The Hippo Signaling Pathway in Organ Size Control and Regeneraton




Ren, Fangfang

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The Hippo (Hpo) signaling pathway controls cell growth, proliferation and apoptosis in both Drosophila and vertebrates. Our lab has previously demonstrated that Hpo signaling regulates gene expression by inhibiting a transcription complex consisting of the transcriptional coactivator Yorkie (Yki) and the TEAD/TEF family of transcription factor Scalloped (Sd) in Drosophila. The inhibition of Yki activity is through modulating its phosphorylation status and subcellular localization by upstream kinase complex. I obtained both genetic and cellular evidence that 14-3-3 proteins are involved in this process. I also identified three Serine residues (S111, S168 and S250 of Yki as essential for restricting Yki activity. I found that 14-3-3 regulates Yki subcellular localization mainly through S168 but not the other two sites. The recent identification of intestinal stem cells (ISCs) has made the Drosophila adult midgut an excellent model to study adult stem cell biology. Multiple signaling pathways have been implicated in the regulation of ISC proliferation, self-renewal and differentiation. I obtained evidence that Hpo signaling plays an essential role in regulating ISC proliferation through both cell-autonomous and non-cell-autonomous mechanisms. Cytokines of the Upd family and multiple EGFR ligands were found to be ectopically induced when Hpo signaling is inactivated in differentiated cells, which in turn activate Jak-Stat and EGFR signaling pathways in ISCs to stimulate their proliferation. I also showed that tissue damaging reagent DSS-induced ISC proliferation is dependent on Yki activity in precursor cells. Although several signaling pathways including Jak-Stat, EGFR and Hpo pathways have been implicated in damage-induced ISC proliferation, the cell intrinsic mechanisms have remained elusive. I found that the Drosophila homolog of Myc oncogene (dMyc), which encodes a transcription regulator that affects cellular growth and cell cycle progression, functions downstream of Hpo, Jak-Stat and EGFR pathways to mediate their effects on ISC proliferation. dMyc is also essential for adult midgut homeostasis as well as regeneration after exposure to damage reagents. I also demonstrated that the regulation of dMyc levels by Hipo, Jak-Stat and EGFR pathways is at the level of transcription.

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