Abstract 787: Epicardial-restricted Deletion of Beta-catenin in Mice Hearts Recapitulates the Abnormal Cardiac Morphogenesis of Epicardial Retinoid Receptor Alpha Deletion and Affects the Sinoatrial Node Development
Introduction: The genetic basis of sinoatrial nodal (SAN) development during embryogenesis remains poorly understood. Compared to the wild-type (WT) mouse, we previously showed that epicardial-restricted deletion of the retinoid receptor alpha (RXRα) impaired embryonic survival, down-regulated epicardial β-catenin, impaired atrial septation, produced hypoplastic & uncompacted ventricular myocardium with leftward rotated ventricular apex, and affected coronary vasculogenesis. The effect of epicardial RXRβ deletion on SAN development remains to be determined. The β-catenin gene acts downstream of the RXRβ pathway and its effects on cardiogenesis and SAN development remain unclear.
Methods: Using Cre-loxP techniques, we generated mice lacking β-catenin in the epicardium (epiBC line) by interbreeding a mouse carrying the floxed β-catenin allele with one from the epicardial G5-Cre line. We further develop a multi-electrode array (MEA) recording system with digital movies to map the electrophysiological (EP) phenotypes of the acutely isolated embryonic hearts at age of 12.5 day post-coitus (E12.5).
Results: Epicardial-conditional deletion of β-catenin recapitulates the cardiac abnormalities of epicardial RXRα deletion, sharing both myocardial and vascular abnormalities previously described in the RXRα mutant mice. In WT mice hearts at E12.5, the HCN4 (pacemaker channel) and connexin 45 (Cx45) staining is restricted to the SAN located at the epicardial side of right atrium (RA), and medial/low septal regions of the RA. However, both atria in E12.5 epiBC mice hearts displayed thickened myocardium with rich HCN4 staining in the endocardial layer. At the SAN region, the CX45 staining was dramatically reduced and the distribution of HCN4 staining was not localized to the SAN. MEA mappings show that E12.5 epiBC mice hearts display slower atrial conduction and SAN rhythm with longer sinus cycle length (777.9 ms vs. 527.7 ms in WT from the same littermates). Other atrial EP properties of E12.5 epiBC mice hearts are relatively normal.
Conclusions: These results support that the epicardial retinoids/Wnt/β-catenin pathway regulates cardiac development, including myocardial compaction, coronary vessel formation and development of the SAN.