{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T05:17:57Z","timestamp":1768972677057,"version":"3.49.0"},"reference-count":53,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2016,1,13]]},"abstract":"\n Background<\/jats:title>\n \n The small\n GTP<\/jats:styled-content>\n ase Rac1 regulates diverse cellular functions, including both apicobasal and planar cell polarity pathways; however, its role in cardiac outflow tract (\n OFT<\/jats:styled-content>\n ) development remains unknown. In the present study, we aimed to examine the role of Rac1 in the anterior second heart field (\n SHF<\/jats:styled-content>\n ) splanchnic mesoderm and subsequent\n OFT<\/jats:styled-content>\n development during heart morphogenesis.\n <\/jats:p>\n <\/jats:sec>\n \n Methods and Results<\/jats:title>\n \n Using the Cre\/loxP system, mice with an anterior\n SHF<\/jats:styled-content>\n \u2010specific deletion of\n Rac1<\/jats:italic>\n (\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n <\/jats:styled-content>\n ) 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\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n <\/jats:styled-content>\n splanchnic mesoderm exhibited disruptions in\n SHF<\/jats:styled-content>\n progenitor cellular organization and proliferation. Consequently, this led to a spectrum of\n OFT<\/jats:styled-content>\n defects along with aortic valve defects in\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n <\/jats:styled-content>\n embryos. Mechanistically, it was found that the ability of the\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n OFT\n <\/jats:styled-content>\n myocardial cells to migrate into the proximal\n OFT<\/jats:styled-content>\n cushion was severely reduced. In addition, expression of the neural crest chemoattractant semaphorin 3c was decreased. Lineage tracing showed that anterior\n SHF<\/jats:styled-content>\n contribution to the\n OFT<\/jats:styled-content>\n myocardium and aortic valves was deficient in\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n <\/jats:styled-content>\n hearts. Furthermore, functional analysis with intrauterine echocardiography at embryonic day 18.5 showed aortic valve regurgitation in\n Rac1<\/jats:italic>\n \n \n SHF<\/jats:italic>\n <\/jats:sup>\n <\/jats:styled-content>\n hearts, which was not seen in control hearts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n Disruptions of Rac1 signaling in the anterior\n SHF<\/jats:styled-content>\n results in aberrant progenitor cellular organization and defects in\n OFT<\/jats:styled-content>\n development. Our data show Rac1 signaling to be a critical regulator of cardiac\n OFT<\/jats:styled-content>\n formation during embryonic heart development.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/jaha.115.002508","type":"journal-article","created":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T02:58:42Z","timestamp":1451617122000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Rac1 Signaling Is Required for Anterior Second Heart Field Cellular Organization and Cardiac Outflow Tract Development"],"prefix":"10.1161","volume":"5","author":[{"given":"Carmen","family":"Leung","sequence":"first","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yin","family":"Liu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangru","family":"Lu","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mella","family":"Kim","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas A.","family":"Drysdale","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingping","family":"Feng","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06801"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1067\/mtc.2002.119064"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2523"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.106.142406"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcm.2005.11.005"},{"key":"e_1_3_5_7_2","first-page":"1986","article-title":"Murine Jagged1\/Notch signaling in the second heart field orchestrates Fgf8 expression and tissue\u2010tissue interactions during outflow tract development","volume":"119","author":"High FA","year":"2009","unstructured":"High FA, Jain R, Stoller JZ, Antonucci NB, Lu MM, Loomes KM, Kaestner KH, Pear WS, Epstein JA. 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