Spen deficiency interferes with Connexin 43 expression and leads to heart failure in zebrafish

https://doi.org/10.1016/j.yjmcc.2021.01.006Get rights and content
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Highlights

  • Loss of sporadic dilated cardiomyopathy GWAS candidate gene Spen leads to heart failure in zebrafish

  • Spen deficiency results in impaired cardiac contractility and arrhythmia

  • Spen function on the heart is mediated by molecular interconnection with Connexin 43

Abstract

Genome-wide association studies identified Spen as a putative modifier of cardiac function, however, the precise function of Spen in the cardiovascular system is not known yet. Here, we analyzed for the first time the in vivo role of Spen in zebrafish and found that targeted Spen inactivation led to progressive impairment of cardiac function in the zebrafish embryo. In addition to diminished cardiac contractile force, Spen-deficient zebrafish embryos developed bradycardia, atrioventricular block and heart chamber fibrillation. Assessment of cardiac-specific transcriptional profiles identified Connexin 43 (Cx43), a cardiac gap junction protein and crucial regulator of cardiomyocyte-to-cardiomyocyte communication, to be significantly diminished in Spen-deficient zebrafish embryos. Similar to the situation in Spen-deficient embryos, Morpholino-mediated knockdown of cx43 in zebrafish resulted in cardiac contractile dysfunction, bradycardia, atrioventricular block and fibrillation of the cardiac chambers. Furthermore, ectopic overexpression of cx43 in Spen deficient embryos led to the reconstitution of cardiac contractile function and suppression of cardiac arrhythmia. Additionally, sensitizing experiments by simultaneously injecting sub-phenotypic concentrations of spen- and cx43-Morpholinos into zebrafish embryos resulted in pathological supra-additive effects. In summary, our findings highlight a crucial role of Spen in controlling cx43 expression and demonstrate the Spen-Cx43 axis to be a vital regulatory cascade that is indispensable for proper heart function in vivo.

Keywords

Spen
Connexin 43
Heart failure
Cardiac arrhythmia
Dilated cardiomyopathy
Zebrafish

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Contributed equally.