg) signaling dominantly inhibits Stat92E activity in the hinge. However, ectopic JAK/STAT signaling does not perturbs Wg expression in the hinge. We report negative interactions between Stat92E and the notum factor Araucan, resulting in restriction of JAK/STAT signaling from the notum. In addition, we find that the distal factor Nub represses the ligand unpaired as well as Stat92E activity. These data suggest that distal expansion of JAK/STAT signaling is deleterious to wing blade development. Indeed, mis-expression of Unpaired within the presumptive wing blade causes small, stunted adult wings. We conclude that JAK/STAT signaling is critical for hinge fate specification and growth of the gap domain and that its restriction to the hinge is required for proper wing development.

Mitogen-activated protein kinases (MAPKs) phosphorylate target proteins in both the cytoplasm and nucleus, and a strong correlation exists between the subcellular localization of MAPK and resulting cellular responses. It was thought that MAPK phosphorylation was always followed by rapid nuclear translocation. However, we and others have found that MAPK phosphorylation is not always sufficient for nuclear translocation in vivo. In the developing Drosophila wing, MAPK-mediated signaling is required both for patterning and for cell proliferation, although the mechanism of this differential control is not fully understood. Here, we show that phosphorylated MAPK (pMAPK) is held in the cytoplasm in differentiating larval and pupal wing vein cells, and we show that this cytoplasmic hold is required for vein cell fate. At the same time, we show that MAPK does move into the nucleus of other wing cells where it promotes cell proliferation. We propose a novel Ras pathway bifurcation in Drosophila and our results suggest a mechanism by which MAPK phosphorylation can signal two different cellular outcomes (differentiation versus proliferation) based on the subcellular localization of MAPK.

A key event in patterning the developing Drosophila compound eye is the progressive restriction of the transcription factor Atonal in the morphogenetic furrow. The Atonal pattern evolves from expression in all cells to an over-dispersed pattern of single founder cells (the future R8 photoreceptors). This restriction involves Notch-mediated lateral inhibition. However, there have been inconsistent data on a similar proposed role for the Egf receptor (Egfr). Experiments using a conditional Egfr mutation(Egfrtsla) suggested that Egfr does not regulate Atonal restriction, whereas experiments using Egfr-null mosaic Minute+ clones suggested that it does. Here, we have re-examined both approaches. We report that the lesion in Egfrtslais a serine to phenylalanine change in a conserved extracellular ligand-binding domain. We show by biochemical and genetic approaches that the Egfrtsla protein is rapidly and completely inactivated upon shift to the non-permissive temperature. We also find that on temperature shift the protein moves from the cell surface into the cell. Finally, we report a flaw in the Egfr-null mosaic Minute+ clone approach. Thus, we demonstrate that Egfr does not play a role in the initial specification or spacing of ommatidial founder cells.

Animal development requires that positional information act on the genome to control cell fate and cell shape. The primary determinant of animal cell shape is the cytoskeleton and thus the mechanisms by which extracellular signals influence the cytoskeleton are crucial for morphogenesis. In the developing Drosophila compound eye, localized polymerization of actin functions to constrict the apical surface of epithelial cells, both at the morphogenetic furrow and later to maintain the coherence of the nascent ommatidia. As elsewhere, actin polymerization in the developing eye is regulated by ADF/cofilin ('Twinstar', or 'Tsr' in Drosophila), which is activated by Slingshot (Ssh), a cofilin phosphatase. Here we show that Ssh does act in the developing eye to limit actin polymerization in the assembling ommatidia, but not in the morphogenetic furrow. While Ssh does control cell shape, surprisingly there are no direct or immediate consequences for cell type. Ssh protein becomes apically concentrated in cells that express elevated levels of the Sevenless (Sev) receptor-tyrosine kinase (RTK), even those which receive no ligand. We interpret this as a non-signal driven, RTK-dependent localization of Ssh to allow for locally increased actin filament turnover. We suggest that there are two modes of actin remodeling in the developing eye: a non-RTK, non-Ssh mediated mechanism in the morphogenetic furrow, and an RTK and Ssh-dependent mode during ommatidial assembly.