A Study of the Surrogate Light chain

Abstract

This thesis has investigated the importance of the VpreB1 protein in early B cell development. Mice lacking the VpreB1 protein showed normal numbers of peripheral mature B cells. The number of B220 positive cells in the bone marrow was also normal, but the amounts of pre-BI cells was increased 2-fold and the numbers of pre-B II cells were reduced by 20%. In all other respects the lymphoid compartments were normal. The conclusion was that the VpreB1 protein is not necessary for the generation of B cells, and in the presence of the VpreB2 protein B lymphocytes develop normally and give rise to immuno competent cells in the periphery. In the second part of the thesis, the regulation of lambda5 and VpreB1 gene expression was investigated. A novel enhancer was isolated upstream of the VpreB1 gene and the core of the lambda5 enhancer was defined. Both enhancers contain elements that restrict reporter gene expression to pre-B cells when tested in cell lines. The transcription factors EBF and PEBP2 were shown to interact with both enhancers in EMSAs. These binding sites were crucial for lambda5 enhancer activity but less so for the VpreB1 enhancer. An E-box, potentially binding products of the E2A gene, E47 or E12, was shown to be functionally important for the lambda5 enhancer. In addition, the proto-oncogene c-myb was shown to interact with a functionally important element in the lamba5 core enhancer