title: Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity.
abstract: BACKGROUND
  Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional coactivator Yes-associated protein (Yap) is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators and signaling pathways that control Yap activity in the heart are poorly understood.
  
  
  OBJECTIVE
  To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout mice.
  
  
  RESULTS
  We used 2 cardiac-specific Cre transgenes to delete both αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes either in the perinatal or in the adult heart. Perinatal depletion of α-catenins increased cardiomyocyte number in the postnatal heart. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-catenin double knockout hearts. Fetal genes were increased in the α-catenin double knockout hearts indicating a less mature cardiac gene expression profile. Knockdown of α-catenins in neonatal rat cardiomyocytes also resulted in increased proliferation, which could be blocked by knockdown of Yap. Finally, inactivation of α-catenins in the adult heart using an inducible Cre led to increased nuclear Yap and cardiomyocyte proliferation and improved contractility after myocardial infarction.
  
  
  CONCLUSIONS
  These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional coactivator essential for cardiomyocyte proliferation. Furthermore, we provide proof of concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration after injury.
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Jifen
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Vite
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Roslyn
authors.initials: R
authors.lastname: Yi
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Gomez
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
authors.forename: Frans
authors.initials: F
authors.lastname: van Roy
authors.affiliation: From the Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA (J.L., E.G., A.V., R.Y., L.G., G.L.R.); Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium (S.G., F.v.R.); Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium (S.G., F.v.R.); and INSERM UMR-1060, Laboratoire CarMeN, Université Lyon 1, Faculté de médecine, Rockefeller et Charles Merieux Lyon-Sud, Lyon, France (L.G.). Current address for E.G.: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA. glenn.radice@jefferson.edu.
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Radice
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000502:physiology*; D002478:Cells, Cultured; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051381:Rats; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051178:alpha Catenin
keywords: Yap protein, mouse; cytokinesis; models, animal; myocardial infarction; myocytes, cardiac; α-catenin