A Hippo-Sized Heart

Science Signaling  26 Apr 2011:
Vol. 4, Issue 170, pp. ec117
DOI: 10.1126/scisignal.4170ec117

Signaling through the kinase Hippo controls various cellular growth and tumorigenesis processes in many species. In the fruit fly, Hippo signaling is important for regulating organ size, but it is unclear whether Hippo exerts analogous control over organ size in mammals. Heallen et al. report that the Hippo pathway regulates heart size in the mouse by antagonizing growth-promoting Wnt signaling in cardiomyocytes. Mice that lacked the Hippo binding partner Salvador (Salv) in cardiac precursor cells, which give rise to the cardiomyocytes, had enlarged hearts and died shortly after birth. The mutant hearts had an increased number of cardiomyocytes, similar to mutants lacking the Hippo signaling mediator Lats2 or the Hippo homologs Mst1 and Mst2. Mutant hearts showed a decrease in the amount of phosphorylated Yap (pYap), a transcription factor that is excluded from the nucleus when phosphorylated by Lats. Nuclear accumulation of the Wnt effector β-catenin and expression of the growth-promoting Wnt targets Sox2 and Snai2 increased in Salv mutant hearts. Removing one copy of β-catenin partially rescued the enlarged heart phenotype and restored normal expression of Sox2 and Snai2 in Salv mutant hearts. Chromatin immunoprecipitation experiments demonstrated that both Yap and β-catenin were present at regulatory regions of Sox2 and Snai2, and experiments in transfected cells showed that Yap and β-catenin cooperated to induce transcription of Sox2 and Snai2 reporters. These results suggest a model in which, in the absence of Hippo signaling, Yap and β-catenin activate expression of growth-promoting genes in cardiac progenitor cells. In cardiomyocytes, Hippo signaling leads to exclusion of pYap from the nucleus, thus reducing the ability of β-catenin to induce transcription of these targets, thereby limiting heart size.

T. Heallen, M. Zhang, J. Wang, M. Bonilla-Claudio, E. Klysik, R. L. Johnson, J. F. Martin, Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011). [Abstract] [Full Text]

M. D. Schneider, A cardiac nonproliferation treaty. Science 332, 426–427 (2011). [Abstract] [Full Text]