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Science 332 (6028): 458-461

Copyright © 2011 by the American Association for the Advancement of Science

Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size

Todd Heallen,1 Min Zhang,1 Jun Wang,1 Margarita Bonilla-Claudio,1 Ela Klysik,1 Randy L. Johnson,2 James F. Martin1,*

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.

1 Institute of Biosciences and Technology, Texas A&M System Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030, USA.
2 Department of Biochemistry and Molecular Biology, M. D. Anderson Cancer Center, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: jmartin{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Circ. Res. 114, 454-468
   Abstract »    Full Text »    PDF »
Hippo Activation in Arrhythmogenic Cardiomyopathy.
Y. Hu and W. T. Pu (2014)
Circ. Res. 114, 402-405
   Full Text »    PDF »
Hippo signaling impedes adult heart regeneration.
T. Heallen, Y. Morikawa, J. Leach, G. Tao, J. T. Willerson, R. L. Johnson, and J. F. Martin (2013)
Development 140, 4683-4690
   Abstract »    Full Text »    PDF »
Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment.
K. Kawamura, Y. Cheng, N. Suzuki, M. Deguchi, Y. Sato, S. Takae, C.-h. Ho, N. Kawamura, M. Tamura, S. Hashimoto, et al. (2013)
PNAS 110, 17474-17479
   Abstract »    Full Text »    PDF »
Wnt/{beta}-catenin signaling directs the regional expansion of first and second heart field-derived ventricular cardiomyocytes.
J. W. Buikema, A. S. Mady, N. V. Mittal, A. Atmanli, L. Caron, P. A. Doevendans, J. P. G. Sluijter, and I. J. Domian (2013)
Development 140, 4165-4176
   Abstract »    Full Text »    PDF »
Molecular Pathways: YAP and TAZ Take Center Stage in Organ Growth and Tumorigenesis.
S. Piccolo, M. Cordenonsi, and S. Dupont (2013)
Clin. Cancer Res. 19, 4925-4930
   Abstract »    Full Text »    PDF »
Hippo pathway effector Yap promotes cardiac regeneration.
M. Xin, Y. Kim, L. B. Sutherland, M. Murakami, X. Qi, J. McAnally, E. R. Porrello, A. I. Mahmoud, W. Tan, J. M. Shelton, et al. (2013)
PNAS 110, 13839-13844
   Abstract »    Full Text »    PDF »
Mutations in NEK8 link multiple organ dysplasia with altered Hippo signalling and increased c-MYC expression.
V. Frank, S. Habbig, M. P. Bartram, T. Eisenberger, H. E. Veenstra-Knol, C. Decker, R. A. C. Boorsma, H. Gobel, G. Nurnberg, A. Griessmann, et al. (2013)
Hum. Mol. Genet. 22, 2177-2185
   Abstract »    Full Text »    PDF »
The Hippo pathway: regulators and regulations.
F.-X. Yu and K.-L. Guan (2013)
Genes & Dev. 27, 355-371
   Abstract »    Full Text »    PDF »
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D. P. Del Re, Y. Yang, N. Nakano, J. Cho, P. Zhai, T. Yamamoto, N. Zhang, N. Yabuta, H. Nojima, D. Pan, et al. (2013)
J. Biol. Chem. 288, 3977-3988
   Abstract »    Full Text »    PDF »
Intersection of Hippo/YAP and Wnt/{beta}-catenin signaling pathways.
W. M. Konsavage Jr and G. S. Yochum (2013)
Acta Biochim Biophys Sin 45, 71-79
   Abstract »    Full Text »    PDF »
Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins.
J. J. Hulmi, B. M. Oliveira, M. Silvennoinen, W. M. H. Hoogaars, H. Ma, P. Pierre, A. Pasternack, H. Kainulainen, and O. Ritvos (2013)
Am J Physiol Endocrinol Metab 304, E41-E50
   Abstract »    Full Text »    PDF »
Cardiac Regeneration.
A. Rosenzweig (2012)
Science 338, 1549-1550
   Abstract »    Full Text »    PDF »
Hippo Signaling Regulates Pancreas Development through Inactivation of Yap.
N. M. George, C. E. Day, B. P. Boerner, R. L. Johnson, and N. E. Sarvetnick (2012)
Mol. Cell. Biol. 32, 5116-5128
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14-3-3{varepsilon} Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle.
Y. Kosaka, K. A. Cieslik, L. Li, G. Lezin, C. T. Maguire, Y. Saijoh, K. Toyo-oka, M. J. Gambello, M. Vatta, A. Wynshaw-Boris, et al. (2012)
Mol. Cell. Biol. 32, 5089-5102
   Abstract »    Full Text »    PDF »
The Hippo pathway member Yap plays a key role in influencing fate decisions in muscle satellite cells.
R. N. Judson, A. M. Tremblay, P. Knopp, R. B. White, R. Urcia, C. De Bari, P. S. Zammit, F. D. Camargo, and H. Wackerhage (2012)
J. Cell Sci. 125, 6009-6019
   Abstract »    Full Text »    PDF »
A dual function for canonical Wnt/{beta}-catenin signaling in the developing mammalian cochlea.
