GATA-Binding Factor 6 Contributes to Atrioventricular Node Development and Function. (April 2015)

• Record Type: Journal Article
• Authors: Liu, Fang; Lu, Min Min; Patel, Neil N.; Schillinger, Kurt J.; Wang, Tao; Patel, Vickas V.
• Is Part Of: Circulation. Volume 8:Number 2(2015)
• Publication Date: 2015-04
• Subjects: Arrhythmia -- Periodicals; Heart -- Electric properties -- Periodicals; 616.1042
• DOI: 10.1161/CIRCGENETICS.113.000587
• Languages: English
• ISSNs: 1942-325X

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background—</title> <p>Several transcription factors regulate cardiac conduction system (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 GATA6 in the embryonic heart and CCS has never been shown.</p> </sec> <sec> <title>Methods and Results—</title> <p>We report that <italic>Gata6</italic> is expressed abundantly in the proximal CCS during midgestation in mice. Myocardial-specific deletion of the carboxyl zinc-finger of <italic>Gata6</italic> induces loss of hyperpolarizing cyclic nucleotide–gated channel, subtype 4 staining in the compact atrioventricular node with some retention of hyperpolarizing cyclic nucleotide–gated channel, subtype 4 staining in the atrioventricular bundle, but has no significant effect on the connexin-40–positive bundle branches. Furthermore, myocardial-specific deletion of the carboxyl zinc-finger of <italic>Gata6</italic> alters atrioventricular 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 <italic>Gata6</italic> is also associated with downregulation of the transcriptional repressor ID2 and the cardiac sodium–calcium exchanger NCX1 in the proximal CCS, where GATA6 transactivates both of these factors. Finally, carboxyl zinc-finger deletion of <italic>Gata6</italic> reduces cell-cycle exit of TBX3+ myocytes in the developing atrioventricular bundle during the period of atrioventricular node specification, which results in fewer TBX3+ cells in the proximal CCS of mature mutant mice.</p> </sec> <sec> <title>Conclusions—</title> <p>GATA6 contributes to the development and postnatal function of the murine atrioventricular node by promoting cell-cycle exit of specified cardiomyocytes toward a conduction system lineage.</p> </sec> </abstract>