title: Molecular analysis of patterning of conduction tissues in the developing human heart.
abstract: BACKGROUND
  Recent studies in experimental animals have revealed some molecular mechanisms underlying the differentiation of the myocardium making up the conduction system. To date, lack of gene expression data for the developing human conduction system has precluded valid extrapolations from experimental studies to the human situation.
  
  
  RESULTS
  We performed immunohistochemical analyses of the expression of key transcription factors, such as ISL1, TBX3, TBX18, and NKX2-5, ion channel HCN4, and connexins in the human embryonic heart. We supplemented our molecular analyses with 3-dimensional reconstructions of myocardial TBX3 expression. TBX3 is expressed in the developing conduction system and in the right venous valve, atrioventricular ring bundles, and retro-aortic nodal region. TBX3-positive myocardium, with exception of the top of the ventricular septum, is devoid of fast-conducting connexin40 and connexin43 and hence identifies slowly conducting pathways. In the early embryonic heart, we found wide expression of the pacemaker channel HCN4 at the venous pole, including the atrial chambers. HCN4 expression becomes confined during later developmental stages to the components of the conduction system. Patterns of expression of transcription factors, known from experimental studies to regulate the development of the sinus node and atrioventricular conduction system, are similar in the human and mouse developing hearts.
  
  
  CONCLUSIONS
  Our findings point to the comparability of mechanisms governing the development of the cardiac conduction patterning in human and mouse, which provide a molecular basis for understanding the functioning of the human developing heart before formation of a discrete conduction system.
authors.affiliation: Heart Failure Research Center, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Aleksander
authors.initials: A
authors.lastname: Sizarov
authors.forename: Harsha D
authors.initials: HD
authors.lastname: Devalla
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.forename: Robert
authors.initials: R
authors.lastname: Passier
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Christoffels
authors.forename: Antoon F M
authors.initials: AF
authors.lastname: Moorman
mesh_terms: D001283:Atrioventricular Node / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D018031:Connexin 43 / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006329:Heart Conduction System / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D015221:Potassium Channels; D012849:Sinoatrial Node / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000097003:Gap Junction alpha-5 Protein; C119587:HCN4 protein, human; C106884:TBX3 protein, human