Abstract
Abstract only BubR1 (Budding uninhibited by Benzimidazole Related -1) is a kinase with a well-established role in regulating the spindle assembly checkpoint during mitosis. Recent studies have found that BubR1 insufficiency leads to premature aging phenotypes, and that BubR1 protein levels naturally decline with age, suggesting a role for BubR1 in aging and age-related diseases. Interestingly, mice carrying hypomorphic alleles of BubR1 expressing approximately 10% of the protein (BubR1 hypomorphic mice, BubR1 H/H ) die suddenly in a manner reminiscent of sudden cardiac death. Subsequent studies further demonstrated that BubR1 hypomorphic mice suffer from conduction abnormalities such as a prolonged QT interval. This abnormality can cause irregular rhythm in the ventricles that can lead to ventricular fibrillation and sudden cardiac death. However, the molecular and cellular basis linking these phenotypes to deficiency of BubR1 remain unknown. To define a role for BubR1 in the heart, we have taken a cellular and organismal approach to test the hypothesis that BubR1 regulates cardiac conduction. Utilizing a conditional BubR1 knockout mouse model, we have crossed this mouse to a cardiac-specific cre driver ( Nkx2.5-cre ) to assess the consequence of loss of BubR1 specifically in the heart. We observed that homozygous cardiac-specific deletion of BubR1 is embryonic lethal, indicating a critical role for BubR1 in heart development. Interestingly, electrocardiography (ECG) analysis of heterozygous deletion of BubR1 (55.4 ms ±3.3) also led to a prolonged QT interval in vivo as compared to wild type control (46.4 ms ±2.3) (N=10, p < 0.01). To determine the molecular basis for our observed phenotypes in vivo, we have performed gene expression profiling on RNA isolated from hearts of 6-month-old BubR1 H/H and wild-type mice in which genetic pathways relating to cardiac conduction such as ion channels were altered in expression (N=3). Finally, we have also identified that intercellular communication is dysregulated upon depletion of BubR1. Together these studies suggests a novel mechanism by which loss of BubR1 may lead to adverse consequences for the heart in vivo .