The role of Shox2 in SAN development and function.
ABSTRACT Embryonic development is a tightly regulated process, and many families of genes functions to provide a regulatory genetic network to achieve such a program. The homeobox genes are an extensive family that encodes transcription factors with a characteristic 60-amino acid homeodomain. Mutations in these genes or in the encoded proteins might result in structural malformations, physiological defects, and even embryonic death. Mutations in the short-stature homeobox gene (SHOX) is associated with idiopathic short stature in humans, as observed in patients with Turner syndrome and/or Leri-Weill dyschondrosteosis. A closely related human homolog, SHOX2, has not been linked to any syndrome or defect so far. In mice, a SHOX ortholog gene is not present in the genome; however, a true SHOX2 ortholog has been identified. Analyses of Shox2 knockout mouse models have showed crucial functions during embryonic development, including limb skeletogenesis, palatogenesis, temporomandibular joint formation, and cardiovascular development. During embryonic cardiac development, Shox2 is restrictedly expressed in the sinus venosus region, including the sinoatrial node (SAN) and the sinus valves. Shox2 null mutant is embryonically lethal due to cardiovascular defects, including a severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation in addition to an abnormal low heartbeat rate (bradycardia). In addition, it has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the SAN fate and thus plays essential roles in its proper formation and differentiation.
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ABSTRACT: The molecular mechanisms underlying atrial fibrillation, the most common sustained cardiac arrhythmia, remain poorly understood. Genome-wide association studies uncovered a major atrial fibrillation susceptibility locus on human chromosome 4q25 in close proximity to the paired-like homeodomain transcription factor 2 (Pitx2) homeobox gene. Pitx2, a target of the left-sided Nodal signaling pathway that initiates early in development, represses the sinoatrial node program and pacemaker activity on the left side. To address the mechanisms underlying this repressive activity, we hypothesized that Pitx2 regulates microRNAs (miRs) to repress the sinoatrial node genetic program. MiRs are small noncoding RNAs that regulate gene expression posttranscriptionally. Using an integrated genomic approach, we discovered that Pitx2 positively regulates miR-17-92 and miR-106b-25. Intracardiac electrical stimulation revealed that both miR-17-92 and miR-106b-25 deficient mice exhibit pacing-induced atrial fibrillation. Furthermore electrocardiogram telemetry revealed that mice with miR-17-92 cardiac-specific inactivation develop prolonged PR intervals whereas mice with miR-17-92 cardiac-specific inactivation and miR-106b-25 heterozygosity develop sinoatrial node dysfunction. Both arrhythmias are risk factors for atrial fibrillation in humans. Importantly, miR-17-92 and miR-106b-25 directly repress genes, such as Shox2 and Tbx3, that are required for sinoatrial node development. Together, to our knowledge, these findings provide the first genetic evidence for an miR loss-of-function that increases atrial fibrillation susceptibility.Proceedings of the National Academy of Sciences 06/2014; 111(25). DOI:10.1073/pnas.1405411111 · 9.81 Impact Factor
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ABSTRACT: Inactivation of Shox2, a member of the short-stature homeobox gene family, leads to defective development of multiple organs and embryonic lethality as a result of cardiovascular defects, including bradycardia and severe hypoplastic sinoatrial node (SAN) and sinus valves, in mice. It has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the fate of the SAN cells. However, the functional mechanism of Shox2 protein as a transcriptional repressor on Nkx2.5 expression remains completely unknown.Journal of the American Heart Association 04/2014; 3(3). DOI:10.1161/JAHA.114.000796