title: Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development.
abstract: BACKGROUND
  Identifying molecular pathways regulating the development of pacemaking and coordinated heartbeat is crucial for a comprehensive mechanistic understanding of arrhythmia-related diseases. Elucidation of these pathways has been complicated mainly by an insufficient definition of the developmental structures involved in these processes and the unavailability of animal models specifically targeting the relevant tissues. Here, we report on a highly restricted expression pattern of the homeodomain transcription factor Shox2 in the sinus venosus myocardium, including the sinoatrial nodal region and the venous valves.
  
  
  RESULTS
  To investigate its function in vivo, we have generated mouse lines carrying a targeted mutation of the Shox2 gene. Although heterozygous animals did not exhibit obvious defects, homozygosity of the targeted allele led to embryonic lethality at 11.5 to 13.5 dpc. Shox2-/- embryos exhibited severe hypoplasia of the sinus venosus myocardium in the posterior heart field, including the sinoatrial nodal region and venous valves. We furthermore demonstrate aberrant expression of connexin 40 and connexin 43 and the transcription factor Nkx2.5 in vivo specifically within the sinoatrial nodal region and show that Shox2 deficiency interferes with pacemaking function in zebrafish embryos.
  
  
  CONCLUSIONS
  From these results, we postulate a critical function of Shox2 in the recruitment of sinus venosus myocardium comprising the sinoatrial nodal region.
authors: Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors: Rüdiger J
authors: RJ
authors: Blaschke
authors: Nathan D
authors: ND
authors: Hahurij
authors: Sanne
authors: S
authors: Kuijper
authors: Steffen
authors: S
authors: Just
authors: Lambertus J
authors: LJ
authors: Wisse
authors: Kirsten
authors: K
authors: Deissler
authors: Tina
authors: T
authors: Maxelon
authors: Konstantinos
authors: K
authors: Anastassiadis
authors: Jessica
authors: J
authors: Spitzer
authors: Stefan E
authors: SE
authors: Hardt
authors: Hans
authors: H
authors: Schöler
authors: Harma
authors: H
authors: Feitsma
authors: Wolfgang
authors: W
authors: Rottbauer
authors: Martin
authors: M
authors: Blum
authors: Frits
authors: F
authors: Meijlink
authors: Gudrun
authors: G
authors: Rappold
authors: Adriana C
authors: AC
authors: Gittenberger-de Groot
mesh_terms: D000818:Animals; D001919:Bradycardia / Q000196:embryology / Q000235:genetics; D018031:Connexin 43 / Q000032:analysis; D017630:Connexins / Q000032:analysis; D047108:Embryonic Development / Q000235:genetics; D005318:Fetal Heart / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005804:Genes, Lethal; D006321:Heart / Q000196:embryology*; D006329:Heart Conduction System / Q000196:embryology / Q000503:physiopathology; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics; D006351:Heart Valves / Q000196:embryology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice / Q000196:embryology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology; D010641:Phenotype; D012849:Sinoatrial Node / Q000196:embryology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D018031:Connexin 43; D017630:Connexins; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D014157:Transcription Factors; D029961:Zebrafish Proteins; D000097003:Gap Junction alpha-5 Protein; C484469:Nkx2-5 protein, mouse; C484663:Shox2 protein, mouse; C519383:Shox2 protein, zebrafish