Regulation of String during Drosophila intestinal stem cell proliferation. Jinyi Xiang, Bruce Edgar. Cell growth and proliferation, DKFZ-ZMBH Alliance, Heidelberg, Germany.

   The adult Drosophila midgut is a highly regenerative organ that is maintained by intestinal stem cells (ISC). ISC proliferation and division produces new ISCs and enteroblast (EB) daughters, which differentiate into the major midgut cell types, enterocytes (EC) or enteroendocrine (EE) cells. The mono-layered epithelium of the midgut is regularly replenished by stem cells once every two weeks under normal physiological circumstances. However in response to epithelial damage and stress condition, such as bacteria infection, DNA damaging agents, oxidative stress, induced apoptosis or JNK stress signaling activation, damaged ECs will produce ligands of EGFR and JAK/STAT to activate these pathways in ISCs and EBs, thus promoting their proliferation and differentiation to compensate for epithelium cell loss. During this feedback, we find that the String (Stg) gene, the Drosophila homologue of Cdc25 phosphatase that is the ultimate regulator of mitosis in most eukaryotic cells, is strongly increased in expression. Gain- and loss- of function studies show that Stg is necessary for midgut stem cell proliferation in response to the extrinsic growth signals from epithelium. Moreover, we find that one small fragment of the Stg enhancer is specific for its transcription in midgut stem cells. To elucidate the mechanism of how extrinsic signals regulate this key cell cycle gene, we will use yeast 1 hybrid (Y1H) to screen the candidate transcription factors that can directly bind this specific enhancer and regulate Stg expression in stem cells. With this work, we expect to find the essential link between signal transduction factors and cell cycle control in stem cells.