The immunoglobulin heavy chain loci initiates gene rearrangements at the late pro-B cell stage of development. The first rearrangement involves the selection of a D and J segment for recombination. This is followed by the selection of a V segment. If these recombinations are successful the developing B cell synthesizes the heavy chain which is expressed on the membrane in association with the surrogate light chain (the pre-B cell receptor). It is currently thought that signaling through the pre-B cell receptor stops any further rearrangement of the other heavy chain allele and initiates light chain rearrangement. This competitive renewal will continue to study the molecular mechanisms responsible for allelic exclusion and initiation of light chain rearrangements using a transgenic mouse line developed during the previous funding period. The transgenic line expresses a murine VDJ expressed with a human gamma 1 constant region. The interesting feature of this line is that B-2 cells from young mice display allelic exclusion without initiating light chain rearrangements. This suggests that these two processes might be independently regulated. The present application will use this transgenic line in experiments designed to uncover the way that the pre-B cell receptor regulates light chain rearrangements.