B. E. Jacques, C. Puligilla, R. M. Weichert, A. Ferrer-Vaquer, A.-K. Hadjantonakis, M. W. Kelley, and A. Dabdoub (2012)
Development 139, 4395-4404
   Abstract »    Full Text »    PDF »
The Induction of Yes-Associated Protein Expression After Arterial Injury Is Crucial for Smooth Muscle Phenotypic Modulation and Neointima Formation.
X. Wang, G. Hu, X. Gao, Y. Wang, W. Zhang, E. Y. Harmon, X. Zhi, Z. Xu, M. R. Lennartz, M. Barroso, et al. (2012)
Arterioscler Thromb Vasc Biol 32, 2662-2669
   Abstract »    Full Text »    PDF »
Nuclear p120 catenin unlocks mitotic block of contact-inhibited human corneal endothelial monolayers without disrupting adherent junctions.
Y.-T. Zhu, H.-C. Chen, S.-Y. Chen, and S. C. G. Tseng (2012)
J. Cell Sci. 125, 3636-3648
   Abstract »    Full Text »    PDF »
Transcriptional analysis of pluripotency reveals the Hippo pathway as a barrier to reprogramming.
H. Qin, K. Blaschke, G. Wei, Y. Ohi, L. Blouin, Z. Qi, J. Yu, R.-F. Yeh, M. Hebrok, and M. Ramalho-Santos (2012)
Hum. Mol. Genet. 21, 2054-2067
   Abstract »    Full Text »    PDF »
Yap1 Protein Regulates Vascular Smooth Muscle Cell Phenotypic Switch by Interaction with Myocardin.
C. Xie, Y. Guo, T. Zhu, J. Zhang, P. X. Ma, and Y. E. Chen (2012)
J. Biol. Chem. 287, 14598-14605
   Abstract »    Full Text »    PDF »
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Z. Li, Y. Wang, M. Zhang, P. Xu, H. Huang, D. Wu, and A. Meng (2012)
J. Biol. Chem. 287, 13005-13015
   Abstract »    Full Text »    PDF »
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H. Abdollahpour, G. Appaswamy, D. Kotlarz, J. Diestelhorst, R. Beier, A. A. Schaffer, E. M. Gertz, A. Schambach, H. H. Kreipe, D. Pfeifer, et al. (2012)
Blood 119, 3450-3457
   Abstract »    Full Text »    PDF »
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W. M. Konsavage Jr., S. L. Kyler, S. A. Rennoll, G. Jin, and G. S. Yochum (2012)
J. Biol. Chem. 287, 11730-11739
   Abstract »    Full Text »    PDF »
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K.-K. Lee and S. Yonehara (2012)
J. Biol. Chem. 287, 9568-9578
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Ferreira-Martins, B. Ogorek, D. Cappetta, A. Matsuda, S. Signore, D. D'Amario, J. Kostyla, E. Steadman, N. Ide-Iwata, F. Sanada, et al. (2012)
Circ. Res. 110, 701-715
   Abstract »    Full Text »    PDF »
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A. von Gise, Z. Lin, K. Schlegelmilch, L. B. Honor, G. M. Pan, J. N. Buck, Q. Ma, T. Ishiwata, B. Zhou, F. D. Camargo, et al. (2012)
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   Abstract »    Full Text »    PDF »
Mst1 and Mst2 protein kinases restrain intestinal stem cell proliferation and colonic tumorigenesis by inhibition of Yes-associated protein (Yap) overabundance.
D. Zhou, Y. Zhang, H. Wu, E. Barry, Y. Yin, E. Lawrence, D. Dawson, J. E. Willis, S. D. Markowitz, F. D. Camargo, et al. (2011)
PNAS 108, E1312-E1320
   Abstract »    Full Text »    PDF »
Regulation of Insulin-Like Growth Factor Signaling by Yap Governs Cardiomyocyte Proliferation and Embryonic Heart Size.
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   Abstract »    Full Text »    PDF »
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A. Klingseisen and A. P. Jackson (2011)
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   Abstract »    Full Text »    PDF »
Not Too Large and Not Too Small-Just the Right Size: A Hippo-Sized Heart.
E. E. Morrisey (2011)
Circ. Res. 109, 614-615
   Full Text »    PDF »
The growing role of the Hippo-NDR kinase signalling in neuronal development and disease.
K. Emoto (2011)
J. Biochem. 150, 133-141
   Abstract »    Full Text »    PDF »
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E. R. Flores and G. Halder (2011)
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   Abstract »    Full Text »    PDF »
E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components.
N.-G. Kim, E. Koh, X. Chen, and B. M. Gumbiner (2011)
PNAS 108, 11930-11935
   Abstract »    Full Text »    PDF »
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J. F. Martin, V. Vasioukhin, M. R. Silvis, and A. M. VanHook (2011)
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   Abstract »    Full Text »
A Cardiac Nonproliferation Treaty.
M. D. Schneider (2011)
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   Abstract »    Full Text »    PDF »

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