Elevated expression of Nkx‐2.5 in developing myocardial conduction cells

Thomas, Penny S.; Kasahara, Hideko; Edmonson, Angela M.; Izumo, Seigo; Yacoub, Magdi H.; Barton, Paul J.R.; Gourdie, Robert G.

doi:10.1002/ar.1106

Cited by 72 publications

(47 citation statements)

References 40 publications

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“…28 Nkx2-5 was reported to be expressed at higher levels in the ventricular conduction system compared with the working myocardium. 12,30 At E11.5, Nkx2-5 was homogeneously expressed in the ventricular myocardium (not shown), but from E12.5 onward, its mRNA ( Figure 2C) and protein ( Figure 5I) were slightly enriched in the crest of the septum. Taken together, expression of Nkx2-5 and Tbx5 is initially broad but becomes significantly higher in the developing AV bundle several days later than Tbx3.…”

Section: Gene Expression In the Developing Av Bundle And Bundle Branchesmentioning

confidence: 95%

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Bakker

Boukens

Mommersteeg

et al. 2008

Circulation Research

179

182

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Abstract-The cardiac conduction system consists of distinctive heart muscle cells that initiate and propagate the electric impulse required for coordinated contraction. The conduction system expresses the transcriptional repressor Tbx3, which is required for vertebrate development and controls the formation of the sinus node. In humans, mutations in Tbx3 cause ulnar-mammary syndrome. Here, we investigated the role of Tbx3 in the molecular specification of the atrioventricular conduction system. Expression analysis revealed early delineation of the atrioventricular bundle and proximal bundle branches by Tbx3 expression in human, mouse, and chicken. Tbx3-deficient mice, which die between embryonic day 12.5 and 15.5, ectopically expressed genes for connexin (Cx)43, atrial natriuretic factor (Nppa), Tbx18, and Tbx20 in the atrioventricular bundle and proximal bundle branches. Cx40 was precociously upregulated in the atrioventricular bundle of Tbx3 mutants. Moreover, the atrioventricular bundle and branches failed to exit the cell cycle in Tbx3 mutant embryos. Finally, Tbx3-deficient embryos developed outflow tract malformations and ventricular septal defects. These data reveal that Tbx3 is required for the molecular specification of the atrioventricular bundle and bundle branches and for the development of the ventricular septum and outflow tract. Our data suggest a mechanism in which Tbx3 represses differentiation into ventricular working myocardium, thereby imposing the conduction system phenotype on cells within its expression domain. Key Words: Tbx3 Ⅲ conduction system Ⅲ atrioventricular bundle Ⅲ bundle branches Ⅲ development T he cardiac conduction system is responsible for the initiation, coordination, and propagation of the electric impulse. The impulse is initiated in the sinus node, delayed in the atrioventricular (AV) node, and then rapidly propagated by the AV bundle (bundle of His), bundle branches, and the peripheral conduction system to activate the ventricular working myocardium from apex to base. Disorders of the conduction system, including sinus node dysfunction and AV block, occur commonly and may cause life-threatening arrhythmias requiring pacemaker implantation or treatment with antiarrhythmic medication. Congenital heart defects and gene mutations significantly contribute to conduction system disorders. [1][2][3] Since the anatomic identification of the conduction system components 100 years ago, knowledge regarding their development, morphology, and physiological function has increased steadily. 4 -10 However, insight into the molecular and genetic underpinnings of the specification and formation of the conduction system is very limited. Human and mouse studies have identified cardiac homeobox factor Nkx2-5, T-box transcription factor Tbx5, Id2, and bone morphogenetic protein signaling as important molecular components for the formation of the AV conduction system [11][12][13][14][15] and Tbx3 as a critical factor in the formation of the sinus node. 14 Tbx3 is a T-box transcription factor in...

