Function and Regulation of Early B Cell Factor (EBF)

描述(申请人提供)：早期B细胞因子(EBF)是从早期祖细胞发育为B淋巴细胞所必需的。EBF调节mb-1基因，该基因编码Ig-α，这是一种在刺激B细胞受体(BCR)后在质膜上显示免疫球蛋白(Ig)和跨膜信号所需的蛋白质。在发育的早期阶段，bcr和替代的前体bcr和前体bcr的细胞表面表达受到非常精确的调控，这种调控对B细胞的正常发育和功能至关重要。我们观察了代表不同发育阶段的细胞系和体外B细胞在多价抗原刺激下mb-1转录本水平的变化。作为设定B细胞中Ig-α水平的一种潜在机制，我们最近定义了B细胞发育不同阶段高水平和低水平mb-1转录所需的核因子星座。高水平的转录需要EBF、碱性螺旋环螺旋(HLH)因子E2a和Run结构域蛋白Runx1(及其共激活因子CBFbeta)，它们在mb-1启动子上组装更高级别的复合体。我们认为细胞内Ig-α的浓度，从而B细胞表面BCR的表达，是由EBF及其相关蛋白调节的。为了更好地了解EBF的分子生物学，我们将确定它如何控制B细胞的发育和BCR密度，从而控制B细胞对抗原的反应。

DESCRIPTION (provided by applicant): Early B cell Factor (EBF) is essential for the development of B lymphocytes from early progenitor cells. EBF regulates the mb-1 gene, which encodes Ig-alpha a protein required for display of immunoglobulin (Ig) on the plasma membrane and transmembrane signaling following stimulation of the B cell receptor (BCR). Cell surface expression of the BCR and the surrogate pro-BCR and pre-BCR at early stages of development is very precisely regulated, and this regulation is critical for proper development and function of B cells. We have observed changes in levels of mb-1 transcripts in cell lines representing different stages of development and in ex vivo B cells following stimulation by polyvalent antigen. As a potential mechanism for setting the level of Ig-alpha in B cells, we recently defined constellations of nuclear factors required for high vs. low level mb-1 transcription at different stages of B cell development. High level transcription requires EBF, the basic-helix-loop-helix (HLH) factor E2A, and the Runt domain protein Runxl (and its coactivator CBFbeta), which assemble higher order complexes on the mb-1 promoter. We propose that the intracellular concentration of Ig-alpha, and thus, expression of the BCR on the surface of B cells, is regulated by EBF and associated proteins. To better understand the molecular biology of EBF, we will determine how it controls B cell development and BCR density, and thus, the response of B cells to antigen.