T-box 2, a mediator of Bmp-Smad signaling, induced hyaluronan synthase 2 and Tgfbeta2 expression and endocardial cushion formation.
During early heart development, Tbx2 gene expression is initiated in the cardiac crescent and then becomes restricted to the outflow tract and the atrioventricular region. We identified a Tbx2 regulatory region, enriched in multiple Smad sites, sufficient to reproduce Tbx2 expression patterns overlapping Bmp2 and Bmp4 gene activity in the heart. The role of Tbx2 in cardiogenesis was analyzed by using Cre-LoxP activated Tbx2 transgenic misexpression in chamber myocardium. Ventricular Tbx2 misexpression exhibited an abnormally narrow chamber lumen owing to the expansion of Hyaluronan synthase 2 expression in the ECM or cardiac jelly and the appearance of the endocardial cushions (ECs). Excessive Tbx2 also induced Tgfbeta2, which coincided with the outgrowth epithelial-mesenchymal transformed cells in ventricular and atrial tissues modifying cardiomyocyte identity from chamber type to non-chamber type. Tbx2, a central intermediary of Bmp-Smad signaling, has a central part in directing Has2 and Tgfbeta2 expression, facilitating EC formation.
Department of Bioscience, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Manabu
M
Shirai
Kyoko
K
Imanaka-Yoshida
Michael D
MD
Schneider
Robert J
RJ
Schwartz
Takayuki
T
Morisaki
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D054089:Endocardial Cushions / Q000196:embryology / Q000201:enzymology*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D004790:Enzyme Induction; D004848:Epithelium / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D000076002:Hyaluronan Synthases; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009024:Morphogenesis; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D019076:Transgenes
D019485:Bone Morphogenetic Proteins; D051785:Smad Proteins; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; D053781:Transforming Growth Factor beta2; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases