Nkx2-5 and congenital heart defects in Xenopus

描述（由申请人提供）：正常心脏的形成需要一系列基因的严格调控激活。当细胞逐渐失去多能性并形成肌肉、内皮、瓣膜和心脏结缔组织的谱系时，这种调节就开始于发育早期。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成形成工作心脏的腔室、瓣膜、隔膜和传导系统。在心脏发育程序的调节因子中有来自NK-2蛋白家族的转录因子。首先在果蝇中被鉴定为tinman基因（因为零突变导致果蝇不能形成背血管（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。即使只有一个Nkx2-5拷贝发生突变，人类也会患上先天性心脏缺陷。他们的问题包括分隔心脏腔室的间隔畸形、心脏瓣膜缺陷和心脏收缩调节异常。最近，一种相关蛋白Nkx2-6的突变被证明会导致心脏流出道出现问题，该区域将心脏泵出的血液连接回血管系统。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、鱼和非洲爪蟾。青蛙的调节分工落在这个家族的三个成员，Nkx2-5， Nkx2-3和Nkx2-10（可能是人类Nkx2-6的同源物）。我们建议通过实验来追踪这些转录因子在早期心脏发育过程中的作用，确定每种转录因子赋予独特功能的蛋白质结构域，并确定每种转录因子的表达是如何被调节的。这将使我们能够分离必须协调形成工作心脏的监管途径。

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.