title: Opposite feedbacks in the Hippo pathway for growth control and neural fate.
abstract: Signaling pathways are reused for multiple purposes in plant and animal development. The Hippo pathway in mammals and Drosophila coordinates proliferation and apoptosis via the coactivator and oncoprotein YAP/Yorkie (Yki), which is homeostatically regulated through negative feedback. In the Drosophila eye, cross-repression between the Hippo pathway kinase LATS/Warts (Wts) and growth regulator Melted generates mutually exclusive photoreceptor subtypes. Here, we show that this all-or-nothing neuronal differentiation results from Hippo pathway positive feedback: Yki both represses its negative regulator, warts, and promotes its positive regulator, melted. This postmitotic Hippo network behavior relies on a tissue-restricted transcription factor network-including a conserved Otx/Orthodenticle-Nrl/Traffic Jam feedforward module-that allows Warts-Yki-Melted to operate as a bistable switch. Altering feedback architecture provides an efficient mechanism to co-opt conserved signaling networks for diverse purposes in development and evolution.
authors.affiliation: Center for Developmental Genetics, Department of Biology, New York University, New York, NY 10003, USA.
authors.forename: David
authors.initials: D
authors.lastname: Jukam
authors.forename: Baotong
authors.initials: B
authors.lastname: Xie
authors.forename: Jens
authors.initials: J
authors.lastname: Rister
authors.forename: David
authors.initials: D
authors.lastname: Terrell
authors.forename: Mark
authors.initials: M
authors.lastname: Charlton-Perkins
authors.forename: Daniela
authors.initials: D
authors.lastname: Pistillo
authors.forename: Brian
authors.initials: B
authors.lastname: Gebelein
authors.forename: Claude
authors.initials: C
authors.lastname: Desplan
authors.forename: Tiffany
authors.initials: T
authors.lastname: Cook
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000254:growth & development*; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D018398:Homeodomain Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D055495:Neurogenesis / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D017956:Photoreceptor Cells, Invertebrate / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C503814:Yki protein, Drosophila; C505057:melt protein, Drosophila; C093053:oc protein, Drosophila; C093503:wts protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases