Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system

Meysen, S.; Marger, Laurine; Hewett, Kenneth W.; Jarry-Guichard, T.; Agarkova, Irina; Chauvin, Jean‐Paul; Perriard, Jean Claude; Izumo, Seigo; Gourdie, Robert G.; Mangoni, Matteo E.; Nargeot, Joël; Gros, Daniël; Miquerol, Lucile

doi:10.1016/j.ydbio.2006.12.044

Cited by 70 publications

(84 citation statements)

References 30 publications

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“…This suppressive activity of Nkx2-5 on atrial conduction cells is in sharp contrast with previous observations in other models that the reduction of Nkx2-5 level causes hypoplastic AV node 21,22 and Purkinje fibers. 56 These opposing functions of Nkx2-5 in atrial and ventricular conduction systems may point to the chamber-specific role of Nkx2-5 during cardiogenesis or may simply reflect the secondary effect of hemodynamic alteration in these models. In either case, cardiogenesis requires tight spatiotemporal control of Nkx2-5 function in diverse cardiac lineages including the working myocardium, septa, and conduction system, as well as coordinated development of the hemodynamic pattern.…”

Section: Discussionmentioning

confidence: 99%

Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Nakashima

Yanez

Touma

et al. 2014

Circulation Research

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A bout 0.9% of human neonates are born with congenital heart disease (CHD). CHD can arise from genetic and epigenetic abnormalities that affect the tight control of specification, proliferation, and migration of cardiac progenitors/myocytes.1,2 During cardiogenesis, cardiac progenitors/myocytes proliferate in two waves: primitive heart tube shows highest proliferative activity at arterial and venous poles where latemigrating second heart field progenitors are recruited. 3,4 Then, after the completion of looping, the working myocytes reinitiate mitotic activity, resulting in the ballooning of chambers at late gestational stages. 3,5 Non-ballooning regions, mainly mediastinal myocardium, 6,7 are distinct from appendage myocardium in their morphology, expression profile, 8 and ionic currents. Nkx2-5 is a cardiac homeobox transcription factor that is expressed in a broad range of cardiac sublineages, from the early committed cardiac progenitors through the adult cardiomyocytes, and plays a pivotal role in the regulation of cardiac, vascular, and hematopoietic lineages. 4,[10][11][12][13][14][15] Human heterozygous mutations of NKX2-5 are associated with a spectrum of CHDs including septal defects, conotruncal malformations, hypoplastic left heart, and atrioventricular (AV) conduction block. In agreement with observations in patients, mouse genetics has revealed the complexity of the role of Nkx2-5. [16][17][18][19] Germline deletion of Nkx2-5 gene results in cardiac lethality at the early stages with defects in the myocardial wall thickening, trabeculation, and endocardial cushion formation, suggesting a pro-mitotic role of Nkx2-5. 4,12,13 Recent studies have shown that Nkx2-5 also plays a critical role at chamber ballooning stages. 3,5 Mutant mouse models with genetic deficiency or dysfunction of Nkx2-5 after midgestational stages lead to atrial septal defect (ASD) and conduction defects. [20][21][22][23][24] Despite common phenotypes, however, these studies show partially inconsistent results as to cardiomyocyte growth. Although the temporary controlled global deletion of Nkx2-5 after midgestational stage results in thin hypomorphic ventricle, 24 ventricular-specific deletion of Nkx2-5 shows hypertrophic ventricle with hypertrabeculation. 22 These apparently conflicting results can be, in part, due to the differential regulation of physiological cardiac growth in spatiotemporarily Rationale: Tight control of cardiomyocyte proliferation is essential for the formation of four-chambered heart.Although human mutation of NKX2-5 is linked to septal defects and atrioventricular conduction abnormalities, early lethality and hemodynamic alteration in the mutant models have caused controversy as to whether Nkx2-5 regulates cardiomyocyte proliferation. diverse cardiac subpopulation. In addition, the secondary effect by altered pump function in Nkx2-5 mutants may be another factor that complicates the interpretation of the phenotypes of mouse models mentioned above. In fact, hemodynamics by itself is known to be an indepen...

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Section: Discussionmentioning

confidence: 99%

Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Nakashima

Yanez

Touma

et al. 2014

Circulation Research

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“…Indeed, previous work has revealed a late role for Nkx2.5 in maturation of Purkinje fiber network. 35 In conclusion, retrospective lineage analysis and genetic tracing experiments have provided new insights into previous controversies existing in the literature concerning the mode of development of the VCS. We reveal that development of the mammalian VCS is biphasic: conductive myocytes develop from common progenitors with working myocytes followed by limited proliferative outgrowth.…”

Section: Miquerol Et Almentioning

confidence: 91%

Biphasic Development of the Mammalian Ventricular Conduction System

Miquerol

Moreno-Rascon

Beyer

et al. 2010

Circulation Research

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127

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Rationale: The ventricular conduction system controls the propagation of electric activity through the heart to coordinate cardiac contraction. This system is composed of specialized cardiomyocytes organized in defined structures including central components and a peripheral Purkinje fiber network. How the mammalian ventricular conduction system is established during development remains controversial. Objective: To define the lineage relationship between cells of the murine ventricular conduction system and surrounding working myocytes. Methods and Results: A retrospective clonal analysis using the ␣-cardiac actin nlaacZ/؉ mouse line was carried out in three week old hearts. Clusters of clonally related myocytes were screened for conductive cells using Key Words: conduction system Ⅲ cell lineage Ⅲ clonal analysis Ⅲ nlaacZ Ⅲ Purkinje fibers T he cardiac conduction system controls the generation and propagation of electric activity through the heart to coordinate cardiac contraction. Atrial contraction is initiated by the sinoatrial node or pacemaker. After a delay mediated by the atrioventricular node (AVN), the ventricular conduction system (VCS) ensures rapid propagation of electric activity to the ventricular apex. 1 The VCS is comprised of a central component, the atrioventricular (AV or His) bundle and right and left bundle branches, and a peripheral component composed of a dense ellipsoid network of Purkinje fibers. These structures have been well characterized in adult mouse and human hearts by their specific histological and electrophysiological properties. 2,3 However, despite the clinical importance of the VCS in regulating cardiac rhythm, important questions remain as to the origin and the mode of development of the mammalian VCS. 4 Existing views of VCS development are largely based on data obtained in avian embryos, despite major anatomic differences within the VCS between birds and mammals. In the avian system, lineage analysis using replication defective retroviral labeling has demonstrated that conductive cells share common progenitors with working cardiomyocytes and that the VCS develops by a process of induction and recruitment of myocytes through endothelial derived signals. 5,6 According to this model, conductive myocytes are nonproliferative and subsequent growth of the conduction system occurs by accretional recruitment of new myocytes (or ingrowth). However, in the chick, a perivascular network of Purkinje fibers is localized deep in the myocardium in proximity to coronary vessels, whereas in the mouse, as in humans, Purkinje fibers are present only at the subendocardial ventricular surface 1,7,8 and it is unclear whether the chick model is applicable to the mammalian VCS. In mammals an outgrowth model has been proposed for development of the central VCS, by which conductive cells develop independently of the working myocardium from a pool of conductive Original

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“…Furthermore, Nkx2-5 haploinsufficiency in mice results in severely hypoplastic Purkinje fibres and upregulation of Bmp10. Interestingly, although the trabecular myocardium in these mutants appears normal during development, normal Nkx2-5 levels were found to be required in a cell-autonomous manner for peri/postnatal maturation of the Purkinje fibres (Meysen et al, 2007). Purkinje fibre hypoplasia in Nkx2-5 mutants was rescued by Prox1 haploinsufficiency (Risebro et al, 2012).…”

Section: Molecular Programming Of the Vcsmentioning

confidence: 95%

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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Nkx2.5 cell-autonomous gene function is required for the postnatal formation of the peripheral ventricular conduction system

Cited by 70 publications

References 30 publications

Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Nkx2-5 Suppresses the Proliferation of Atrial Myocytes and Conduction System

Biphasic Development of the Mammalian Ventricular Conduction System

The formation and function of the cardiac conduction system

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