Genetic control of cardioblast gene expression and heart tube morphogenesis

描述(申请人提供)：果蝇和脊椎动物的心脏发育有相似之处，特别是在器官形成的早期阶段。在这两个系统中，心脏发生都涉及到在配对的祖细胞区域内指定前体细胞，然后它们移动到一个线性的心管结构中，最终变成一个功能器官。我们的长期目标是使用果蝇模型来方便地研究和更全面地理解心管形成的遗传基础，特别是当它与分析保守的调控因子有关时，这些调控因子也可能在人类心脏发育中发挥作用。为了达到这些目标，已经证实了Toll跨膜蛋白在背侧血管形成过程中的表达和功能。它受T盒因子Dorocross和同源结构域因子Tinman的调节将被进一步研究，以及确定Toll作为细胞黏附分子对心脏管形成至关重要的功能。在背侧血管形态发生的晚期，精选的成心细胞分化成专门的细胞，形成心管的瓣膜。无翼基因的12个心脏母细胞增强子已经被鉴定出来，可以准确地标记这些细胞。这一高度专门化的转录控制序列的调节由Dorocross和HOX-C因子BUBAL-A将被研究。最后，将详细分析脊椎动物编码LIM同源结构域因子Islet1的果蝇同源基因Tailup的背部血管表达和功能。总之，这些研究将提供关于保守的生心因子在心管形态发生中的作用的广泛的新信息，这与我们对人类观察到的某些先天性心脏病的病因学的理解有关。先天性心脏畸形是儿童最常见的出生缺陷。要了解这些异常的遗传基础，需要关于控制心脏基因表达和形态发生的调控因素的详细信息。在模式生物果蝇和人类的早期心脏形成之间存在着发育和遗传上的相似性。确定保守的生心因子的功能和相互作用，以及它们控制的细胞过程，将为控制果蝇和人类心脏发育的机制提供必要的见解。

DESCRIPTION (provided by applicant): Similarities exist between heart development in Drosophila and vertebrates, particularly during early stages of organ formation. Cardiogenesis in both systems involves specification of precursor cells within paired progenitor fields, followed by their movement into a linear heart tube structure that eventually morphs into a functional organ. Our long-term objectives are to use the Drosophila model to expediently study and more fully comprehend the genetic bases of heart tube formation, especially as it relates to the analysis of conserved regulatory factors that likely function in human heart development as well. Towards these goals, the expression and function of the Toll transmembrane protein during dorsal vessel formation has been demonstrated. Its regulation by the T-box factor Dorsocross and homeodomain factor Tinman will be further investigated, as well as determining Toll's function as a cell adhesion molecule essential for heart tube formation. During late dorsal vessel morphogenesis, select cardioblasts differentiate into specialized cells that form the valves of the heart tube. A 12-cardioblast enhancer of the wingless gene has been identified that precisely marks these cells. The regulation of this highly-specialized transcriptional control sequence by Dorsocross and the Hox-C factor Abdominal-A will be investigated. Finally, the dorsal vessel expression and function of tailup, the Drosophila homolog of the vertebrate gene encoding the LIM homeodomain factor Isletl, will be analyzed in detail. Together, these investigations will provide extensive new information on the functions of conserved cardiogenic factors in heart tube morphogenesis, with relevance to our understanding of the etiology of certain congenital heart defects observed in humans. Congenital malformations of the heart are the most common birth defects observed in children. An understanding of the genetic bases of these anomalies will require detailed information on the regulatory factors controlling cardiac gene expression and morphogenesis. Developmental and genetic similarities exist between early heart formation in the model organism Drosophila and humans. The determination of the functions and interactions of conserved cardiogenic factors, and the cellular processes they control, will provide needed insights into mechanisms controlling heart development, in both Drosophila and humans.