RBFOX2 is required for establishing RNA regulatory networks essential for heart development.

Autor:	Verma SK; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA., Deshmukh V; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA., Thatcher K; Department of Pediatrics, Medical College of Wisconsin, Division of Pediatric Cardiology, The Herma Heart Institute, Children's WI, Milwaukee, WI 53226, USA., Belanger KK; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA., Rhyner AM; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX 77030, USA., Meng S; Houston Methodist Research Institute, Department of Cardiovascular Sciences, Houston, TX 77030, USA., Holcomb RJ; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA., Bressan M; Department of Cell Biology and Physiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC27599, USA., Martin JF; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX 77030, USA.; Cardiomyocyte Renewal Lab;Texas Heart Institute, Houston, TX77030, USA., Cooke JP; Houston Methodist Research Institute, Department of Cardiovascular Sciences, Houston, TX 77030, USA., Wythe JD; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Organ Repair and Renewal, Baylor College of Medicine, Houston, TX 77030, USA.; Cardiomyocyte Renewal Lab;Texas Heart Institute, Houston, TX77030, USA., Widen SG; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA., Lincoln J; Department of Pediatrics, Medical College of Wisconsin, Division of Pediatric Cardiology, The Herma Heart Institute, Children's WI, Milwaukee, WI 53226, USA., Kuyumcu-Martinez MN; Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.; Department of Neuroscience, Cell Biology and Anatomy, Institute for Translational Sciences, University of Texas Medical Branch, 301 University Blvd. Galveston, TX 77555, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2022 Feb 28; Vol. 50 (4), pp. 2270-2286.
DOI:	10.1093/nar/gkac055
Abstrakt:	Human genetic studies identified a strong association between loss of function mutations in RBFOX2 and hypoplastic left heart syndrome (HLHS). There are currently no Rbfox2 mouse models that recapitulate HLHS. Therefore, it is still unknown how RBFOX2 as an RNA binding protein contributes to heart development. To address this, we conditionally deleted Rbfox2 in embryonic mouse hearts and found profound defects in cardiac chamber and yolk sac vasculature formation. Importantly, our Rbfox2 conditional knockout mouse model recapitulated several molecular and phenotypic features of HLHS. 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 adhesion to extracellular matrix (ECM) mediated by Rho GTPases. We identified two Rho GTPase cycling genes as targets 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 cell cycle defects and 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. (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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