c-myb in B Cell Development and Function

描述（由申请人提供）：很明显，c-myb原癌基因在造血过程中起着至关重要的作用。在每个造血谱系中，c-myb在分化的不成熟阶段大量表达，并且在分化过程中的相对较晚的时间被关闭。然而，几乎没有什么是已知的c-myb在造血成熟过程中发挥的作用，这种作用是如何介导的或什么信号通路是调节c-myb的表达。在c-myb基因座处纯合无效的小鼠在胚胎发生期间的第15天死于严重贫血。这一发现生动地证明了c-myb在造血过程中的重要性，但排除了在分化后期c-myb活性的研究。缺乏一个易于处理的遗传系统，将允许c-myb在造血成熟的后期阶段的突变一直是理解c-myb在造血过程中的作用的主要障碍。在骨髓中B细胞发育期间，c-myB在前B细胞和前B细胞中表达，但在未成熟的再循环B细胞和外周B细胞中表达水平低约20倍。为了开始理解c-myB在B细胞发育过程中所起的作用，我们已经产生了携带c-myB等位基因的小鼠，所述等位基因被Cre重组酶用用于缺失的IoxP位点靶向。通过将这些小鼠培育成可获得的小鼠品系，这些小鼠品系将Cre表达引导至骨髓中B细胞发育的早期阶段或以可诱导的方式，我们将确定c-myB在B细胞发育和维持外周B细胞亚群中所起的作用。此外，这些小鼠将是至关重要的领域，并将允许一个开始获得深入了解c-myb的功能在造血过程中，以及在其他系统中，c-myb的功能仍然知之甚少。该提议的目标是：1）确定在什么阶段c-myB表达对于B细胞发育和功能是必需的，2）确定不适当的c-myB表达对B细胞发育和功能的后果，以及3）鉴定驱动骨髓中B细胞发育所需的c-myB功能结构域。

DESCRIPTION (provided by applicant): It is clear that the c-myb protooncogene plays a crucial role during hematopoiesis. In each hematopoietic lineage, c-myb is abundantly expressed at the immature stages of differentiation and is turned off at a relatively late time during the differentiation process. However, virtually nothing is known about what role c-myb plays during hematopoietic maturation, how that role is mediated or what the signaling pathways are that regulate c-myb expression. Mice that are homozygous null at the c-myb locus die at day fifteen during embryo genesis from a severe anemia. This finding graphically demonstrated the significance of c-myb during hematopoiesis but has precluded study of c-myb activity at the later stages of differentiation. The lack of a tractable genetic system that will allow mutation of c-myb during the later stages of hematopoietic maturation has been a major impediment to understanding the role of c-myb during hematopoiesis. During B cell development in the bone marrow, c-myb is expressed in pre-B and pre-B cells but is expressed at levels approximately 20-fold lower in immature, recirculating B cells and peripheral B cells. To begin to understand the role played by c-myb during B cell development we have produced mice that carry a c-myb allele targeted with IoxP sites for deletion by the Cre recombinase. By breeding these mice to available mouse strains that direct Cre expression either to the early stages of B cell development in the bone marrow or in an inducible fashion, we will define the role played by c-myb during B cell development and the maintenance of peripheral B cell subsets. In addition, these mice will be crucial to the field and will allow one to begin to gain insight into c-myb function during hematopoiesis as well as in other systems where c-myb function remains poorly understood. The goals of this proposal are: 1) to determine at what stage c-myb expression is essential for B cell development and function, 2) to determine the consequences of inappropriate c-myb expression to B cell development and function and 3) to identify c-myb functional domains required to drive B cell development in the bone marrow.