REGULATION OF MYOCARDIAL DEVELOPMENT

描述（改编自研究者摘要）：在果蝇中， 基因tinman是绝对必要的发展的心脏。在 脊椎动物，一个与锡人有关的同源盒基因小家族， Nkx 2 -5、Nkx 2 -3、Nkx 2 -6、Nkx 2 -7和Nkx 2 -8。虽然 这些基因在发育中的心脏组织中表达，它们在 心脏发育的调节仍不清楚。说明了这一点 研究Nkx 2 -5基因在心脏发生中作用的实验。 尽管小鼠中Nkx 2 -5基因的切除导致胚胎死亡， 心脏缺陷，胚胎含有分化的，表面正常的心脏 并且主要的可观察缺陷是成环形态发生的失败。的作用 因此，Nkx 2 -5基因的表达与tinman基因的表达没有明显的相似性。 飞翔紧紧Nkx 2 -5消融的这种相对较小的后果可以解释为 由于存在额外的具有冗余活性的Tinman家族基因， 但目前对候选拯救基因的表征非常困难， 初步的因此，tinman基因家族在脊椎动物中的重要性 心脏发育是目前尚未解决的问题。为进一步 探索心脏发育过程中tinman基因的作用， 研究人员对非洲爪蟾进行了一系列实验 光滑。首先，调查人员已经确定了一个新的成员， 在心脏发育早期表达的家族。二是 研究人员进行了一些实验， 青蛙胚胎中Nkx 2 -5的抑制性突变形式导致 消除可检测的心肌分化。研究人员建议， 这种效果是通过抑制多个成员的功能来实现的， 锡人基因家族的成员拟议研究的长期目标是 为了了解脊椎动物的锡人相关基因 调节心脏发育。具体的实验目的如下： 为了进一步研究导致心肌基因消除的机制， 表情2)使用酶诱导表达系统来确定 发育过程中Nkx 2 -5在心肌细胞中发挥作用的时间 分化3）。为了确定Nkx 2 -5与加塔-4的组合是否 SRF足以指导心肌基因表达。4)识别 在心肌细胞凋亡过程中表达的tinman家族成员的完整谱 在Xenopus的发展。总的来说，这项研究将进一步加深我们对 脊椎动物心脏形成的分子机制。这 这些信息将提高我们对先天性心脏病病因的认识 缺陷，从而帮助制定预防和治疗的策略。

DESCRIPTION (adapted from investigator's abstract): In Drosophila, the homeobox gene tinman is absolutely required for development of the heart. In vertebrates, a small family of homeobox genes that are related to tinman have been identified, including Nkx2-5, Nkx2-3, Nkx2-6, Nkx2-7 and Nkx2-8. Although these genes are expressed in developing heart tissues, their precise role in regulation of cardiac development remains unclear. This is illustrated by experiments investigating the role of the Nkx2-5 gene in cardiogenesis. Although ablation of the Nkx2-5 gene in mouse results in embryonic death due to heart defects, the embryos contain a differentiated, superficially normal heart and the major observable defect is a failure of looping morphogenesis. The role of Nkx2-5 therefore, is not obviously similar to that of the tinman gene in the fly. This relatively minor consequences of Nkx2-5 ablation, could be explained by the presence of additional tinman family genes with redundant activities, but at present the characterization of candidate rescuing genes is very preliminary. Therefore, the importance of the tinman gene family for vertebrate heart development is currently an unresolved question. In order to further explore the role of the tinman genes during heart development, the investigators have carried out a series of experiments in the frog, Xenopus laevis. First, the investigators have identified a novel member of the tinman family that is expressed early during heart development. Second, the investigators have carried out experiments in which expression of a dominant inhibitory mutant form of Nkx2-5 in the frog embryo results in total elimination of detectable myocardial differentiation. The investigators propose that this effect is achieved by inhibition of the function of multiple members of the tinman gene family. The long term objective of the proposed research is to understand the mechanism by which the vertebrate tinman-related genes regulate cardiac development. The specific experimental aims are as follows:-1) to further examine the mechanism leading to the elimination of myocardial gene expression. 2) to use a hormone-inducible expression system to determine the time during development that Nkx2-5 plays its role in regulation of myocardial differentiation. 3). To determine whether Nkx2-5, in combination with GATA-4 and SRF is sufficient to direct myocardial gene expression. 4) To identify the complete repertoire of tinman family members expressed during myocardial development in Xenopus. Overall this research will further our understanding of the molecular mechanisms underlying formation of the vertebrate heart. This information will improve our knowledge of the causes of congenital heart defects and thereby aid in devising strategies for prevention and cure.