Abstract 17815: Canonical Wnt/beta-catenin Signaling During Late Embryonic Heart Development
Backgrounds: Canonical Wnt/beta-catenin signaling regulates cardiogenesis dependent on developmental stage and cellular context. Beta-catenin, an obligatory transcriptional activator in this signaling pathway, is required for early cardiac organogenesis. On the other hand, adenomatous polyposis coli (APC), a negative regulator of beta-catenin, is essential for cardiac morphogenesis in zebrafish. How canonical Wnt/beta-catenin signaling regulates cardiac chamber remodeling and growth in late heart development remains unclear.
Methods: APC and beta-catenin were deleted in cardiomyocytes (CMs) using the Cre recombinase driven by alpha-myosin heavy chain promoter (MHC-Cre). Wnt target gene expression and cardiac phenotype of targeted mice were analyzed by real-time RT-PCR, axin2-beta-Gal reporter assay, histology, cardiac differentiation and proliferation markers.
Result: Homozygous deletion of beta-catenin by MHC-Cre caused ventricular hypoplasia resulting in fetal demise by embryonic day (E) 14.5. On the other hand, cardiac homozygous APC deficiency promoted ventricular hyperplasia and had no adverse effect on fetal survival. No increase in apoptosis was observed in either APC or beta-catenin knockout mice. Cell cycle activity was reduced in beta-catenin deficient hearts, but increased in APC null hearts. Real-time RT-PCR revealed that neither APC nor beta-catenin deletion had significant effect on the expression of cardiac differentiation markers such as Nkx2.5, GATA4, alpha-MHC, and beta-MHC. Using axin2-beta-Gal reporter mice, we detected axin2 (a universal Wnt/beta-catenin target gene) expression in atrial and valvular regions, but not in ventricles of wild-type mice at E17.5. Beta-Gal activity was significantly increased in both atria and ventricles when APC was deleted by MHC-Cre. Axin2 mRNA was also significantly upregulated in APC null hearts and downregulated in beta-catenin deficient hearts at E13.5.
Conclusion: Our findings indicate that canonical Wnt/beta-catenin signaling is inhibited by APC in CMs. Activation of this signaling pathway by cardiac specific deletion of APC positively regulates CM proliferation without adverse effect on cardiac differentiation.
- © 2012 by American Heart Association, Inc.