title: Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network.
abstract: 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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Zhang
authors.forename: Kyoung-Han
authors.initials: KH
authors.lastname: Kim
authors.forename: Anna
authors.initials: A
authors.lastname: Rosen
authors.forename: James W
authors.initials: JW
authors.lastname: Smyth
authors.forename: Rui
authors.initials: R
authors.lastname: Sakuma
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguín
authors.forename: Mark
authors.initials: M
authors.lastname: Davis
authors.forename: Neil C
authors.initials: NC
authors.lastname: Chi
authors.forename: Vijitha
authors.initials: V
authors.lastname: Puviindran
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gaborit
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sukonnik
authors.forename: John N
authors.initials: JN
authors.lastname: Wylie
authors.forename: Koroboshka
authors.initials: K
authors.lastname: Brand-Arzamendi
authors.forename: Gerrie P
authors.initials: GP
authors.lastname: Farman
authors.forename: Jieun
authors.initials: J
authors.lastname: Kim
authors.forename: Robert A
authors.initials: RA
authors.lastname: Rose
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Marsden
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Zhou
authors.forename: Lucile
authors.initials: L
authors.lastname: Miquerol
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: Robin M
authors.initials: RM
authors.lastname: Shaw
authors.forename: Chi-chung
authors.initials: CC
authors.lastname: Hui
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
mesh_terms: D000818:Animals; D002036:Bundle of His / Q000502:physiology*; D018031:Connexin 43 / Q000235:genetics; D017630:Connexins / Q000235:genetics; D017629:Gap Junctions; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D006329:Heart Conduction System; D006352:Heart Ventricles; D018398:Homeodomain Proteins / Q000502:physiology*; D051379:Mice; D011690:Purkinje Fibers / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D018031:Connexin 43; D017630:Connexins; C484032:GJD4 protein, human; D018398:Homeodomain Proteins; C501599:Irx3 protein, mouse; D014157:Transcription Factors