Targeted Mutation Reveals Essential Functions of the Homeodomain Transcription Factor Shox2 in Sinoatrial and Pacemaking Development

Blaschke, R.J., Hahurij, N.D., Kuijper, S., Just, S., Wisse, L.J., Deissler, K., Maxelon, T., Anastassiadis, K., Spitzer, J., Hardt, S.E., Scholer, H., Feitsma, H., Rottbauer, W., Blum, M., Meijlink, F., Rappold, G., and Gittenberger-de Groot, A.C.
Circulation   115(14): 1830-1838 (Journal)
Registered Authors
Feitsma, Harma, Just, Steffen, Rottbauer, Wolfgang
arrhythmia, genes, heart defects, congenital, heart rate, immunohistochemistry
MeSH Terms
  • Animals
  • Bradycardia/embryology
  • Bradycardia/genetics
  • Connexin 43/analysis
  • Connexins/analysis
  • Embryonic Development/genetics
  • Fetal Heart/pathology
  • Gene Expression Regulation, Developmental*
  • Gene Targeting
  • Genes, Lethal
  • Heart/embryology*
  • Heart Conduction System/embryology
  • Heart Conduction System/physiopathology
  • Heart Defects, Congenital/embryology
  • Heart Defects, Congenital/genetics
  • Heart Valves/embryology
  • Homeodomain Proteins/analysis
  • Homeodomain Proteins/genetics
  • Homeodomain Proteins/physiology*
  • Mice/embryology
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium/pathology
  • Myocytes, Cardiac/cytology
  • Phenotype
  • Sinoatrial Node/embryology
  • Transcription Factors/analysis
  • Transcription Factors/genetics
  • Transcription Factors/physiology*
  • Zebrafish/embryology
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology*
17372176 Full text @ Circulation
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. METHODS AND 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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes