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

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.

Pubmed ID: 21825130


  • Zhang SS
  • Kim KH
  • Rosen A
  • Smyth JW
  • Sakuma R
  • Delgado-OlguĂ­n P
  • Davis M
  • Chi NC
  • Puviindran V
  • Gaborit N
  • Sukonnik T
  • Wylie JN
  • Brand-Arzamendi K
  • Farman GP
  • Kim J
  • Rose RA
  • Marsden PA
  • Zhu Y
  • Zhou YQ
  • Miquerol L
  • Henkelman RM
  • Stainier DY
  • Shaw RM
  • Hui CC
  • Bruneau BG
  • Backx PH


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

August 16, 2011

Associated Grants

  • Agency: NCRR NIH HHS, Id: C06 RR018928
  • Agency: PHS HHS, Id: HHSN271200723701C
  • Agency: NINDS NIH HHS, Id: N01NS02331
  • Agency: NHLBI NIH HHS, Id: R01 HL094414
  • Agency: NHLBI NIH HHS, Id: R01 HL094414-01A1
  • Agency: NHLBI NIH HHS, Id: R01 HL93414
  • Agency: NHLBI NIH HHS, Id: R01 HL94414
  • Agency: Canadian Institutes of Health Research, Id:

Mesh Terms

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