Opposing Roles of Tcf7/Lef1 and Tcf7l2 in Cyclin D2 and Bmp4 Expression and Cardiomyocyte Cell Cycle Control during Late Heart Development

Bone morphogenetic protein (Bmp) and Wnt pathways regulate cell proliferation and differentiation, but how these two pathways interact and mediate their nuclear actions in the heart, especially during late cardiac development, remains poorly defined. T-cell factor (TCF) and lymphoid enhancer factor (LEF) family transcriptional factors, including Lef1, Tcf7, Tcf7l1, and Tcf7l2, are important nuclear mediators of canonical Wnt/β-catenin signaling throughout cardiac development. We reveal that these TCF/LEF family members direct heart maturation through distinct temporal and spatial control. Tcf7 and Lef1 decreases while Tcf7l1 and Tcf7l2 remain relatively stable during heart development. Lef1 is mainly expressed in mesenchymal cells in valvular regions. Tcf7 and Tcf7l1 are detected in the nucleus of mesothelial and endothelial cells, but not in cardiomyocytes or mesenchymal cells. Tcf7l2 is the primary TCF/LEF family member in cardiomyocytes and undergoes alternative splicing during heart development. A Tcf7l2 intensity gradient opposite to that of β-catenin and cardiomyocyte proliferative activity is present in fetal hearts. Wnt activation by cardiac deletion of adenomatosis polyposis coli, a negative Wnt regulator, dramatically increases Cyclin D2 and Bmp4 expression. Bmp signal transducing transcription factors, the mothers against decapentaplegic homologs (Smads) are increasingly phosphorylated upon Wnt activation. Lef1/Tcf7 displaces Tcf7l2 and cooperates with pSmad1/5/8 in the regulatory elements of Cyclin D2 and Bmp4 promoters to promote β-catenin recruitment and transcriptional activation. Finally, we demonstrate that Tcf7l2 is a transcriptional suppressor of Cyclin D2 and Bmp 4 in a cardiac cell line by overexpression and knockdown experiments.