GATA-Binding Factor 6 Contributes to Atrioventricular Node Development and Function.
GATA-Binding Factor 6 Contributes to Atrioventricular Node Development and Function.
复制标题
DOI：
10.1161/circgenetics.113.000587
复制
发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Patel VV
中科院分区：
文献类型：
--
作者：
Liu F;Lu MM;Patel NN;Schillinger KJ;Wang T;Patel VV
几个转录因子调节CCS的发展和功能，但在指定不同的CCS组件中的作用仍然不清楚。GATA结合因子6（GATA 6）是一种锌指转录因子，对心血管系统的形成至关重要。然而，GATA 6在胚胎心脏和/或CCS中的作用从未被显示。我们报告说，Gata6是在近端CCS在妊娠中期的小鼠大量表达。心肌特异性缺失Gata6的羧基锌指可诱导致密房室结（AV）中HCN 4染色的丧失，AV束中保留一些HCN 4染色，但对连接蛋白40阳性束支无显著影响。此外，心肌特异性缺失的羧基锌指Gata6改变AV传导在出生后的生活中评估的表面和侵入性电生理评价，以及减少心室肌细胞的数量和诱导代偿性肌细胞肥大。心肌特异性缺失Gata6的羧基锌指也与近端CCS中转录阻遏物ID2和钠钙交换剂NCX1的下调相关，其中GATA6反式激活这两种因子。最后，Gata6的羧基锌指缺失减少了房室结特化期间发育中房室束中TBX3+肌细胞的细胞周期退出，这导致成熟突变小鼠近端CCS中TBX3+细胞较少。GATA 6通过促进特定心肌细胞向传导系统谱系的细胞周期退出而促进鼠房室结的发育和出生后功能。
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 GATA6 in the embryonic heart and/or CCS has never been shown. We report that Gata6 is expressed abundantly in the proximal CCS during mid-gestation in mice. Myocardial-specific deletion of the carboxyl zinc-finger of Gata6 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 Gata6 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 GATA6 transactivates both of these factors. Finally, carboxyl zinc-finger deletion of Gata6 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. GATA6 contributes to development and postnatal function of the murine AV node by promoting cell-cycle exit of specified cardiomyocytes towards a conduction system lineage.