Genes Controlling Blood Cell Development in Drosophila

描述(申请人提供)：造血是一个复杂的发育过程，包括干细胞的产生，然后是多能祖细胞的承诺和不同谱系中成熟血细胞的分化。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，这些转录因子联合发挥作用，指导特定血统的基因表达。在脊椎动物中，这些因子中的许多是基于它们作为血细胞表达基因的反式调节基因的作用，或者它们的特征是在特定的白血病中染色体被中断或重排的位点。在模式生物果蝇中也存在造血系统，最近的研究表明，果蝇中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。在转录调控方面，利用苍蝇遗传学可以快速分析GATA因子蛇、GATA因子U形的朋友和RUNX相关蛋白质片在血细胞规格和分化中的功能。这项建议进一步分析了这些基本调控因子的表达、相互作用和功能，并将使用新型造血试剂来筛选这一复杂过程所需的额外基因。研究的目标将是描述一种新发现的血细胞亚型蛇的表达和功能，确定蛇和U型在胚胎和幼虫造血的不同细胞事件中的特殊作用，并对在晶体细胞指定和分化中起作用的基因进行全基因组筛选。由于最近的研究表明控制造血的基因具有令人信服的跨物种保存，这些已知的转录调控因子和新发现的遗传因子的特征应该为控制血细胞产生及其疾病的基本机制提供必要的见解，包括人类的白血病。

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.