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Section: Gene Expression In the Developing Av Bundle And Bundle Branchesmentioning

confidence: 95%

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Bakker

Boukens

Mommersteeg

et al. 2008

Circulation Research

179

182

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“…The periarterial Purkinje system develops late in chicken development (second half of the incubation time), which is well after the development of the ECG and of the preferential conduction of the impulse toward the apex of the ventricle (53,63,232,277,289). The periarterial Purkinje system expresses a slow tonic myosin (105) and a distinct gap junctional protein Cx42 (110), and it displays a unique transcription factor expression profile (295,301). The periarterial Purkinje system has not yet been characterized functionally.…”

Section: F Origin Of the Ventricular Conduction Systemmentioning

confidence: 99%

Cardiac Chamber Formation: Development, Genes, and Evolution

Moorman

Christoffels

2003

Physiological Reviews

650

526

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Moorman, Antoon F. M., and Vincent M. Christoffels. Cardiac Chamber Formation: Development, Genes, and Evolution. Physiol Rev 83: 1223-1267, 2003; 10.1152/physrev.00006.2003.—Concepts of cardiac development have greatly influenced the description of the formation of the four-chambered vertebrate heart. Traditionally, the embryonic tubular heart is considered to be a composite of serially arranged segments representing adult cardiac compartments. Conversion of such a serial arrangement into the parallel arrangement of the mammalian heart is difficult to understand. Logical integration of the development of the cardiac conduction system into the serial concept has remained puzzling as well. Therefore, the current description needed reconsideration, and we decided to evaluate the essentialities of cardiac design, its evolutionary and embryonic development, and the molecular pathways recruited to make the four-chambered mammalian heart. The three principal notions taken into consideration are as follows. 1) Both the ancestor chordate heart and the embryonic tubular heart of higher vertebrates consist of poorly developed and poorly coupled “pacemaker-like” cardiac muscle cells with the highest pacemaker activity at the venous pole, causing unidirectional peristaltic contraction waves. 2) From this heart tube, ventricular chambers differentiate ventrally and atrial chambers dorsally. The developing chambers display high proliferative activity and consist of structurally well-developed and well-coupled muscle cells with low pacemaker activity, which permits fast conduction of the impulse and efficacious contraction. The forming chambers remain flanked by slowly proliferating pacemaker-like myocardium that is temporally prevented from differentiating into chamber myocardium. 3) The trabecular myocardium proliferates slowly, consists of structurally poorly developed, but well-coupled, cells and contributes to the ventricular conduction system. The atrial and ventricular chambers of the formed heart are activated and interconnected by derivatives of embryonic myocardium. The topographical arrangement of the distinct cardiac muscle cells in the forming heart explains the embryonic electrocardiogram (ECG), does not require the invention of nodes, and allows a logical transition from a peristaltic tubular heart to a synchronously contracting four-chambered heart. This view on the development of cardiac design unfolds fascinating possibilities for future research.

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“…Nkx2.5 is an early differentiation marker that is known to be expressed in the working myocardium and elements of the cardiac conduction system, including the AV node and bundle branches (Thomas et al, 2001). In early developmental stages, it is not expressed in the second heart fieldderived sinus venosus myocardium (Christoffels et al, 2006;Gittenbergerde Groot et al, 2007), which also includes the developing SAN.…”

Section: Resultsmentioning

confidence: 99%

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

Jongbloed

Vicente‐Steijn

Douglas

et al. 2011

Developmental Dynamics

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The inhibitor of differentiation Id2 is expressed in mesoderm of the second heart field, which contributes myocardial and mesenchymal cells to the primary heart tube. The role of Id2 in cardiac development is insufficiently known. Heart development was studied in sequential developmental stages in Id2 wildtype and knockout mouse embryos. Expression patterns of Id2, MLC-2a, Nkx2.5, HCN4, and WT-1 were analyzed. Id2 is expressed in myocardial progenitor cells at the inflow and outflow tract, in the endocardial and epicardial lineage, and in neural crest cells. Id2 knockout embryos show severe cardiac defects including abnormal orientation of systemic and pulmonary drainage, abnormal myocardialization of systemic and pulmonary veins, hypoplasia of the sinoatrial node, large interatrial communications, ventricular septal defects, double outlet right ventricle, and myocardial hypoplasia. Our results indicate a role for Id2 in the second heart field contribution at both the arterial and the venous poles of the heart.

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Elevated expression of Nkx‐2.5 in developing myocardial conduction cells

Cited by 72 publications

References 40 publications

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Transcription Factor Tbx3 Is Required for the Specification of the Atrioventricular Conduction System

Cardiac Chamber Formation: Development, Genes, and Evolution

Expression of Id2 in the second heart field and cardiac defects in Id2 knock‐out mice

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