Genetic control of cardioblast gene expression and heart tube morphogenesis

描述（由申请人提供）：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。这两种系统的心脏发生都涉及成对祖区内前体细胞的特化，随后它们运动成线性心管结构，最终演变成一个功能器官。我们的长期目标是利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，特别是因为它涉及到对可能在人类心脏发育中起作用的保守调节因子的分析。为了实现这些目标，研究人员已经证实了Toll跨膜蛋白在背侧血管形成过程中的表达和功能。将进一步研究T-box因子Dorsocross和同域因子Tinman对其的调控，以及确定Toll作为心脏管形成所必需的细胞粘附分子的功能。在后期背血管形态形成过程中，选择的成心细胞分化为形成心管瓣膜的特化细胞。无翼基因的一种12型成心细胞增强子已经被确定，它可以精确地标记这些细胞。Dorsocross和cox - c因子abal - a对这一高度特化的转录控制序列的调控将被研究。最后，详细分析了编码LIM同源结构域因子Isletl的果蝇同源基因tailup的背血管表达和功能。总之，这些研究将为保守的心源性因子在心管形态发生中的功能提供广泛的新信息，与我们对人类某些先天性心脏缺陷病因的理解相关。先天性心脏畸形是儿童最常见的先天缺陷。要了解这些异常的遗传基础，就需要了解控制心脏基因表达和形态发生的调节因子的详细信息。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。确定保守的心源性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.