The stem-like STAT3-responsive cells of zebrafish intestine are WNT/β-catenin dependent

The transcription factor STAT3 is required for proliferation and pluripotency of embryonic stem cells; we have prepared and characterized fluorescent STAT3-reporter zebrafish based on repeats of minimal responsive elements. These transgenic lines mimic in vivo STAT3 expression patterns and are responsive to exogenous STAT3; notably, fluorescence is inhibited by both stat3 knock-out and IL6/JAK/STAT inhibitors. At larval stages, STAT3 reporter activity correlates with proliferating regions of the brain, haematopoietic tissue and intestine. In the adult gut the reporter is active in sparse proliferating cells, located at the base of intestinal folds, expressing the stemness marker sox9b and having the mammalian Crypt Base Columnar cells morphology; noteworthy, zebrafish stat3 mutants show defects in intestinal folding. The STAT3 reporter activity in the gut is abolished in mutants of Tcf7l2, the intestinal mediator of Wnt/β-catenin-dependent transcription, and the Wnt/β-catenin dependence of STAT3 activity in the gut is confirmed by abrupt expansion of STAT3-positive cells in intestinal adenomas of apc heterozygotes. Our findings indicate that Jak/STAT3 signalling is needed for intestinal stem cells maintenance and possibly crucial in controlling Wnt/β-catenin-dependent colorectal cancer cells proliferation.