Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.
Bottom Line: Throughout their lifetime, cells may suffer insults that reduce their fitness and disrupt their function, and it is unclear how these potentially harmful cells are managed in adult tissues.We address this question using the adult Drosophila posterior midgut as a model of homeostatic tissue and ribosomal Minute mutations to reduce fitness in groups of cells.Finally, we show that winner cell proliferation is fueled by the JAK-STAT ligand Unpaired-3, produced by Minute(-/+) cells in response to chronic JNK stress signaling.
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.Show MeSH
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Mentions: We next addressed how JNK signaling induces the proliferation of fitter cells. A potential candidate was the secreted JAK-STAT cytokine Unpaired-3 (Upd-3), because it has been shown that JNK signaling can activate Upd-3 expression, which mediates proliferation, tissue repair, and in some cases tumor growth (Pastor-Pareja et al., 2008; Beebe et al., 2010; Buchon et al., 2009b; Wu et al., 2010; Osman et al., 2012). Indeed, we found that M−/+ guts display robust upd-3 activation (detected using upd3-Gal4 and UAS-GFP; Agaisse et al., 2003; Figures 6A and 6B). Consistently, JAK-STAT activity (reported by 10×Stat-GFP; Bach et al., 2007) was higher in M−/+ guts compared to control (Figures S4A and S4B). In addition, we found that inhibiting JNK signaling in ECs (with JNKDN) was sufficient to restore JAK-STAT activity in M−/+ guts back to wild-type levels (Figures S4A–S4C), indicating that JAK-STAT activation is downstream of JNK signaling. To assess whether Upd-3 is the proliferative signal boosting wild-type tissue overgrowth during cell competition, we tested whether reducing JAK-STAT signaling was able to contain the clonal expansion of wild-type cells in M−/+ guts. Notably, expression of the dominant-negative Upd-3 receptor Domeless (DomeDN) across the posterior midgut resulted in significant size reduction of competing wild-type clones (Figure 6E, left). In addition, reducing the dome gene dosage was able to contain substantially the overgrowth of wild-type clones in competing conditions (Figures 6C and 6D; Figure 6E, right), whereas it had no effect on clone size in control wild-type guts (Figure 6E, center). Altogether, we conclude that Upd-3, produced by M−/+ cells downstream of chronic JNK signaling, fuels the proliferative expansion of wild-type clones during cell competition in this tissue.
Affiliation: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.