Canonical Wnt/β-catenin signaling controls cardiogenesis and cardiomyocyte (CM) proliferation during fetal development and regulates CM hypertrophy and remodeling in response to a variety of stresses including myocardial infarction (MI). These diverse context-specific functions have been increasingly recognized, but how they are modulated remains unclear. Upon Wnt activation, β-catenin is stabilized and enters the nucleus to interact with T-cell factor/lymphoid enhancer factor (TCF/LEF) family transcription factors, which use their sequence-specific DNA-binding domain (DBD) to find target genes and variable regulatory domains for transcriptional activation and suppression. This group's data showed that although all four TCF/LEFs were expressed in the heart, Tcf7l2 becomes the main nuclear partner of β-catenin during cardiac maturation. Lef1 and positive cell cycle regulatory genes dropped as CM proliferation attenuated. On the other hand, Tcf7l2 mRNA remained relatively stable, but switched isoforms with differential activation and repression potentials. Population studies have associated Tcf7l2 single nucleotide polymorphisms (SNPs) in several noncoding loci with coronary artery disease, a major health problem worldwide. Although the SNPs do not change coding sequence, these common variants have been shown to influence the expression of Tcf7l2 isoforms.
This project has two specific aims:
- Aim 1: To determine the roles of Tcf7l2 isoforms in CM proliferation during cardiac development
- Aim 2: To investigate the role of Tcf7l2 isoforms in cardiac regeneration and remodeling with and without Wnt stimulation after MI