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GATA-binding Factor 6 Contributes to AV Node Development and Function

Significance Statement

Conduction disorders are a significant cause of morbidity and mortality that are often treated with electronic pacemakers to initiate and/or coordinate cardiac chambers activation. While modern pacemaker technology is quite advanced and effective, there are important limitations associated with device-based therapies. These limitations include the risk of infection which may necessitate revising or extracting the system, the need for regular generator replacements that exposes the patient to higher risks of infection, and restrictions on patients with pacemakers to use machines or work in areas where they could be exposed to strong magnetic and electric fields. Regenerative approaches for treating cardiac diseases are currently being tested in animals and humans, where one strategy involves reprogramming a defined cell type into another, different cell type. In this regard, our study provides evidence that the transcription factor GATA-binding factor 6 is important for in vivo formation and function of the atrioventricular node by directing cardiomyocytes towards the conduction system lineage. The involvement of this factor in the proper formation of the proximal conduction system may provide insights that could someday augment or improve pacemaker therapy in patients with cardiac conduction disorders.

Figure Legend:  Immunohistochemical staining of E12.5 wild-type hearts (A-C) against PCNA (red, a marker of cell proliferation) and TBX3 (green, a marker of CCS myocytes in mice), as well as similarly staged Gata6 mutant hearts (D-F). The dashed yellow outline indicates the TBX3-expressing AV bundle. Note there are significantly fewer PCNA/TBX3-positive cells in the Gata6f/f heart compared to the mutant heart. (G) PCNA-positive nuclei in the crest of the septum that overlap with TBX3-expressing cells averaged from five hearts of each genotype. *P<0.01. Scale bar=100 μm. Scale bar in (A) applies to (A-F). AVN=atrioventricular node; AVB=atrioventricular bundle.

Note: Figure shown after permission from the Journal.

GATA-binding Factor 6 Contributes to AV Node Development and Function. Global Medical Discovery

 

 

 

 

 

 

 

Liu F1, Lu MM1, Patel NN1, Schillinger KJ1, Wang T1, Patel VV2. Circ Cardiovasc Genet. 2015 Jan 22.

1Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA.

2Cardiovascular Research Center, Department of Physiology & Section of Clinical Cardiac Electrophysiology, Temple University School of Medicine, Philadelphia, PA [email protected]

Abstract

BACKGROUND:

Several transcription factors regulate CCS development and function but the role of each in specifying distinct CCS components remains unclear. GATA-binding factor 6 (GATA6) is a zinc-finger transcription factor that is critical for patterning the cardiovascular system. However the role of GATA-binding factor 6 in the embryonic heart and/or CCS has never been shown.

METHODS AND RESULTS:

-We report that GATA-binding factor 6 is expressed abundantly in the proximal CCS during mid-gestation in mice. Myocardial-specific deletion of the carboxyl zinc-finger of GATA-binding factor 6 induces loss of HCN4-staining in the compact atrioventricular (AV) node with some retention of HCN4-staining in the AV bundle, but has no significant effect on the connexin40-positive bundle branches. Furthermore, myocardial-specific deletion of the carboxyl zinc-finger of GATA-binding factor 6 alters AV conduction in postnatal life as assessed by surface and invasive electrophysiological evaluation, as well as decreasing the number of ventricular myocytes and inducing compensatory myocyte hypertrophy. Myocardial-specific deletion of the carboxyl zinc-finger of Gata6 is also associated with down-regulation of the transcriptional repressor ID2 and the sodium-calcium exchanger NCX1 in the proximal CCS, where GATA-binding factor 6 transactivates both of these factors. Finally, carboxyl zinc-finger deletion of GATA-binding factor 6 reduces cell-cycle exit of TBX3+ myocytes in the developing AV bundle during the period of AV node specification, which results in fewer TBX3+ cells in the proximal CCS of mature mutant mice.

CONCLUSIONS:

GATA-binding factor 6 contributes to development and postnatal function of the murine AV node by promoting cell-cycle exit of specified cardiomyocytes towards a conduction system lineage.

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