Genes Controlling Blood Cell Development in Drosophila

描述（由申请人提供）：造血是一个复杂的发育过程，涉及干细胞生成，随后是多能祖细胞的定型和成熟血细胞在不同谱系内的分化。这些复杂事件的关键是各种造血转录因子的协同激活或抑制，这些造血转录因子的组合功能指导谱系特异性基因表达。在脊椎动物中，这些因子中的许多已经基于它们作为血细胞表达基因的反式调节剂的作用或它们作为在特定白血病中染色体中断或重排的基因座的表征而被鉴定。造血系统也存在于模式生物果蝇中，最近的研究表明，果蝇血细胞发育所必需的基因代表了高等真核生物中某些造血因子的功能同源物。关于转录调节因子，利用蝇遗传学已经允许在血细胞特化和分化中快速分析加塔因子Serpent、加塔因子U形之友和Runx相关蛋白菱形的功能。该提案进一步分析了这些基本调节剂的表达，相互作用和功能方面，并且新的造血试剂将用于筛选这个复杂过程所需的其他基因。研究目标将是表征一种新发现的Serpent血细胞亚型的表达和功能，确定Serpent和U形在胚胎和幼虫造血的不同细胞事件中的专门作用，并对在晶体细胞规范和分化中发挥作用的基因进行全基因组筛选。由于最近的研究已经证明了一个引人注目的跨物种保护的基因控制造血，这些已知的转录调控因子和新发现的遗传球员的特性应该提供必要的见解控制血细胞的生产和他们的疾病，包括人类白血病的基本机制。

DESCRIPTION (provided by applicant): Hematopoiesis is a complex developmental process that involves stem cell generation, followed by the commitment of multipotent progenitors and the differentiation of mature blood cells within distinct lineages. Seminal to these intricate events is the coordinated activation or repression of various hematopoietic transcription factors that function combinatorially to direct lineage-specific gene expression. In vertebrates, many of these factors have been identified based on their role as trans-regulators of blood cell expressed genes or their characterization as loci that are chromosomally interrupted or rearranged in specific leukemias. A hematopoietic system also exists in the model organism Drosophila and recent studies have demonstrated that genes essential for blood cell development in the fly represent functional homologues of certain of the hematopoietic factors found in higher eukaryotes. Concerning transcriptional regulators, the utilization of fly genetics has allowed for the rapid functional analysis of the GATA factor Serpent, Friend of GATA factor Ushaped, and Runx-related protein Lozenge in blood cell specification and differentiation. This proposal further analyzes aspects of the expression, interaction, and function of these essential regulators and novel hematopoietic reagents will be used to screen for additional genes required for this complex process. The research objectives will be to characterize the expression and function of a newly discovered blood cell isoform of Serpent, determine the specialized roles of Serpent and U-shaped in the distinct cellular events of embryonic and larval hematopoiesis, and conduct a genome-wide screen for genes that function in crystal cell specification and differentiation. Since recent studies have demonstrated a compelling cross species conservation of genes controlling hematopoiesis, the characterization of these known transcriptional regulators and newly identified genetic players should provide needed insights into fundamental mechanisms controlling blood cell production and their disorders, including leukemia in humans.