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(Circulation. 2007;115:1830-1838.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

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

Rüdiger J. Blaschke, PhD; Nathan D. Hahurij, MSc; Sanne Kuijper, PhD^*; Steffen Just, MD^*; Lambertus J. Wisse, BSc; Kirsten Deissler, PhD; Tina Maxelon, BSc; Konstantinos Anastassiadis, PhD; Jessica Spitzer, MD; Stefan E. Hardt, MD; Hans Schöler, PhD; Harma Feitsma, BSc; Wolfgang Rottbauer, MD; Martin Blum, PhD; Frits Meijlink, PhD; Gudrun Rappold, PhD; Adriana C. Gittenberger-de Groot, PhD

From the Institute of Human Genetics (R.J.B., T.M., J.S., G.R.) and Department of Internal Medicine III (S.J., S.E.H., W.R.), University of Heidelberg, Heidelberg, Germany; Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands (N.D.H., L.J.W., A.C.G.-d.G.); Hubrecht Laboratory, Netherlands Institute of Developmental Biology, Uppsalalaan, Utrecht, the Netherlands (S.K., H.F., F.M.); University Hohenheim, Institute for Zoology, Stuttgart, Germany (K.D., M.B.); BIOTEC, TU Dresden, Max-Planck-Institute for Molecular Cell Biology and Genetics MPI-CBG, Dresden, Germany (K.A.); and Max-Planck-Institute of Molecular Biomedicine, Münster, Germany (H.S.).

Correspondence to Adriana C. Gittenberger-de Groot, Leiden University Medical Center, Department of Anatomy and Embryology, PO Box 9600, Postzone S-1-P, 2300 RC Leiden, The Netherlands (e-mail acgitten{at}lumc.nl); or Gudrun Rappold, Institute of Human Genetics, Department of Human Molecular Genetics, University of Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany (e-mail Gudrun_Rappold@med.uni-heidelberg.de).

Received May 3, 2006; accepted February 2, 2007.

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.

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