The EGFR and JAK/STAT pathways synergize to promote ISC proliferation. Expression of the esgGal4TS, UAS-GFP reporter gene (a-c) and quantification of PH3-positive cells per midgut (d) were monitored in UC flies. Overexpression of upd3 (A2) or domeless (B2) in ISCs induced higher levels of epithelium renewal in UC flies, which was reduced by depletion of EGFR or Ras activity (A3 and B3). Conversely, the high levels of epithelium renewal induced by overexpressing an activated form of the EGFR (C2) in ISCs was slightly reduced by coexpression of a negative regulator of the JAK/STAT pathway (UAS-Socs36E), a dominant-negative form of Domeless (UAS-DomeDN) or a UAS-STAT-IR construct (C3 and D). Ectopic expression of the EGFR in ISCs expressing a dominant-negative form of Domeless did not rescue the differentiation defect caused by the lack of JAK/STAT activity, but instead aggravated the expansion of undifferentiated escargot-GFP precursor cells (C3 and inset).