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,,||,,|| The Children's Hospital, Boston, Massachusetts 02115; the Center for Blood Research and the || Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115; and the ¶ Infectious Disease Unit, Massachusetts General Hospital, Boston, Massachusetts 02114
To elucidate the intracellular pathways that mediate early B cell development, we directed expression of activated Ras to the B cell lineage in the context of the recombination-activating gene 1 (RAG1)-deficient background (referred to as Ras–RAG). Similar to the effects of an immunoglobulin (Ig) µ heavy chain (HC) transgene, activated Ras caused progression of RAG1–deficient progenitor (pro)-B cells to cells that shared many characteristics with precursor (pre)-B cells, including downregulation of surface CD43 expression plus expression of
5, RAG2, and germline 
locus transcripts. However, these Ras–RAG pre-B cells also upregulated surface markers characteristic of more mature B cell stages and populated peripheral lymphoid tissues, with an overall phenotype reminiscent of B lineage cells generated in a RAG- deficient background as a result of expression of an Ig µ HC together with a Bcl-2 transgene. Taken together, these findings suggest that activated Ras signaling in pro-B cells induces developmental progression by activating both differentiation and survival signals.
Key Words: B cell development • pre-B cell receptor • signal transduction • Ras • recombinase-activating gene 2–deficient blastocyst complementation
Abbreviations used: BCR, B cell receptor; ES, embryonic stem; DP, double positive (CD4+ CD8+); HC, immunoglobulin heavy chain; RAG, recombinase-activating gene; RT, reverse transcriptase.
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