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          Institute: MPI für molekulare Biomedizin     Collection: Publikationen molekulare Biomedizin     Display Documents

ID: 357267.0, MPI für molekulare Biomedizin / Publikationen molekulare Biomedizin
Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development
Authors:Blaschke, R. J.; Hahurij, N. D.; Kuijper, S.; Just, S.; Wisse, L. J.; Deissler, K.; Maxelon, T.; Anastassiadis, K.; Spitzer, J.; Hardt, S. E.; Schöler, H.; Feitsma, H.; Rottbauer, W.; Blum, M.; Meijlink, F.; Rappold, G.; Gittenberger-de Groot, A. C.
Date of Publication (YYYY-MM-DD):2007
Title of Journal:Circulation
Issue / Number:14
Start Page:1830
End Page:1838
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Animals Bradycardia/embryology/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/physiopathology Heart Defects, Congenital/embryology/genetics Heart Valves/embryology Homeodomain Proteins/analysis/genetics/*physiology Mice/embryology Mice, Inbred C57BL Mice, Knockout Myocardium/pathology Myocytes, Cardiac/cytology Phenotype Sinoatrial Node/embryology Transcription Factors/analysis/genetics/*physiology Zebrafish/embryology Zebrafish Proteins/deficiency/genetics/*physiology
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für molekulare Biomedizin
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