B-CELL DEVELOPMENT REGULATED BY GENE REARRANGEMENT - ARREST OF MATURATION BY MEMBRANE-BOUND D-MU PROTEIN AND SELECTION OF DH ELEMENT READING FRAMES

In productively rearranged murine V(H)-D(H)-J(H) genes (encoding immunoglobulin heavy chain variable regions), the D(H) elements are preferentially used in one particular reading frame (RF1), although the recombination breakpoints at the D(H)-J(H) border vary. Despite this variability, the bias of RF usage is not due to cellular selection by antigen but is quantitatively established at the stage of D(H)-J(H) rearrangement: RF3 is counterselected on the basis of stop codons. RF2 allows the expression of a truncated-mu-chain (D-mu-protein) from most D(H)-J(H) joints. Using B cells in which the membrane exon of the mu-chain is disrupted by homologous recombination on one of the two homologous chromosomes, we obtain evidence that membrane-bound D-mu-signals arrest of differentiation, presumably by preventing V(H)-D(H)J(H) joining. In addition to RF3 and RF2 counterselection, promotion of D(H)-J(H) joining in areas of sequence homology further enforces RF1 usage.