Deletion of the Wilms' Tumor Suppressor Gene in the Cardiac Troponin-T Lineage Reveals Novel Functions of WT1 in Heart Development

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