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We generated a unique series of\n                    <jats:italic>Tbx3<\/jats:italic>\n                    hypomorphic and conditional mouse mutants with varying levels and locations of Tbx3 activity within the heart, and developed techniques for evaluating in vivo embryonic conduction system function. Disruption of\n                    <jats:italic>Tbx3<\/jats:italic>\n                    function in different regions of the developing heart causes discrete phenotypes and lethal arrhythmias: sinus pauses and bradycardia indicate sinoatrial node dysfunction, whereas preexcitation and atrioventricular block reveal abnormalities in the atrioventricular junction. Surviving\n                    <jats:italic>Tbx3<\/jats:italic>\n                    mutants are at increased risk for sudden death. Arrhythmias induced by knockdown of\n                    <jats:italic>Tbx3<\/jats:italic>\n                    in adults reveal its requirement for conduction system homeostasis. Arrhythmias in\n                    <jats:italic>Tbx3<\/jats:italic>\n                    -deficient embryos are accompanied by disrupted expression of multiple ion channels despite preserved expression of previously described conduction system markers. These findings indicate that Tbx3 is required for the conduction system to establish and maintain its correct molecular identity and functional properties. In conclusion, Tbx3 is required for the functional development, maturation, and homeostasis of the conduction system in a highly dosage-sensitive manner.\n                    <jats:italic>TBX3<\/jats:italic>\n                    and its regulatory targets merit investigation as candidates for human arrhythmias.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1115165109","type":"journal-article","created":{"date-parts":[[2011,12,27]],"date-time":"2011-12-27T22:30:36Z","timestamp":1325025036000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":122,"title":["Lethal arrhythmias in\n                    <i>Tbx3<\/i>\n                    -deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis"],"prefix":"10.1073","volume":"109","author":[{"given":"Deborah U.","family":"Frank","sequence":"first","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kandis L.","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk R.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Molecular Medicine Program, University of Utah, Salt Lake City, UT 84158;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Michael","family":"Burr","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn L.","family":"Bakker","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1012 WX Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Coetzee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, New York University, New York, NY 10016; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Tristani-Firouzi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Bamshad","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Washington, Seattle, WA 98195"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent M.","family":"Christoffels","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, 1012 WX Amsterdam, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Moon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and"},{"name":"Molecular Medicine Program, University of Utah, Salt Lake City, UT 84158;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2011,12,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1161\/CIRCRESAHA.109.205419","article-title":"Development of the pacemaker tissues of the heart","volume":"106","author":"Christoffels VM","year":"2010","unstructured":"VM Christoffels, GJ Smits, A Kispert, AF Moorman, Development of the pacemaker tissues of the heart. 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