B cell development regulated by gene rearrangement: arrest of maturation by membrane-bound D mu protein and selection of DH element reading frames

Abstract

In productively rearranged murine VH-DH-JH genes (encoding immunoglobulin heavy chain variable regions), the DH elements are preferentially used in one particular reading frame (RF1), although the recombination breakpoints at the DH-JH 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 DH-JH rearrangement: RF3 is counterselected on the basis of stop codons. RF2 allows the expression of a truncated mu chain (D mu protein) from most DH-JH 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 VH-DHJH joining. In addition to RF3 and RF2 counterselection, promotion of DH-JH joining in areas of sequence homology further enforces RF1 usage.