脊椎动物心脏的发育，受到多种因子的精密调控，相关调控因子的异常会引起先天性心脏病。我们分离到一株心脏发育畸形的斑马鱼突变体，突变基因为kctd10。Kctd家族有20多个成员，序列保守，但它们在发育中的功能目前研究得很少。我们的研究发现，Kctd10蛋白能够与Tbx5直接结合，调控Tbx5的活性，进而影响心脏的环化过程。由此推测，Kctd10的突变可能影响了以Tbx5为核心的几种重要转录因子复合体的活性，改变了直接调控房室间隔形成和心脏环化的关键基因的表达，造成心脏畸形。本项目将深入研究Kctd10调控Tbx5活性的分子机理，阐明Kctd10对调控心脏环化的关键转录因子复合物活性的调节，揭示Kctd10参与的相关信号转导网络以及Kctd10蛋白调控心脏发育的机制。本项目的研究将深化人们对心脏发育的机制以及先天性心脏病致病机理的认识。

Many essential factors controlling heart development have been identified in vertebrates. The T-box transcription factor Tbx5 (Tbx5a in zebrafish) plays a crucial role in the formation of the cardiac chambers in a dose-dependent manner. Its deregulation leads to a congenital heart disease (CHD), Holt-Oram syndrome (HOS). However, little is known regarding its dosage balance. We isolated a zebrafish mutant with heart malformations. Based on positional cloning, the affected gene was identified as kctd10, a member of the potassium channel tetramerization domain (KCTD)-containing family. We showed that Kctd10 directly bound to Tbx5 and subsequently moderated the activity of this transcription factor. We hypothesize that Kctd10 directly regulates the activity of the master cardiac transcription factor complexes, which are composed of Tbx5 and other key factors, such as Nkx2.5, Gata4 and Mef2, etc. The target genes of these master transcription complexes play key roles in the differentiation of cardiomyocyte and heart looping. Thus, the deficiency of Kctd10 affects the expression of these target genes and results in heart malformations. To test this hypothesis, we will focus on the regulation of the master cardiac transcription factor complexes by Kctd10. Through this study, we anticipate to determine whether Kctd10 affects the activity of these transcription complexes and alters the expression of their target genes. We will further elucidate the role of Kctd10 in the signal pathways controlling the formation of the heart. Therefore, our study will likely identify a new molecule essential for the cardiac development.