Genetic control of cardioblast gene expression and heart tube morphogenesis

成心细胞基因表达和心管形态发生的遗传控制

• 批准号: 7105752
• 负责人: ROBERT A. SCHULZ
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-05 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105752
• 关键词: DNA binding protein; Drosophilidae; arthropod genetics; biochemical evolution; biological models; blood vessels; cardiogenesis; cell adhesion molecules; cell differentiation; congenital heart disorder; developmental genetics; gene expression; genetic regulatory element; heart valves; membrane proteins; protein protein interaction; protein structure function; tissue /cell culture; transcription factor; yeast two hybrid system

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.

描述（由申请人提供）：果蝇和脊椎动物的心脏发育之间存在相似之处，特别是在器官形成的早期阶段。两个系统中的心脏发生都涉及成对祖细胞域内前体细胞的特化，然后它们运动成线性心管结构，最终演变成功能器官。我们的长期目标是利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，特别是因为它涉及对可能在人类心脏发育中发挥作用的保守调节因子的分析。为了实现这些目标，Toll 跨膜蛋白在背血管形成过程中的表达和功能已得到证实。我们将进一步研究其受 T-box 因子 Dorsocross 和同源域因子 Tinman 的调节，并确定 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后期，选择的成心细胞分化成形成心管瓣膜的特殊细胞。已鉴定出 wingless 基因的 12-成心细胞增强子，它可以精确标记这些细胞。我们将研究 Dorsocross 和 Hox-C 因子 Abdominal-A 对这种高度专业化的转录控制序列的调节。最后，将详细分析尾部血管的表达和功能，尾部是编码 LIM 同源域因子 Islet1 的脊椎动物基因的果蝇同源物。总之，这些研究将提供有关心管形态发生中保守心源性因子功能的广泛新信息，这与我们对人类观察到的某些先天性心脏缺陷的病因学的理解相关。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有关控制心脏基因表达和形态发生的调节因素的详细信息。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，将为果蝇和人类控制心脏发育的机制提供所需的见解。