Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart

Puskaric, Sandra; Schmitteckert, Stefanie; Mori, Alessandro; Gläser, Anne; Schneider, Katja; Bruneau, Benoit G.; Blaschke, R.; Steinbeißer, Herbert; Rappold, Gudrun

doi:10.1093/hmg/ddq393

Cited by 98 publications

(96 citation statements)

References 35 publications

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“…In addition, we further performed in situ hybridization in E12.5 miR-17-92 null/null mutants and wild-type controls using Bmp4 probe, which was previously shown as a downstream target of Shox2 (28). The in situ hybridization and heart-sectioning data indicated that Bmp4 expression is up-regulated in miR-17-92 null/null mutants (Fig.…”

Section: Sinoatrial-node Dysfunction In Mice With Mir-17-92 Cardiac-smentioning

confidence: 77%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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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. irregular heart rate | single nucleotide variant | mouse genetics A trial fibrillation (AF), the most common arrhythmia in adult patients, increases in prevalence with age to almost 5% of the population over 65. Patients with AF have an increased risk of stroke, dementia, and heart failure (1). Electrical impulses that are critical for a coordinated, physiologic heartbeat originate in the sinoatrial node (SAN). In AF, abnormal fibrillatory atrial impulses override normal SAN function, with resultant irregular conduction to the ventricles. Many cases of ectopic electrical activity originate in the pulmonary vein (2). Other sites of ectopy include the left atrial posterior wall, superior vena cava, interatrial septum, crista terminalis, and coronary sinus myocardium (3, 4).Multiple approaches have been used to uncover genes that may contribute to the AF phenotype in adult patients. A seminal genome-wide association study (GWAS), subsequently replicated by multiple studies, uncovered a single nucleotide variant (SNV) on human 4q25 that was strongly associated with familial AF (5). Patients with the 4q25 variant exhibited early onset AF that was independent from other risk factors such as hypertension and diabetes, suggesting a novel biologic mechanism involving genes located on chromosome 4q25. The presence of the 4q25 SNV also had prognostic value because patients with the SNV are prone to cardioembolic str...

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Section: Sinoatrial-node Dysfunction In Mice With Mir-17-92 Cardiac-smentioning

confidence: 77%

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Wang¹,

Bai

Li³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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“…It is expressed in the SV and atria throughout development and interacts with Nkx2-5 to regulate the expression of short stature homeobox transcription factor 2 (Shox2), Tbx3 and Bmp4 -key regulators of SAN programming (Mori et al, 2006;Puskaric et al, 2010;Fig. 3).…”

Section: Transcriptional Programming Of the Sanmentioning

confidence: 99%

“…3). Shox2 is specifically expressed in the SV and is required for early SAN development and function (Blaschke et al, 2007;Espinoza-Lewis et al, 2009;Puskaric et al, 2010). In cultured embryonic stem cells (ESCs), Shox2 directs differentiation towards a pacemaker-like phenotype (Ionta et al, 2015).…”

Section: Transcriptional Programming Of the Sanmentioning

confidence: 99%

The formation and function of the cardiac conduction system

2016

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The cardiac conduction system (CCS) consists of distinctive components that initiate and conduct the electrical impulse required for the coordinated contraction of the cardiac chambers. CCS development involves complex regulatory networks that act in stage-, tissue-and dose-dependent manners, and recent findings indicate that the activity of these networks is sensitive to common genetic variants associated with cardiac arrhythmias. Here, we review how these findings have provided novel insights into the regulatory mechanisms and transcriptional networks underlying CCS formation and function.

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“…To further clarify the relevance of such co-occurrence of Shox2 and Nkx2-5 binding sites in venous pole development, we intersected the Shox2 binding sites and Shox2-Nkx2-5 cooccupied sites with the published binding peaks of Tbx5 (He et al, 2011), a transcription factor that is crucial for CCS development and may act upstream of Shox2 (Bruneau et al, 1999;Moskowitz et al, 2004;Puskaric et al, 2010). We found that 73% of Shox2 binding sites co-occur with Tbx5 binding peaks and, most significantly, Tbx5 binding peaks account for 67% of the Shox2-Nkx2-5 co-occupied sites (53% of the total Shox2 binding peaks) (Fig.…”

Section: Shox2 Antagonizes Nkx2-5 Repression Of the Pacemaker Programmentioning

confidence: 99%

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

et al. 2015

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In humans, atrial fibrillation is often triggered by ectopic pacemaking activity in the myocardium sleeves of the pulmonary vein (PV) and systemic venous return. The genetic programs that abnormally reinforce pacemaker properties at these sites and how this relates to normal sinoatrial node (SAN) development remain uncharacterized. It was noted previously that Nkx2-5, which is expressed in the PV myocardium and reinforces a chamber-like myocardial identity in the PV, is lacking in the SAN. Here we present evidence that in mice Shox2 antagonizes the transcriptional output of Nkx2-5 in the PV myocardium and in a functional Nkx2-5 + domain within the SAN to determine cell fate. Shox2 deletion in the Nkx2-5 + domain of the SAN caused sick sinus syndrome, associated with the loss of the pacemaker program. Explanted Shox2 + cells from the embryonic PV myocardium exhibited pacemaker characteristics including node-like electrophysiological properties and the capability to pace surrounding Shox2 − cells. Shox2 deletion led to Hcn4 ablation in the developing PV myocardium. Nkx2-5 hypomorphism rescued the requirement for Shox2 for the expression of genes essential for SAN development in Shox2 mutants. Similarly, the pacemaker-like phenotype induced in the PV myocardium in Nkx2-5 hypomorphs reverted back to a working myocardial phenotype when Shox2 was simultaneously deleted. A similar mechanism is also adopted in differentiated embryoid bodies. We found that Shox2 interacts with Nkx2-5 directly, and discovered a substantial genomewide co-occupancy of Shox2, Nkx2-5 and Tbx5, further supporting a pivotal role for Shox2 in the core myogenic program orchestrating venous pole and pacemaker development.

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Shox2 mediates Tbx5 activity by regulating Bmp4 in the pacemaker region of the developing heart

Cited by 98 publications

References 35 publications

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

The formation and function of the cardiac conduction system

A common Shox2-Nkx2-5 antagonistic mechanism primes the pacemaking cell fate in the pulmonary vein myocardium and sinoatrial node

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