{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:46:15Z","timestamp":1789145175613,"version":"build-2803163510"},"posted":{"date-parts":[[2024,8,30]]},"group-title":"Developmental Biology","reference-count":74,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,2,13]]},"abstract":"<jats:p>\n                  The cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factors\n                  <jats:italic>TBX3<\/jats:italic>\n                  and\n                  <jats:italic>TBX5<\/jats:italic>\n                  are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role of\n                  <jats:italic>Tbx3<\/jats:italic>\n                  and\n                  <jats:italic>Tbx5<\/jats:italic>\n                  in the murine ventricular conduction system (VCS). We engineered a compound\n                  <jats:italic>Tbx3:Tbx5<\/jats:italic>\n                  conditional knockout allele for both genes located in\n                  <jats:italic>cis<\/jats:italic>\n                  on mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specific\n                  <jats:italic>Mink:Cre,<\/jats:italic>\n                  caused loss of VCS function and molecular identity. Combined\n                  <jats:italic>Tbx3<\/jats:italic>\n                  and\n                  <jats:italic>Tbx5<\/jats:italic>\n                  deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiologic defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect.\n                  <jats:italic>Tbx3:Tbx5<\/jats:italic>\n                  double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, suggesting reprogramming of their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate that\n                  <jats:italic>Tbx3<\/jats:italic>\n                  and\n                  <jats:italic>Tbx5<\/jats:italic>\n                  coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.\n                <\/jats:p>","DOI":"10.1101\/2024.08.29.610377","type":"posted-content","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T20:40:26Z","timestamp":1725050426000},"source":"Crossref","is-referenced-by-count":1,"title":["Coordinated\n                  <i>Tbx3\/Tbx5<\/i>\n                  transcriptional control of the adult ventricular conduction system"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3770-4314","authenticated-orcid":false,"given":"Ozanna","family":"Burnicka-Turek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy A","family":"Trampel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6919-8922","authenticated-orcid":false,"given":"Brigitte","family":"Laforest","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T","family":"Broman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoheb","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Rytkin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binjie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Schaffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Gadek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn M","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1483-5039","authenticated-orcid":false,"given":"Igor R","family":"Efimov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-4963","authenticated-orcid":false,"given":"Ivan P","family":"Moskowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025021505400670000_2024.08.29.610377v2.1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI62617"},{"key":"2025021505400670000_2024.08.29.610377v2.2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.110.942284"},{"key":"2025021505400670000_2024.08.29.610377v2.3","first-page":"1365","article-title":"A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system.","volume":"129","year":"2007","journal-title":"Development. 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