Perinatal Loss of Nkx2-5 Results in Rapid Conduction and Contraction Defects

2008/08/09 by Laura E. Briggs, Morihiko Takeda, Adolfo E. Cuadra +16 · 26 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Congenital heart defects research #Cardiac electrophysiology and arrhythmias #Ion channel regulation and function

paper · pdf · doi:10.1161/circresaha.108.171835

Abstract

Homeobox transcription factor Nkx2-5, highly expressed in heart, is a critical factor during early embryonic cardiac development. In this study, using tamoxifen-inducible Nkx2-5 knockout mice, we demonstrate the role of Nkx2-5 in conduction and contraction in neonates within 4 days after perinatal tamoxifen injection. Conduction defect was accompanied by reduction in ventricular expression of the cardiac voltage-gated Na+ channel pore-forming alpha-subunit (Na(v)1.5-alpha), the largest ion channel in the heart responsive for rapid depolarization of the action potential, which leads to increased intracellular Ca2+ for contraction (conduction-contraction coupling). In addition, expression of ryanodine receptor 2, through which Ca2+ is released from sarcoplasmic reticulum, was substantially reduced in Nkx2-5 knockout mice. These results indicate that Nkx2-5 function is critical not only during cardiac development but also in perinatal hearts, by regulating expression of several important gene products involved in conduction and contraction.

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• Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. [europepmc]
• TBX5 drives Scn5a expression to regulate cardiac conduction system function. [europepmc]
• Myocardial Notch signaling reprograms cardiomyocytes to a conduction-like phenotype. [europepmc]
• Crystal structure of the human NKX2.5 homeodomain in complex with DNA target. [europepmc]
• Functional characterization of a novel mutation in NKX2-5 associated with congenital heart disease and adult-onset cardiomyopathy. [europepmc]
• Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. [europepmc]
• Impact of aldosterone antagonists on the substrate for atrial fibrillation: aldosterone promotes oxidative stress and atrial structural/electrical remodeling. [europepmc]
• Transcriptome-guided functional analyses reveal novel biological properties and regulatory hierarchy of human embryonic stem cell-derived ventricular cardiomyocytes crucial for maturation. [europepmc]
• Transcriptional networks regulating the costamere, sarcomere, and other cytoskeletal structures in striated muscle. [europepmc]
• A mouse model of human congenital heart disease: high incidence of diverse cardiac anomalies and ventricular noncompaction produced by heterozygous Nkx2-5 homeodomain missense mutation. [europepmc]
• An early requirement for nkx2.5 ensures the first and second heart field ventricular identity and cardiac function into adulthood. [europepmc]
• Mouse Model of Human Congenital Heart Disease: Progressive Atrioventricular Block Induced by a Heterozygous Nkx2-5 Homeodomain Missense Mutation. [europepmc]
• Irx3 is required for postnatal maturation of the mouse ventricular conduction system. [europepmc]
• Transcription factor ETV1 is essential for rapid conduction in the heart. [europepmc]
• Whole-genome association analysis of pork meat pH revealed three significant regions and several potential genes in Finnish Yorkshire pigs. [europepmc]
• Point mutations in murine Nkx2-5 phenocopy human congenital heart disease and induce pathogenic Wnt signaling. [europepmc]
• Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice. [europepmc]
• Nkx genes establish second heart field cardiomyocyte progenitors at the arterial pole and pattern the venous pole through Isl1 repression. [europepmc]
• Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy. [europepmc]
• Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function. [europepmc]
• A small-molecule LF3 abrogates β-catenin/TCF4-mediated suppression of Na V 1.5 expression in HL-1 cardiomyocytes. [europepmc]
• Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis. [europepmc]
• Human heart-forming organoids recapitulate early heart and foregut development. [europepmc]

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