1. Deletion of the Wilms' Tumor Suppressor Gene in the Cardiac Troponin-T Lineage Reveals Novel Functions of WT1 in Heart Development
- Author
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Sandra Díaz del Moral, Silvia Barrena, Francisco Hernández-Torres, Amelia Aránega, José Manuel Villaescusa, Juan José Gómez Doblas, Diego Franco, Manuel Jiménez-Navarro, Ramón Muñoz-Chápuli, Rita Carmona, [Díaz del Moral,S, Barrena,S, Muñoz-Chápuli,R, Carmona,R] Department of Animal Biology, University of Málaga, Málaga, Spain. [Hernández-Torres,F] Department of Biochemistry and Molecular Biology III and Immunology, Faculty of Medicine, University of Granada, Granada, Spain. [Hernández-Torres,F, Aránega,A] Medina Foundation, Technology Park of Health Sciences, Granada, Spain. [Aránega,A, Franco,D] Department of Experimental Biology, Faculty of Experimental Sciences, University of Jaén, Jaén, Spain. [Villaescusa,JM, Gómez Doblas,JJ, Jiménez-Navarro,M] Heart Area Clinical Management Unit, University Hospìtal Virgen de la Victoria, CIBERCV Enfermedades Cardiovasculares Health Institute Carlos III, Biomedical Research Institute of Malaga (IBIMA), University of Málaga, Málaga, Spain., and This work was supported by: Spanish Ministry of Economy, Industry and Competitivity (BFU2017-83907-P to RM-C and RC and PID2019-107492GB-I00 to AA and DF), Consejería de Salud, Junta de Andalucía (PC0066?2017/PC-0081-2017 to RC, JV, and JG), Instituto de Salud Carlos III-TERCEL network (RD16/0011/0030 to RM-C and RC), Instituto de Salud Carlos III-CIBERCV 'Enfermedades Cardiovasculares' (CB16/11/00360 to MJ-N), and Consejería de Economía yConocimiento, Junta de Andalucía (UMA18-FEDERJA-146 to RM-C and RC and FEDER-UJA to AA and DF).
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0301 basic medicine ,Pathology ,Genes supresores de tumores ,TNNT2 ,cardiac development ,Canales de potasio ,cardiomyocytes ,Genes del tumor de Wilms ,0302 clinical medicine ,Calcium homeostasis ,Homeostasis ,Wilms’ tumor suppressor gene ,Atrium (heart) ,Biology (General) ,Anatomy::Cardiovascular System::Heart::Pericardium [Medical Subject Headings] ,Original Research ,Cardiomyocytes ,Anatomy::Musculoskeletal System::Muscles::Myocardium [Medical Subject Headings] ,Heart development ,calcium homeostasis ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Carrier Proteins::Membrane Transport Proteins::Ion Channels::Potassium Channels [Medical Subject Headings] ,potassium channels ,Chemicals and Drugs::Inorganic Chemicals::Elements::Metals, Alkaline Earth::Calcium [Medical Subject Headings] ,medicine.anatomical_structure ,Chemicals and Drugs::Macromolecular Substances::Polymers::Biopolymers::Microfilament Proteins::Troponin::Troponin T [Medical Subject Headings] ,cardiovascular system ,Crecimiento y desarrollo ,medicine.medical_specialty ,QH301-705.5 ,Biology ,Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors [Medical Subject Headings] ,Pectinate muscles ,Potassium channels ,03 medical and health sciences ,QRS complex ,Cell and Developmental Biology ,Calcio ,Cardiac development ,medicine ,Interventricular septum ,cardiovascular diseases ,Sinus venosus ,Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Genes, Recessive::Genes, Tumor Suppressor [Medical Subject Headings] ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings] ,Wilms' tumor ,Cell Biology ,medicine.disease ,Wilms' tumor supressor gene ,030104 developmental biology ,Diseases::Neoplasms::Neoplastic Syndromes, Hereditary::Wilms Tumor [Medical Subject Headings] ,Anatomy::Cardiovascular System::Heart::Myocardium::Myocytes, Cardiac [Medical Subject Headings] ,Miocitos cardíacos ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
This work was supported by: Spanish Ministry of Economy, Industry and Competitivity (BFU2017-83907-P to RM-C and RC and PID2019-107492GB-I00 to AA and DF), Consejeria de Salud, Junta de Andalucia (PC0066?2017/PC-0081-2017 to RC, JV, and JG), Instituto de Salud Carlos III-TERCEL network (RD16/0011/0030 to RM-C and RC), Instituto de Salud Carlos III-CIBERCV "Enfermedades Cardiovasculares" (CB16/11/00360 to MJ-N), and Consejeria de Economia y Conocimiento, Junta de Andalucia (UMA18-FEDERJA-146 to RM-C and RC and FEDER-UJA to AA and DF)., Expression of Wilms’ tumor suppressor transcription factor (WT1) in the embryonic epicardium is essential for cardiac development, but its myocardial expression is little known. We have found that WT1 is expressed at low levels in 20–25% of the embryonic cardiomyocytes. Conditional ablation of WT1 using a cardiac troponin T driver (Tnnt2Cre) caused abnormal sinus venosus and atrium development, lack of pectinate muscles, thin ventricular myocardium and, in some cases, interventricular septum and cardiac wall defects, ventricular diverticula and aneurisms. Coronary development was normal and there was not embryonic lethality, although survival of adult mutant mice was reduced probably due to perinatal mortality. Adult mutant mice showed electrocardiographic anomalies, including increased RR and QRS intervals, and decreased PR intervals. RNASeq analysis identified differential expression of 137 genes in the E13.5 mutant heart as compared to controls. GO functional enrichment analysis suggested that both calcium ion regulation and modulation of potassium channels are deeply altered in the mutant myocardium. In summary, together with its essential function in the embryonic epicardium, myocardial WT1 expression is also required for normal cardiac development., Spanish Ministry of Economy, Industry and Competitivity BFU2017-83907-P PID2019-107492GB-I00, Junta de Andalucia PC0066?2017/PC-0081-2017, Instituto de Salud Carlos III-TERCEL network RD16/0011/0030 Instituto de Salud Carlos III-CIBERCV "Enfermedades Cardiovasculares" CB16/11/00360, Junta de Andalucia UMA18-FEDERJA-146
- Published
- 2021