title: Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development.
abstract: BACKGROUND
  The small GTPase Rac1 regulates diverse cellular functions, including both apicobasal and planar cell polarity pathways; however, its role in cardiac outflow tract (OFT) development remains unknown. In the present study, we aimed to examine the role of Rac1 in the anterior second heart field (SHF) splanchnic mesoderm and subsequent OFT development during heart morphogenesis.
  
  
  RESULTS
  Using the Cre/loxP system, mice with an anterior SHF-specific deletion of Rac1 (Rac1(SHF)) were generated. Embryos were collected at various developmental time points for immunostaining and histological analysis. Intrauterine echocardiography was also performed to assess aortic valve blood flow in embryos at embryonic day 18.5. The Rac1(SHF) splanchnic mesoderm exhibited disruptions in SHF progenitor cellular organization and proliferation. Consequently, this led to a spectrum of OFT defects along with aortic valve defects in Rac1(SHF) embryos. Mechanistically, it was found that the ability of the Rac1(SHF) OFT myocardial cells to migrate into the proximal OFT cushion was severely reduced. In addition, expression of the neural crest chemoattractant semaphorin 3c was decreased. Lineage tracing showed that anterior SHF contribution to the OFT myocardium and aortic valves was deficient in Rac1(SHF) hearts. Furthermore, functional analysis with intrauterine echocardiography at embryonic day 18.5 showed aortic valve regurgitation in Rac1(SHF) hearts, which was not seen in control hearts.
  
  
  CONCLUSIONS
  Disruptions of Rac1 signaling in the anterior SHF results in aberrant progenitor cellular organization and defects in OFT development. Our data show Rac1 signaling to be a critical regulator of cardiac OFT formation during embryonic heart development.
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Carmen
authors.initials: C
authors.lastname: Leung
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Mella
authors.initials: M
authors.lastname: Kim
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Drysdale
authors.affiliation: Departments of Physiology and Pharmacology, Medicine and Pediatrics, Schulich School of Medicine and Dentistry, Collaborative Program in Developmental Biology, Children's Health Research Institute, University of Western Ontario, London, Ontario, Canada (C.L., Y.L., X.L., M.K., T.A.D., Q.F.).
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities / Q000201:enzymology*; D001022:Aortic Valve Insufficiency / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics; D019070:Cell Lineage; D002465:Cell Movement; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics; D018345:Mice, Knockout; D009024:Morphogenesis; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D009432:Neural Crest / Q000002:abnormalities / Q000201:enzymology; D009479:Neuropeptides / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D039961:Semaphorins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020830:rac1 GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D009479:Neuropeptides; C484602:Rac1 protein, mouse; D039961:Semaphorins; C510203:semaphorin 3C protein, mouse; D020830:rac1 GTP-Binding Protein
keywords: Rac1; cellular organization; congenital heart defect; outflow tract development