title: Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development.
abstract: BACKGROUND
  Defects in cardiac septation are the most common form of congenital heart disease, but the mechanisms underlying these defects are still poorly understood. The small GTPase Rac1 is implicated in planar cell polarity of epithelial cells in Drosophila; however, its role in mammalian cardiomyocyte polarity is not clear. We tested the hypothesis that Rac1 signaling in the second heart field regulates cardiomyocyte polarity, chamber septation, and right ventricle development during embryonic heart development.
  
  
  RESULTS
  Mice with second heart field-specific deficiency of Rac1 (Rac1(SHF)) exhibited ventricular and atrial septal defects, a thinner right ventricle myocardium, and a bifid cardiac apex. Fate-mapping analysis showed that second heart field contribution to the interventricular septum and right ventricle was deficient in Rac1(SHF) hearts. Notably, cardiomyocytes had a spherical shape with disrupted F-actin filaments in Rac1(SHF) compared with elongated and well-aligned cardiomyocytes in littermate controls. Expression of Scrib, a core protein in planar cell polarity, was lost in Rac1(SHF) hearts with decreased expression of WAVE and Arp2/3, leading to decreased migratory ability. In addition, Rac1-deficient neonatal cardiomyocytes displayed defects in cell projections, lamellipodia formation, and cell elongation. Furthermore, apoptosis was increased and the expression of Gata4, Tbx5, Nkx2.5, and Hand2 transcription factors was decreased in the Rac1(SHF) right ventricle myocardium.
  
  
  CONCLUSIONS
  Deficiency of Rac1 in the second heart field impairs elongation and cytoskeleton organization of cardiomyocytes and results in congenital septal defects, thin right ventricle myocardium, and a bifid cardiac apex. Our study suggests that Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development.
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada (C.L., X.L., Q.F.) Collaborative Program in Developmental Biology, The University of Western Ontario, London, Ontario, Canada (C.L.).
authors.forename: Carmen
authors.initials: C
authors.lastname: Leung
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada (C.L., X.L., Q.F.).
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.affiliation: Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada (M.L., Q.F.).
authors.forename: Murong
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada (C.L., X.L., Q.F.) Department of Medicine, Schulich School of Medicine and Dentistry The University of Western Ontario, London, Ontario, Canada (Q.F.) Lawson Health Research Institute, The University of Western Ontario, London, Ontario, Canada (M.L., Q.F.).
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology* / Q000235:genetics*; D006344:Heart Septal Defects, Atrial / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006352:Heart Ventricles / Q000196:embryology; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D020830:rac1 GTP-Binding Protein / Q000235:genetics*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: Rac1; congenital heart defects; heart septal defects; second heart field