Journal
SCIENCE SIGNALING
Volume 8, Issue 375, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.2005781
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Funding
- NIH [1U01HL087365, 5T32HL007676-23, HL 118761, R01HG007538, U54 HG006348]
- Cancer Prevention and Research Institute of Texas (CPRIT) [RP150292]
- Vivian L. Smith Foundation
- American Heart Association (AHA) [AHA10POST4140029, AHA12POST11760019, AHA NCRP SDG 0930240N, AHA 13POST17040027, AHA 12PRE11720003]
- Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (IDDRC) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development [1 U54 HD083092]
- Mouse Phenotyping Core at Baylor College of Medicine
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The mammalian heart regenerates poorly, and damage commonly leads to heart failure. Hippo signaling is an evolutionarily conserved kinase cascade that regulates organ size during development and prevents adult mammalian cardiomyocyte regeneration by inhibiting the transcriptional coactivator Yap, which also responds to mechanical signaling in cultured cells to promote cell proliferation. To identify Yap target genes that are activated during cardiomyocyte renewal and regeneration, we performed Yap chromatin immunoprecipitation sequencing (ChIP-Seq) and mRNA expression profiling in Hippo signaling-deficient mouse hearts. We found that Yap directly regulated genes encoding cell cycle progression proteins, as well as genes encoding proteins that promote F-actin polymerization and that link the actin cytoskeleton to the extracellular matrix. Included in the latter group were components of the dystrophin glycoprotein complex, a large molecular complex that, when defective, results in muscular dystrophy in humans. Cardiomyocytes near the scar tissue of injured Hippo signaling-deficient mouse hearts showed cellular protrusions suggestive of cytoskeletal remodeling. The hearts of mdx mutant mice, which lack functional dystrophin and are a model for muscular dystrophy, showed impaired regeneration and cytoskeleton remodeling, but normal cardiomyocyte proliferation, after injury. Our data showed that, in addition to genes encoding cell cycle progression proteins, Yap regulated genes that enhance cytoskeletal remodeling. Thus, blocking the Hippo pathway input to Yap may tip the balance so that Yap responds to mechanical changes associated with heart injury to promote repair.
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