The 15 gene is a homoiog of immunogiobuiin J1-CL genes, expressed specifically in immature B-lineage cells. Xl-encoded molecules form membrane complexes with p or D, proteins in association with an additional protein speciflcaliy expressed in immature B cells that is encoded by the Vpr,~ gene. We have generated mice in which the h5 gene is inactivated by targeted gene disruption in embryonic stem ceils. in these mice, B ceil development in the bone marrow is blocked at the pre-B cell stage. However, the blockade is leaky, allowing B cells to populate the peripheral immune system at a low rate. These ceils are allelically excluded and able to respond to antigen. to two proteins that in independent experiments were shown to be expressed in association with tr chains on the surface of several mouse pre-B cell lines (Pillai and Baltimore, 1987, 1988; Cherayil and Pillai, 1991) and also on human pre-B cells (Nishimoto et al., 1991) and pre-B cell lines (Kerr et al., 1989).

Analysis of immunoglobulin transgenic mice (Nussenzweig et al., 1987; Manz et al., 1988) and of pre-B cell lines transfected with immunoglobulin gene constructs (Reth et al., 1987) suggested that the expression of membranebound tr (urn) chains is essential for allelic exclusion, preventing further gene rearrangements in the second IgH locus. urn expression may also initiate L chain gene rearrangement (Reth et al., 1987). Indeed, the analysis of mice heterozygous for a deleterious mutation in the membrane exon of the cu gene (~ IMT) showed that in the absence of pm chain expression, allelic exclusion is lost (Kitamura and Rajewsky, 1992). In addition, in homozygous mutant mice B cell development is blocked at the pre-B cell stage (Kitamura et al., 1991). If the regulatory role of the pm chain in early B cell development is mediated by the~ m--h5-Vp, e. 8 complex, then a h&deficient mouse should exhibit a block in B cell generation similar to that seen in the pMT mutant. Accordingly, we generated a mouse mutant in which the h5 gene is disrupted by targeted integration of a neomycin resistance gene (neo). In these mice the functional role of the h5 protein in B cell development became apparent.