Drosophila activating transcription factor 3 non-autonomously regulating intestinal stem cell division and differentiation. Jun Zhou, Anna-Lisa Boettcher, Michael Boutros. Signaling and Functional Genomics, German Cancer Research Center, Heidelberg, Germany.

   Activating transcription factor 3 (ATF3) is a member of the CREB/ATF family of transcription factors. Previous study in mice suggest ATF3 may represent a down-regulated tumor suppressor in colon cancer however the underlying mechanism is poorly understood. In the Drosophila gut, the replacement of damaged enterocytes (EC) relies on intestinal stem cell (ISC) proliferation and their progenitor cells (Enteroblast-EB) differentiation. Recent studies show a number of signaling pathways are involved in the modulation of ISC division and EB differentiation upon aging and environmental stresses. To understand the role of ATF3 in tumor suppression, we first show that Drosophila ATF3 is expressed in ISC, EB and EC but not enteroendocrine cells (EEs). Using two independent RNAi line, we find that loss of Atf3 in midgut precursor cells stimulate ISC division and EB differentiation. We also observed an upregulation of several signaling pathways ligand or targets like JAK/STAT signaling, EGFR signaling and JNK signaling after loss of ATF3 in ISCs and EBs. We also show that RNAi dATF3 in ECs stimulate ISC proliferation and differentiation which is dependent on JNK and Yki activation. These results suggest loss of ATF3 in intestinal stem cells non-autonomous activate JNK pathway in neighboring enterocytes which secrete ligands like Upd3 and then positively feedback on ISC by activating JAK/STAT signaling to stimulate ISC proliferation and EB differentiation. We are currently using ChIP-seq and other genomic techniques to identify targets of dATF3 in regulating intestine homeostasis.