Development of the Secondary Heart Field

描述（由申请人提供）：先天性心脏病是所有出生缺陷中最常见的，由“心脏或胸内大血管的总体结构异常”引起。要了解先天性心脏病的病因，最重要的是了解正常的心脏发育。我们最近发现了一个新的模式，心脏的发展，通过研究LIM同源结构域转录因子，胰岛1（isl1）。isl1基因纯合子小鼠胚胎死亡，心脏异常。详细的组织学和标记物分析表明，isl突变的心脏缺乏流出道、右心室，并且具有相对较少的心房组织，isl不在原代心脏新月体中表达，而是在相邻的中内胚层细胞群中表达。令人惊讶的是，对isl表达细胞的谱系分析已经证明isl的后代在胚胎心脏中产生流出道、右心室和大部分心房细胞。总之，我们的研究结果需要重新定义的次级心脏领域，远比以前怀疑的更广泛，胰岛表达都标志着这一重新定义的次级心脏领域，并需要次级心脏领域产生的主要部分的胚胎心脏。在isl突变体中，似乎存在较少的胰岛表达细胞，并且在次级心脏区域中许多成纤维细胞和骨形态发生蛋白生长因子的表达下调。这些观察结果表明，假设胰岛决定生长，存活，迁移和规范的心脏祖细胞在次级心脏领域的FGF和BMP生长因子途径的调节。所提出的研究将通过进一步研究isl突变型表型和选择性消融次级心脏区域内的FGF和BMP受体来调查这一假设。我们的实验将产生新的洞察所需的维持心源性干细胞状态的途径，和途径所需的规范不同的谱系在心脏内产生的次级心脏领域。

DESCRIPTION (provided by applicant): Congenital heart disease is the most common of all birth defects, and results from a "gross structural abnormality of the heart or intrathoracic great vessels". To understand the etiology of congenital heart disease, it is of utmost importance to understand normal heart development. We have recently discovered a new paradigm for heart development, through studies of a LIM-homeodomain transcription factor, islet1 (isl1). Mice homozygous null for isl1 die embryonically, with strikingly abnormal hearts. Detailed histological and marker analysis has demonstrated that isl mutant hearts are lacking an outflow tract, right ventricle, and have relatively little atrial tissue, isl is not expressed in the primary cardiac crescent but rather is expressed in a population of adjacent mesendodermal cells. Surprisingly, lineage analysis of isl expressing cells has demonstrated that descendents of isl give rise to the outflow tract, right ventricle, and a majority of atrial cells in the embryonic heart. Together, our results necessitate a redefinition of the secondary heart field, as being far more extensive than previously suspected, islet expression both marks this redefined secondary heart field, and is required for the secondary heart field to give rise to major segments of the embryonic heart. In isl mutants, there appear to be fewer islet expressing cells, and expression of a number of fibroblast and bone morphogenetic protein growth factors is downregulated in the secondary heart field. These observations suggest the hypothesis that islet dictates growth, survival, migration, and specification of cardiac progenitors in the secondary heart field by its regulation of FGF and BMP growth factor pathways. The proposed studies will investigate this hypothesis by further studies of the isl mutant phenotype, and selective ablation of FGF and BMP receptors within the secondary heart field. Our experiments will yield novel insight into pathways required for maintenance of the cardiogenic stem cell state, and pathways required for specification of distinct lineages within the heart which arise from secondary heart field.