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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}ibt.tamhsc.edu


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