Targeted Mutation Reveals Essential Functions of the Homeodomain Transcription Factor Shox2 in Sinoatrial and Pacemaking Development
| Autor: | Rüdiger J. Blaschke, Lambertus J. Wisse, Wolfgang Rottbauer, Stefan E. Hardt, Sanne Kuijper, Frits Meijlink, Hans R. Schöler, Adriana C. Gittenberger-de Groot, Kirsten Deissler, Martin Blum, Gudrun A. Rappold, Steffen Just, Jessica Spitzer, Nathan D. Hahurij, Tina Maxelon, Konstantinos Anastassiadis, Harma Feitsma |
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| Rok vydání: | 2007 |
| Předmět: |
Heart Defects
Congenital Embryonic Development Biology Connexins Homeobox protein Nkx-2.5 Mice Fetal Heart Heart Conduction System Physiology (medical) Bradycardia medicine Animals Myocytes Cardiac Transcription factor Zebrafish Sinoatrial Node Homeodomain Proteins Mice Knockout Sinus venosus Genetics Regulation of gene expression Heart development Myocardium Gene Expression Regulation Developmental Gene targeting Heart Zebrafish Proteins Heart Valves Cell biology Mice Inbred C57BL Phenotype medicine.anatomical_structure Targeted Mutation Connexin 43 Gene Targeting Homeobox Protein Nkx-2.5 Homeobox Genes Lethal Cardiology and Cardiovascular Medicine Transcription Factors |
| Zdroj: | Circulation. 115:1830-1838 |
| ISSN: | 1524-4539 0009-7322 |
| DOI: | 10.1161/circulationaha.106.637819 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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