title: The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration.
abstract: Identification of the signaling pathways that control the proliferation of stem cells (SCs), and whether they act in a cell or non-cell autonomous manner, is key to our understanding of tissue homeostasis and cancer. In the adult Drosophila midgut, the Jun N-Terminal Kinase (JNK) pathway is activated in damaged enterocyte cells (ECs) following injury. This leads to the production of Upd cytokines from ECs, which in turn activate the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway in Intestinal SCs (ISCs), stimulating their proliferation. In addition, the Hippo pathway has been recently implicated in the regulation of Upd production from the ECs. Here, we show that the Hippo pathway target, Yorkie (Yki), also plays a crucial and cell-autonomous role in ISCs. Activation of Yki in ISCs is sufficient to increase ISC proliferation, a process involving Yki target genes that promote division, survival and the Upd cytokines. We further show that prior to injury, Yki activity is constitutively repressed by the upstream Hippo pathway members Fat and Dachsous (Ds). These findings demonstrate a cell-autonomous role for the Hippo pathway in SCs, and have implications for understanding the role of this pathway in tumorigenesis and cancer stem cells.
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. pkarpowicz@genetics.med.harvard.edu
authors.forename: Phillip
authors.initials: P
authors.lastname: Karpowicz
authors.forename: Jessica
authors.initials: J
authors.lastname: Perez
authors.forename: Norbert
authors.initials: N
authors.lastname: Perrimon
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D020895:Enterocytes / Q000166:cytology; D007422:Intestines / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D013696:Temperature; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D015820:Cadherins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D050791:STAT Transcription Factors; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C094449:ds protein, Drosophila; C467520:esg protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases