Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT-Dependent Manner.
Bottom Line: 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.We also find that competition induces stem cell proliferation and self-renewal in healthy tissue, promoting selective advantage and tissue colonization.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
Related in: MedlinePlus
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.