Nkx2-5 and congenital heart defects in Xenopus

描述(申请人提供)：正常心脏的形成需要一系列基因的严格调控激活。这种调节开始于发育早期，因为细胞逐渐失去多能性，并稳定在导致肌肉、内皮、瓣膜和心脏结缔组织形成的谱系中。确定合适的谱系很重要，但同样重要的是将这些不同类型的细胞建模为形成工作心脏的腔室、瓣膜、隔膜和传导系统。在心脏发育计划的调节中，有来自NK-2蛋白家族的转录因子。我们首先在果蝇中发现了名为tinman的基因(因为零突变导致果蝇不能形成背部血管(果蝇的心脏))，现在我们将人类和其他脊索动物中的同源物称为Nkx2-5。即使Nkx2-5的一个拷贝发生突变，人类也会患上先天性心脏病。他们的问题包括分隔心腔的畸形隔膜、心脏瓣膜缺陷和心脏收缩的异常调节。最近，相关蛋白Nkx2-6的突变被证明会导致心脏流出道出现问题，流出道是连接心脏泵送的血液返回血管系统的区域。参与心脏形成的NK-2基因已经在多种系统中得到了很好的研究，包括小鼠、鸡、蝇、鱼和非洲爪蛙。青蛙的调节分工落在这个家族的三个成员身上，Nkx2-5，Nkx2-3和Nkx2-10(可能是人类Nkx2-6的同源物)。我们建议进行实验，跟踪这些转录因子中的每一个在心脏早期发育中的作用，定义每个转录因子的蛋白结构域，并确定每个转录因子的表达是如何调控的。这将使我们能够分离出必须协调才能形成一个工作心脏的调控途径。

DESCRIPTION (provided by applicant): The formation of a normal heart requires the tightly regulated activation of a series of genes. This regulation begins early in development as cells progressively lose pluripotency and settle into lineages that result in muscle, endothelium, valves and the connective tissue of the heart. Defining the appropriate lineages is important, but equally important is the modeling of these different cell types into the chambers, valves, septae and conduction system that form a working heart. Among the regulators of the cardiac developmental program are transcription factors from NK-2 family of proteins. First identified in fruit fly as the gene called tinman (because the null mutation gave rise to flies that failed to form a dorsal vessel (the fly's heart)) we now refer to the homologue in man and other chordates as Nkx2-5. Humans with mutations in even one of their copies of Nkx2-5 develop congenital heart defects. Among their problems are malformed septae that separate the chambers of the heart, heart valve defects and abnormal regulation of heart contraction. Recently, mutations in a related protein Nkx2-6, was shown to cause problems in the outflow tract of the heart, the region that connects the blood pumped by the heart back into the vascular system. The NK-2 genes involved in heart formation have been studied to good advantage in a variety of system, including mouse, chicken, fly, fish and the frog Xenopus laevis. The regulatory division of labor in frog falls to three members of this family, Nkx2-5, Nkx2-3 and Nkx2-10 (the likely homologue of human Nkx2-6). We propose experiments to track the role of each of these transcription factors during early cardiac development, define the protein domains of each that confer unique function and identify how the expression of each is regulated. This will allow us to separate the regulatory pathways that must be coordinated to form a working heart.