Paper of the Month - November 2016

Kim KH, Rosen A, Hussein SM, Puviindran V, Korogyi AS, Chiarello C, Nagy A, Hui CC, Backx PH. Irx3 is required for postnatal maturation of the mouse ventricular conduction system. Sci Rep. 2016 Jan 20;6:19197. doi: 10.1038/srep19197.

Our collaborative studies with Dr CC Hui at Sickkids Hospital have been exploring the role the family of Iroquois transcription factors (TFs) in the development and function of the heart.  We have found that this family of TFs, which are critical for global patterning during early development, continues to play functional roles later in development and into adulthood, by modulating the pattern of electrical properties of the heart via the transcriptional regulation of key ion channel genes.  We showed in previous studies that Irx5, a member of the Iroquois TFs regulates repolarization heterogeneity (Constantini et al, Cell 2005) in the ventricular while another member of the Iroquois family, Irx3, regulates electrical propagation in ventricles by modulating the transcription of gap junction genes (i.e. Gja5 and Gja1) in the ventricular conduction system (VCS) as well as voltage-gated Na+ channels (Zhang et al, PNAS 2011).  Our continued interest in Irx3 has been fueled by the observation that mutations of this gene are associated with idiopathic ventricular fibrillation possibly as a result of impaired transcriptional regulation of Gja5. Moreover, in earlier studies, we found that the conduction deficiencies, seen in mice lacking Irx3, could not be fully explained by changes in gap junction expression and function.  The present study was designed to better understand the role of Irx3 in electrical function of the heart. We found that the loss of Irx3 resulted in progressive changes in the electrocardiogram (ECG) during the early postnatal period (i.e. conduction block in the AV node also called heart block). We further found that this heart block was related to structural deterioration of the VCS, virtually identical to that reported in mice lacking one allele of the developmental transcriptional fact Nkx2.5. These structural defects were found to be temporally distinct from the effects of the loss of Irx3 on gap junction expression. We then established that Irx3 interacts with Tbx5 another TF as well as Nkx2.5 in a transcriptional complex. Together this cluster of TFs regulates the expression of VCS-enriched genes to which Nkx2.5 and/or Tbx5 bind. We conclude that from our studies that Irx3 plays an essential role in the postnatal maturation of the VCS, via its interactions with Tbx5 and Nkx2.5.  These studies provide new insights into possible mechanisms for some common arrhythmias associated with defective ventricular conduction, including heart block as well as ventricular tachycardia and ventricular fibrillation.

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