title: Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size.
abstract: Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M System Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Heallen
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Margarita
authors.initials: M
authors.lastname: Bonilla-Claudio
authors.forename: Ela
authors.initials: E
authors.lastname: Klysik
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000033:anatomy & histology* / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D009929:Organ Size; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D055748:SOXB1 Transcription Factors; D000090742:Serine-Threonine Kinase 3; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051153:Wnt Proteins; D000091102:YAP-Signaling Proteins; D051176:beta Catenin; C485935:Sav1 protein, mouse; C000604449:Snai2 protein, mouse; C527783:Sox2 protein, mouse; C486223:Yap1 protein, mouse; C000604451:sna protein, Drosophila; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490818:Stk3 protein, mouse