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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Cardiomegaly / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Nucleus / metabolism
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Cell Proliferation
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Chromatin Immunoprecipitation
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Gene Expression Profiling
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Gene Expression Regulation, Developmental
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Heart / anatomy & histology*
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Heart / embryology
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Mice
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Mice, Transgenic
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Myocardium / cytology
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Myocytes, Cardiac / cytology*
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Myocytes, Cardiac / metabolism*
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Organ Size
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Phosphoproteins / metabolism
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
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Serine-Threonine Kinase 3
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Signal Transduction*
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Snail Family Transcription Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Wnt Proteins / metabolism*
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YAP-Signaling Proteins
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Phosphoproteins
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SOXB1 Transcription Factors
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Sav1 protein, mouse
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Snai2 protein, mouse
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Snail Family Transcription Factors
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Sox2 protein, mouse
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Transcription Factors
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Wnt Proteins
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YAP-Signaling Proteins
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Yap1 protein, mouse
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beta Catenin
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sna protein, Drosophila
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Stk4 protein, mouse
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Protein Serine-Threonine Kinases
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Serine-Threonine Kinase 3
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Stk3 protein, mouse