title: Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice.
abstract: 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.
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Morikawa
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Heallen
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: John
authors.initials: J
authors.lastname: Leach
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Tao
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Division of Biostatistics, Dan L. Duncan Cancer Center, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: Willerson
authors.affiliation: Texas Heart Institute, Houston, TX 77030, USA. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA. Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. jfmartin@bcm.edu.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D006801:Humans; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000199:Actins; D017346:Protein Serine-Threonine Kinases