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To determine the molecular drivers of these cardiac defects, we performed RNA-sequencing in Rbfox2 mutant hearts and identified dysregulated alternative splicing (AS) networks that affect cell\u00a0adhesion to extracellular matrix (ECM) mediated by Rho GTPases. We identified two Rho GTPase cycling genes as\u00a0targets of RBFOX2. Modulating AS of these two genes using antisense oligos led to cell cycle and cell-ECM adhesion defects. Consistently, Rbfox2 mutant hearts displayed\u00a0cell cycle\u00a0defects\u00a0and inability to undergo endocardial-mesenchymal transition, processes dependent on cell-ECM adhesion and that are seen in HLHS. Overall, our work not only revealed that loss of Rbfox2 leads to heart development defects resembling HLHS, but also identified RBFOX2-regulated AS networks that influence cell-ECM communication vital for heart development.<\/jats:p>","DOI":"10.1093\/nar\/gkac055","type":"journal-article","created":{"date-parts":[[2022,1,25]],"date-time":"2022-01-25T20:14:11Z","timestamp":1643141651000},"page":"2270-2286","source":"Crossref","is-referenced-by-count":49,"title":["RBFOX2 is required for establishing RNA regulatory networks essential for heart development"],"prefix":"10.1093","volume":"50","author":[{"given":"Sunil K","family":"Verma","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX\u00a077555,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaibhav","family":"Deshmukh","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaitlyn","family":"Thatcher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical College of Wisconsin, Division of Pediatric Cardiology, The Herma Heart Institute, Children's WI, Milwaukee, WI\u00a053226,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"KarryAnne K","family":"Belanger","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX\u00a077555,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander\u00a0M","family":"Rhyner","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"},{"name":"Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Meng","sequence":"additional","affiliation":[{"name":"Houston Methodist Research Institute, Department of Cardiovascular Sciences, Houston, TX\u00a077030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard\u00a0Joshua","family":"Holcomb","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX\u00a077555,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Bressan","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC27599,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James\u00a0F","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"},{"name":"Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"},{"name":"Cardiomyocyte Renewal Lab;Texas Heart Institute, Houston, TX77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John\u00a0P","family":"Cooke","sequence":"additional","affiliation":[{"name":"Houston Methodist Research Institute, Department of Cardiovascular Sciences, Houston, TX\u00a077030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua\u00a0D","family":"Wythe","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"},{"name":"Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX\u00a077030,\u00a0USA"},{"name":"Cardiomyocyte Renewal Lab;Texas Heart Institute, Houston, TX77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven\u00a0G","family":"Widen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX\u00a077555,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Lincoln","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Medical College of Wisconsin, Division of Pediatric Cardiology, The Herma Heart Institute, Children's WI, Milwaukee, WI\u00a053226,\u00a0USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-5861","authenticated-orcid":false,"given":"Muge\u00a0N","family":"Kuyumcu-Martinez","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX\u00a077555,\u00a0USA"},{"name":"Department of Neuroscience, Cell Biology and Anatomy, 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