Kctd10 通过抑制斑马鱼 Tbx5a 的转录活性调节心脏形态发生。

Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish.

机构信息

1] Key Laboratory of Cell Proliferation and Differentiation of Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, PR China [2].

1] State Key Laboratory Breeding Base of Marine Genetic Resources, Third Institute of Oceanography, State Oceanic Administration, 184 University Road, Xiamen 361005, Fujian Province, PR China [2].

出版信息

Nat Commun. 2014;5:3153. doi: 10.1038/ncomms4153.

DOI:10.1038/ncomms4153

PMID:24430697

Abstract

The T-box transcription factor Tbx5 (Tbx5a in zebrafish) plays a crucial role in the formation of cardiac chambers in a dose-dependent manner. Its deregulation leads to congenital heart disease. However, little is known regarding its regulation. Here we isolate a zebrafish mutant with heart malformations, called 34c. The affected gene is identified as kctd10, a member of the potassium channel tetramerization domain (KCTD)-containing family. In the mutant, the expressions of the atrioventricular canal marker genes, such as tbx2b, hyaluronan synthase 2 (has2), notch1b and bmp4, are changed. The knockdown of tbx5 rescues the ectopic expression of has2, and knockdown of either tbx5a or has2 alleviates the heart defects. We show that Kctd10 directly binds to Tbx5 to repress its transcriptional activity. Our results reveal a new essential factor for cardiac development and suggest that KCTD10 could be considered as a new causative gene of congenital heart disease.

摘要

T 盒转录因子 Tbx5（斑马鱼中的 Tbx5a）以剂量依赖的方式在心脏室形成中发挥关键作用。其失调会导致先天性心脏病。然而，关于其调控机制知之甚少。在这里，我们分离到一个具有心脏畸形的斑马鱼突变体，称为 34c。受影响的基因被鉴定为 kctd10，它是钾通道四聚化结构域（KCTD）包含家族的成员。在突变体中，房室管标记基因如 tbx2b、透明质酸合酶 2（has2）、 notch1b 和 bmp4 的表达发生改变。Tbx5 的敲低可挽救 has2 的异位表达，而 tbx5a 或 has2 的敲低均可减轻心脏缺陷。我们表明 Kctd10 可直接与 Tbx5 结合以抑制其转录活性。我们的结果揭示了心脏发育的一个新的必需因子，并表明 KCTD10 可被视为先天性心脏病的一个新的致病基因。