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PMID:21512031

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Citation

Heallen, T, Zhang, M, Wang, J, Bonilla-Claudio, M, Klysik, E, Johnson, RL and Martin, JF (2011) Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332:458-61

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.

Links

PubMed PMC3133743 Online version:10.1126/science.1199010

Keywords

Adaptor Proteins, Signal Transducing/metabolism; Animals; Cardiomegaly/metabolism; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Nucleus/metabolism; Cell Proliferation; Chromatin Immunoprecipitation; Gene Expression Profiling; Gene Expression Regulation, Developmental; Heart/anatomy & histology; Heart/embryology; Mice; Mice, Transgenic; Myocardium/cytology; Myocytes, Cardiac/cytology; Myocytes, Cardiac/metabolism; Organ Size; Phosphoproteins/metabolism; Phosphorylation; Protein-Serine-Threonine Kinases/genetics; Protein-Serine-Threonine Kinases/metabolism; SOXB1 Transcription Factors/genetics; SOXB1 Transcription Factors/metabolism; Signal Transduction; Transcription Factors/genetics; Transcription Factors/metabolism; Wnt Proteins/metabolism; beta Catenin/genetics; beta Catenin/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:YAP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q02248

F

Seeded From UniProt

complete

MOUSE:YAP1

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:98364)|has_input:(MGI:MGI:1096393)

Seeded From UniProt

complete

MOUSE:CTNB1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P46938

F

Seeded From UniProt

complete

MOUSE:CTNB1

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • has_input:(MGI:MGI:98364)|has_input:(MGI:MGI:1096393)

Seeded From UniProt

complete

MOUSE:LATS2

acts_upstream_of_or_within

GO:0046620: regulation of organ growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2654594,MGI:MGI:4430538

P

  • regulates_o_occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:LATS2

acts_upstream_of_or_within

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:88276

P

  • regulates_o_occurs_in:(CL:0000746)
  • regulates_o_occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0060412: ventricular septum morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2654594,MGI:MGI:4430538

P

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0046620: regulation of organ growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2654594,MGI:MGI:4430538

P

  • regulates_o_occurs_in:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0060044: negative regulation of cardiac muscle cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2654594,MGI:MGI:4430538

P

Seeded From UniProt

complete

MOUSE:SAV1

acts_upstream_of_or_within

GO:0035329: hippo signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2654594,MGI:MGI:4430538

P

  • occurs_in:(EMAPA:16346)|occurs_in:(EMAPA:16353)

Seeded From UniProt

complete

MOUSE:CTNB1

enables

GO:0003682: chromatin binding

ECO:0000314: direct assay evidence used in manual assertion

F

has_participant:(MGI:MGI:98364)|has_participant:(MGI:MGI:1096393)

Seeded From UniProt

complete


See also

References

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