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The heart’s rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 is involved in the specification and patterning of the SAN. While the  Shox2  knockout in mice results in embryonic lethality due to severe cardiac defects including improper SAN development, Shox2 knockdown in zebrafish causes a reduced heart rate (bradycardia). In order to gain deeper insight into molecular pathways involving  Shox2 , we compared gene expression levels in right atria of wildtype and  Shox2   − / −  hearts using microarray experiments and identified the LIM homeodomain transcription factor Islet1 (Isl1) as one of its putative target genes. The downregulation of  Isl1  expression in  Shox2   − / −  hearts was confirmed and the affected region narrowed down to the SAN by whole-mount in situ hybridization. Using luciferase reporter assays and EMSA studies, we identified two specific SHOX2 binding sites within intron 2 of the  ISL1  locus. We also provide functional evidence for  Isl1  as a transcriptional target of Shox2 by rescuing the  Shox2 -mediated bradycardia phenotype with  Isl1  using zebrafish as a model system. Our findings demonstrate a novel epistatic relationship between  Shox2  and  Isl1  in the heart with important developmental consequences for SAN formation and heart beat.   Electronic supplementary material  The online version of this article (doi:10.1007/s00395-013-0339-z) contains supplementary material, which is available to authorized users.

Islet1 is a direct transcriptional target of the homeodomain transcription factor Shox2 and rescues the Shox2-mediated bradycardia