Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network

Proc Natl Acad Sci U S A. 2011 Aug 16;108(33):13576-81. doi: 10.1073/pnas.1106911108. Epub 2011 Aug 8.


Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His-Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart.

Publication types

  • Research Support, American Recovery and Reinvestment Act
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bundle of His / physiology*
  • Connexin 43 / genetics
  • Connexins / genetics
  • Gap Junctions
  • Gene Expression Regulation
  • Genes, Homeobox
  • Heart Conduction System*
  • Heart Ventricles
  • Homeodomain Proteins / physiology*
  • Mice
  • Purkinje Fibers / physiology*
  • Transcription Factors / physiology*
  • Transcription, Genetic


  • Connexin 43
  • Connexins
  • GJD4 protein, human
  • Homeodomain Proteins
  • Irx3 protein, mouse
  • Transcription Factors