Tbx3 is required for normal cardiac conduction system development

Abstract

TBX3 is mutated in human Ulnar‐Mammary Syndrome. Tbx3 null mice die in mid‐gestation with mammary gland, limb, and yolk sac defects. Tbx3 is also expressed in the conduction system and valves of the developing heart.We generated mutants from a series of null, and severe and mild hypomorphic Tbx3 alleles to examine the dosage‐dependent requirements for Tbx3 during mouse cardiac development. Echocardiography, EKGs, and histology were used for cardiac phenotyping. Severe hypomorphs die by e13.5; and limb defects are indistinguishable from null homozygotes. Mild hypomorphs survive to e13.5 with mildly affected limbs. Real time rt‐PCR levels of Tbx3 correlate with the severity of phenotype.Serial echocardiography of embryos reveals a range of embryonic death in severe hypomorphs which correlates with arrhythmias. Embryos that die from e10.5‐12.5 have marked bradycardia prior to death, and those dying from e12.5–13.5 have atrioventricular (AV) block. Some mutants display poorly coordinated ventricular contraction. Mild hypomorphs develop AV block a day later. The developing sinoatrial and AV nodes are smaller in Tbx3 mutants. There are morphologic abnormalities of the developing valves and ventricles.Our data support a dosage‐dependent requirement for Tbx3 during cardiac development. Supported by R01HD046767‐01 to AMM. DF is supported by T32‐HL07576‐22 and UofU CHRC.