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存在相似性，特别是在器官形成的早期阶段。在这两个系统中，心脏发生都涉及成对祖细胞区域内的前体细胞的特化，随后它们运动成线性心管结构，最终演变成功能器官。我们的长期目标是使用果蝇模型方便地研究和更全面地理解心管形成的遗传基础，特别是因为它涉及到保守的调节因子，可能在人类心脏发育中发挥作用的分析。为了实现这些目标，Toll跨膜蛋白在背侧血管形成过程中的表达和功能已被证明。它的调节T-盒因子Dorsocross和同源结构域因子Tinman将进一步研究，以及确定Toll的功能作为心管形成所必需的细胞粘附分子。在背侧血管形态发生晚期，选择性的成心细胞分化成形成心管瓣膜的特化细胞。一个12-cardioblast增强子的无翅基因已被确定，精确地标记这些细胞。将研究Dorsocross和Hox-C因子Abdominal-A对这种高度特异性转录控制序列的调控。最后，背血管的表达和功能的尾，果蝇同源的脊椎动物基因编码的LIM同源域因子Isletl，将进行详细分析。总之，这些调查将提供广泛的新信息保守的心源性因素的功能，在心管形态发生，与我们的理解有关的某些先天性心脏病的病因在人类中观察到的。先天性心脏畸形是儿童中最常见的出生缺陷。了解这些异常的遗传基础将需要控制心脏基因表达和形态发生的调控因子的详细信息。在模式生物果蝇和人类的早期心脏形成之间存在发育和遗传相似性。保守的心源性因子的功能和相互作用的确定，以及它们控制的细胞过程，将提供必要的洞察机制控制心脏发育，在果蝇和人类。

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.