title: Hippo pathway effector Yap promotes cardiac regeneration.
abstract: The adult mammalian heart has limited potential for regeneration. Thus, after injury, cardiomyocytes are permanently lost, and contractility is diminished. In contrast, the neonatal heart can regenerate owing to sustained cardiomyocyte proliferation. Identification of critical regulators of cardiomyocyte proliferation and quiescence represents an important step toward potential regenerative therapies. Yes-associated protein (Yap), a transcriptional cofactor in the Hippo signaling pathway, promotes proliferation of embryonic cardiomyocytes by activating the insulin-like growth factor and Wnt signaling pathways. Here we report that mice bearing mutant alleles of Yap and its paralog WW domain containing transcription regulator 1 (Taz) exhibit gene dosage-dependent cardiac phenotypes, suggesting redundant roles of these Hippo pathway effectors in establishing proper myocyte number and maintaining cardiac function. Cardiac-specific deletion of Yap impedes neonatal heart regeneration, resulting in a default fibrotic response. Conversely, forced expression of a constitutively active form of Yap in the adult heart stimulates cardiac regeneration and improves contractility after myocardial infarction. The regenerative activity of Yap is correlated with its activation of embryonic and proliferative gene programs in cardiomyocytes. These findings identify Yap as an important regulator of cardiac regeneration and provide an experimental entry point to enhance this process.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kim
authors.forename: Lillian B
authors.initials: LB
authors.lastname: Sutherland
authors.forename: Masao
authors.initials: M
authors.lastname: Murakami
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Qi
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: Enzo R
authors.initials: ER
authors.lastname: Porrello
authors.forename: Ahmed I
authors.initials: AI
authors.lastname: Mahmoud
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: James A
authors.initials: JA
authors.lastname: Richardson
authors.forename: Hesham A
authors.initials: HA
authors.lastname: Sadek
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D006321:Heart / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D006652:Histological Techniques; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012038:Regeneration / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013778:Tetrazolium Salts; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017931:DNA Primers; D010750:Phosphoproteins; D013778:Tetrazolium Salts; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C009591:triphenyltetrazolium; D000217:Acyltransferases; C486363:tafazzin protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: cardiac fibrosis; cardiomyopathy; cell cycle
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