Abstract 18584: Cardiac Beta-Catenin Deletion Mediated by Alpha-MHC Promoter Causes Ventricular Hypoplasia
Backgrounds: During early cardiogenesis, canonical Wnt signaling appears to have biphasic and antagonistic roles: stimulatory effects before and inhibitory effects during and after gastrulation. However, genetic targeting has revealed that beta-catenin, an obligatory transcriptional activator in the canonical Wnt pathway plays a positive cell-autonomous role which is necessary and irreplaceable in early cardiac organogenesis. As beta-catenin signaling alterations targeted to cardiac progenitor cells result in early fetal demise, it remains unclear if beta-catenin is indispensable for cardiac chamber remodeling after initial heart chamber formation.
Methods: To overcome early embryonic lethality of beta-catenin intervention in cardiac progenitor cells, we used the Cre recombinase driven by alpha-myosin heavy chain promoter to delete beta-catenin genes floxed with lox P sites between exons 2 and 6. Homozygous β-catenin deletion (KO) and wild-type (WT) mice were phenotyped by morphological analysis, cardiac and proliferation markers.
Result: Beta-catenin expression started to decrease in KO mice at embryonic day (E) 10.5. At E11.5, β-catenin was uniformly reduced in cardiomyocytes of KO mice, but there was not any gross difference between WT and KO mice. At 12.5, KO mice were grossly unremarkable except that the pericardial space was slightly enlarged. At 13.5, about one third of KO embryos (4 out of 13) were pale and necrotic consistent with autolysis. The remaining two third (9 out of 13) showed signs of congestive heart failure with vascular congestion and pericardial edema. Hearts were smaller with thinner left and right ventricular walls in KO mice compared to that of WT controls. No increase in apoptosis was observed in KOs with TUNEL labeling and anti-cleaved caspase 3 staining. Ki67 labeling index and mitotic rate were reduced by 40% and 35% respectively in KO hearts compared to WT ones. No changes in either Nkx2.5 or GATA4 were observed between KO and WT hearts by immunohistochemistry.
Conclusion: beta-Catenin positively regulates cardiomyocyte proliferation during cardiac chamber maturation. The hypoplastic phenotype of β-catenin deleted hearts is due to defects in cardiomyocyte proliferation rather than cell death.
- © 2010 by American Heart Association, Inc.