Irx3 is required for postnatal maturation of the mouse ventricular conduction system

Kyoung Han Kim, Anna Rosen, Samer M.I. Hussein, Vijitha Puviindran, Adam S. Korogyi, Carmelina Chiarello, Andras Nagy, Chi Chung Hui, Peter H. Backx

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3/) mice. In this study, we show that during the early postnatal period, Irx3/mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.

Original languageEnglish
Article number19197
Number of pages14
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 20 Jan 2016
Externally publishedYes

Cite this

Kim, K. H., Rosen, A., Hussein, S. M. I., Puviindran, V., Korogyi, A. S., Chiarello, C., ... Backx, P. H. (2016). Irx3 is required for postnatal maturation of the mouse ventricular conduction system. Scientific Reports, 6, [19197]. https://doi.org/10.1038/srep19197
Kim, Kyoung Han ; Rosen, Anna ; Hussein, Samer M.I. ; Puviindran, Vijitha ; Korogyi, Adam S. ; Chiarello, Carmelina ; Nagy, Andras ; Hui, Chi Chung ; Backx, Peter H. / Irx3 is required for postnatal maturation of the mouse ventricular conduction system. In: Scientific Reports. 2016 ; Vol. 6.
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abstract = "The ventricular conduction system (VCS) orchestrates the harmonious contraction in every heartbeat. Defects in the VCS are often associated with life-threatening arrhythmias and also promote adverse remodeling in heart disease. We have previously established that the Irx3 homeobox gene regulates rapid electrical propagation in the VCS by modulating the transcription of gap junction proteins Cx40 and Cx43. However, it is unknown whether other factors contribute to the conduction defects observed in Irx3 knockout (Irx3/) mice. In this study, we show that during the early postnatal period, Irx3/mice develop morphological defects in the VCS which are temporally dissociated from changes in gap junction expression. These morphological defects were accompanied with progressive changes in the cardiac electrocardiogram including right bundle branch block. Hypoplastic VCS was not associated with increased apoptosis of VCS cardiomyocytes but with a lack of recruitment and maturation of ventricular cardiomyocytes into the VCS. Computational analysis followed by functional verification revealed that Irx3 promotes VCS-enriched transcripts targeted by Nkx2.5 and/or Tbx5. Altogether, these results indicate that, in addition to ensuring the appropriate expression of gap junctional channels in the VCS, Irx3 is necessary for the postnatal maturation of the VCS, possibly via its interactions with Tbx5 and Nkx2.5.",
author = "Kim, {Kyoung Han} and Anna Rosen and Hussein, {Samer M.I.} and Vijitha Puviindran and Korogyi, {Adam S.} and Carmelina Chiarello and Andras Nagy and Hui, {Chi Chung} and Backx, {Peter H.}",
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Kim, KH, Rosen, A, Hussein, SMI, Puviindran, V, Korogyi, AS, Chiarello, C, Nagy, A, Hui, CC & Backx, PH 2016, 'Irx3 is required for postnatal maturation of the mouse ventricular conduction system' Scientific Reports, vol. 6, 19197. https://doi.org/10.1038/srep19197

Irx3 is required for postnatal maturation of the mouse ventricular conduction system. / Kim, Kyoung Han; Rosen, Anna; Hussein, Samer M.I.; Puviindran, Vijitha; Korogyi, Adam S.; Chiarello, Carmelina; Nagy, Andras; Hui, Chi Chung; Backx, Peter H.

In: Scientific Reports, Vol. 6, 19197, 20.01.2016.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Irx3 is required for postnatal maturation of the mouse ventricular conduction system

AU - Kim, Kyoung Han

AU - Rosen, Anna

AU - Hussein, Samer M.I.

AU - Puviindran, Vijitha

AU - Korogyi, Adam S.

AU - Chiarello, Carmelina

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AU - Hui, Chi Chung

AU - Backx, Peter H.

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Kim KH, Rosen A, Hussein SMI, Puviindran V, Korogyi AS, Chiarello C et al. Irx3 is required for postnatal maturation of the mouse ventricular conduction system. Scientific Reports. 2016 Jan 20;6. 19197. https://doi.org/10.1038/srep19197