Regulation of Lymphocyte Development by Helix Loop Helix Proteins

描述(由申请人提供)：B淋巴细胞，产生抗体，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通过依赖于众多转录调节蛋白的协调活动的过程发展而来。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调节的，人们知之甚少。缺乏E2A或EBF基因编码的转录因子的小鼠患有严重的B细胞免疫缺陷，这是由于未能发育出致力于通过B淋巴细胞谱系分化的细胞。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系特异性基因表达和促进B系决定的机制目前尚不清楚(目标1)。我们的初步数据表明，EBF是E2A促进B系确定的重要靶点之一。我们建议检验这一假设，即EBF是B血统承诺所需的E2A的主要靶点(目标2)。E2A蛋白在转录级联的顶端发挥作用，最终导致B血统承诺；然而，目前尚不清楚E2A活性在这一过程中是如何调节的。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变化通过影响E2A的活性来限制发育中细胞的命运。这一假说将使用ID基因调节的体外和体内模型(Aim3)进行验证。这些研究将有助于更好地理解谱系确定的遗传基础，并将提供对淋巴细胞正常发育的基本要求的洞察。

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.