Regulation of Lymphocyte Development by Helix Loop Helix Proteins

描述（由申请人提供）：B淋巴细胞，抗体的产生者，是适应性免疫反应的重要组成部分。这些细胞由多能祖细胞发育而来，这一过程依赖于许多转录调节蛋白的协调活动。然而，关于这些因子控制分化过程的机制以及它们的活动是如何被调节的，我们知之甚少。缺乏E2A或EBF基因编码的转录因子的小鼠具有严重的B细胞免疫缺陷，导致无法通过B淋巴细胞谱系发育出致力于分化的细胞。E2A蛋白El2和E47也是T淋巴细胞正常发育和抑制T细胞淋巴瘤发展所必需的。E2A蛋白激活B谱系特异性基因表达和促进B谱系确定的机制目前尚不清楚（Aim 1）。我们的初步数据表明EBF是E2A促进B谱系测定的重要靶点之一。我们建议验证EBF是B谱系承诺所需的E2A主要靶点的假设（目的2）。E2A蛋白在转录级联的顶端起作用，最终在B谱系承诺中达到顶峰；然而，在这个过程中，E2A的活性是如何被调节的尚不清楚。我们假设E2A拮抗剂（Id蛋白）在谱系不受限制的祖细胞中的表达改变通过影响E2A活性来限制发育中的细胞的命运。这一假设将通过体外和体内的Id基因调控模型（Aim3）进行验证。这些研究将导致对谱系测定的遗传基础有更深入的了解，并将提供对适当淋巴细胞发育的基本要求的见解。

DESCRIPTION (provided by applicant): B lymphocytes, the producers of antibodies, are an essential component of the adaptive immune response. These cells develop from multipotent progenitors through a process that is dependent on the coordinated activity of numerous transcriptional regulatory proteins. However, very little is known about the mechanisms by which these factors control the differentiation process and how their activities are regulated. Mice that lack the transcription factors encoded by the E2A or EBF genes have a profound B cell immune deficiency resulting from the failure to develop cells that are committed to differentiation through the B lymphocyte lineage. The E2A proteins, El2 and E47, are also required for proper T lymphocyte development and to suppress the development of T cell lymphoma. The mechanisms by which the E2A proteins activate B lineage specific gene expression and promote B lineage determination are currently not known (Aim 1). Our preliminary data indicate that EBF is one of the essential targets of E2A that promote B lineage determination. We propose to test the hypothesis that EBF is the major target of E2A required for B lineage commitment (Aim 2). The E2A proteins function at the apex of a transcriptional cascade that culminates in B lineage commitment; however, it is not known how E2A activity is regulated during this process. We hypothesize that altered expression of E2A antagonists, the Id proteins, in lineage-unrestricted progenitors restricts the fate of the developing cell by influencing E2A activity. This hypothesis will be tested using both in vitro and in vivo models of Id gene regulation (Aim3). These studies will lead to a greater understanding of the genetic basis for lineage determination and will provide insight into the essential requirements for proper lymphocyte development.