Role of Homeobox Gene Nkx2-5 in Heart Development and Congenital Heart Disease

在西方人群中，约每100名活产婴儿中有1名先天性心脏异常，每10名死胎中有1名先天性心脏异常。心脏发育背后的遗传途径现在正被越来越有力地解剖，以了解心脏缺陷的形态学进展和遗传基础。编码转录调节蛋白的心脏基因Nkx 2 -5的突变可导致人类家族和孤立个体的心脏缺陷，最主要的是与心脏电活动异常相关的房间隔缺损（心脏穿孔）。Nkx 2 -5在胚胎中构成心脏的肌肉和其他谱系的前体细胞中表达，然后在整个胎儿和成人生活中在心脏的肌肉层中表达。缺乏Nkx 2 -5基因的小鼠心脏在心脏发育的早期阶段完全停止，显示心室腔形成的完全阻断。只缺少一个Nkx 2 -5基因拷贝的小鼠会出现ASD和电缺陷，类似于人类疾病。在这些发现的基础上，我们开发了一套新的基因试剂，以更深入地了解Nkx-5在发育和疾病中的作用。其中包括一种小鼠品系，其中Nkx 2 -5阳性肌肉细胞可以从心脏中的其他细胞类型中纯化出来，另一种小鼠品系代表了常见先天性心脏缺陷的良好模型。我们将使用这些试剂进一步研究Nkx 2 -5在心脏细胞类型分配、腔室形成和出生缺陷中的作用。

Congenital abnormalities of the heart occur in ~1 in 100 live births and 1 in 10 still births in Western populations. The genetic pathways underlying cardiac development are now being dissected with increasing vigour in an effort to understand both the morphological progressions and genetic basis of heart defects. Mutations in a cardiac gene called Nkx2-5, which encodes a transcriptional regulatory protein, can cause heart defects in human families and isolated individuals, most predominantly atrial septal defect (hole in the heart) associated with an abnormality in electrical activity of the heart. Nkx2-5 is expressed in the precursor cells of the muscle and other lineages that make up the heart in the embryo, then in the muscle layer of the heart throughout foetal and adult life. Mouse hearts that lack the Nkx2-5 gene altogether arrest at an early stage of heart development showing a complete block to ventricular chamber formation. Mice lacking only one copy of the Nkx2-5 gene have ASD and electrical defects, similar to the human disease. Building on these findings we have developed a suite of new genetic reagents with which to gain a deeper understanding of the role of Nkx-5 in development and disease. These include a mouse strain from which Nkx2-5-positive muscle cells can be purified away from other cell types in the heart, and another mouse strain that represents a good model for common congenital heart defects. We will further investigate the role of Nkx2-5 in allocation of cell types in the heart, chamber formation and birth defects using these reagents.