Reduced dosage of <i>β-catenin</i> provides significant rescue of cardiac outflow tract anomalies in a <i>Tbx1</i> conditional null mouse model of 22q11.2 deletion syndrome

<div><p>The 22q11.2 deletion syndrome (22q11.2DS; velo-cardio-facial syndrome; DiGeorge syndrome) is a congenital anomaly disorder in which haploinsufficiency of <i>TBX1</i>, encoding a T-box transcription factor, is the major candidate for cardiac outflow tract (OFT) malformations. Inactivation of <i>Tbx1</i> in the anterior heart field (AHF) mesoderm in the mouse results in premature expression of pro-differentiation genes and a persistent truncus arteriosus (PTA) in which septation does not form between the aorta and pulmonary trunk. Canonical <i>Wnt/β-catenin</i> has major roles in cardiac OFT development that may act upstream of <i>Tbx1</i>. Consistent with an antagonistic relationship, we found the opposite gene expression changes occurred in the AHF in <i>β-catenin</i> loss of function embryos compared to <i>Tbx1</i> loss of function embryos, providing an opportunity to test for genetic rescue. When both alleles of <i>Tbx1</i> and one allele of <i>β-catenin</i> were inactivated in the <i>Mef2c-AHF-Cre</i> domain, 61% of them (n = 34) showed partial or complete rescue of the PTA defect. Upregulated genes that were oppositely changed in expression in individual mutant embryos were normalized in significantly rescued embryos. Further, <i>β-catenin</i> was increased in expression when <i>Tbx1</i> was inactivated, suggesting that there may be a negative feedback loop between canonical Wnt and <i>Tbx1</i> in the AHF to allow the formation of the OFT. We suggest that alteration of this balance may contribute to variable expressivity in 22q11.2DS.</p>