Published Online
on March 19, 2007

A more recent version of this article appeared on April 10, 2007

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Submitted on May 3, 2006
Accepted on February 2, 2007

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, and 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.).

^* To whom correspondence should be addressed. E-mail: acgitten{at}lumc.nl.

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.

Key words: arrhythmia • genes • heart defects, congenital • heart rate • immunohistochemistry

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