Abstract 17136: Irx3 and Irx5 Cooperatively Regulate Mouse Heart Development and Adult Cardiac Function
Transcriptional regulation of heart development takes place via spatio-temporal and coordinated expression of multimeric complexes of transcription factors. Members of the Iroquois homeobox (Irx) family of transcription factors are expressed in highly cell type-specific and often overlapping patterns in the developing heart, suggesting that these genes may interact in important pathways during cardiogenesis. Single deletions of Irx genes showed subtle but significant defects in several aspects of cardiac function, including cardiac repolarization for Irx5, and ventricular conduction for Irx3. Additionally, Irx3 and Irx5 expression overlap in the cardiac ventricular chambers. Our study suggests that their overlapping expression may mask additional roles of these genes in cardiac development and adult function. Supporting a combinatorial role in pre-natal cardiac development, mice lacking both Irx3 and Irx5 are embryonically lethal due to major structural heart defects that model human congenital heart disease, including a common atrio-ventricular canal and a double outlet right ventricle. We show that the cardiac phenotype originates from the loss of function of Irx3 and Irx5 in endocardial cells. In the adult heart, our data suggest that Irx3 and Irx5 double knockout mice have a prolonged QRS complex and PR interval that is worse than the Irx3 single knockout mice. Moreover, the T wave absent in the Irx5 single knockout mice reappears with the additional deletion of Irx3. These results strongly suggest a role for Irx3 and Irx5 in the ventricular conduction of the electrical influx. All together, our data suggest that Irx3 and Irx5 cooperatively regulate heart development and adult cardiac function.
- © 2011 by American Heart Association, Inc.