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The Dpp/TGFβ-Dependent Corepressor Schnurri Protects Epithelial Cells from JNK-Induced Apoptosis in Drosophila Embryos

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Jun N-terminal kinase (JNK) often mediates apoptosis in response to cellular stress. However, during normal development, JNK signaling controls a variety of live cell behaviors, such as during dorsal closure in Drosophila embryos. During this process, the latent proapoptotic activity of JNK becomes apparent following Dpp signaling suppression, which leads to JNK-dependent transcriptional activation of the proapoptotic gene reaper. Dpp signaling also protects cells from JNK-dependent apoptosis caused by epithelial disruption. We find that repression of reaper transcription by Dpp is mediated by Schnurri. Moreover, reporter gene analysis shows that a transcriptional regulatory module comprising AP-1 and Schnurri binding sites located upstream of reaper integrate the activities of JNK and Dpp. This arrangement allows JNK to control a migratory behavior without triggering apoptosis. Dpp plays a dual role during dorsal closure. It cooperates with JNK in stimulating cell migration and also prevents JNK from inducing apoptosis.
The reaper Promoter Integrates Inputs from JNK and Dpp Signaling (A) Diagram of the reporter constructs that were tested in transgenic embryos; 5.5 kb of the reaper promoter were used to create rpr-GFP. Predicted binding sites for Schnurri or AP-1 were mutated to generate the variants listed. Details of the mutations are indicated in the text. (B) The unmutated reporter (rpr-GFP) is almost silent in wild-type embryos. En, Engrailed. (C) In crumbs mutant embryos, the same reporter is active in the ventrolateral, but not the dorsal (double-headed arrow), epidermis. (D) By contrast, in schnurri mutants, rpr-GFP becomes active in the dorsal epidermis, suggesting that Schnurri is an essential repressive factor. (E) Embryos lacking both crumbs and schnurri upregulate rpr-GFP throughout much of the epidermis. (F) Mutation of the predicted Schnurri binding site leads to upregulation of the reporter in the dorsal epidermis wild-type embryos at stage 13. (G) In crumbs mutant embryos, rpr[DShn]-GFP upregulation is seen in the dorsal epidermis (double-headed arrow) as well as in the ventrolateral epidermis, consistent with the notion that Schnurri contributes to preventing reaper expression in the dorsal epidermis of crumbs embryos. (H-J) Upregulation of the reaper reporter in crumbs mutants requires the two predicted AP-1 binding sites. Deletion of either site leads to reduced expression while the double mutant reporter (rpr[DAP1 D ; DAP1 P ]-GFP) is silent. (K) Gamma-irradiated embryos carrying the rpr [DAP1 D ; DAP1 P ]-GFP transgene express GFP throughout, showing that this reporter is functional. All embryos are shown at stage 11 except for (F), which shows a stage 12-13 embryo. Engrailed (En), shown in white, provides an indication of the embryos' overall morphology.
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... Discs with neutral clones (GFP-marked cells) show a normal appearance with a typical planar-organized layer of epithelial cells (S4A-S4C Fig). When activating JNK in such clones, by expressing an activated form of hemipterous (UAS-hep act ) that acts upstream of the main JNK kinase [33], a reduced number of clones was recovered (S4D-S4G Fig), in line with the well-described pro-apoptotic function of JNK that can lead to elimination of cells from the tissue [9,19,34]. We also confirmed that the JNK reporter was detected in or around clones with overactive JNK (S4G Fig). ...
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