Activated Ras Signals Developmental Progression of Recombinase-activating Gene (RAG)-deficient Pro-B Lymphocytes

doi:10.1084/jem.189.1.123

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J. Exp. Med., Volume 189, Number 1, January 4, 1999 123-129

Activated Ras Signals Developmental Progression of Recombinase-activating Gene (RAG)-deficient Pro-B Lymphocytes

By Albert C. Shaw,^*^¶ Wojciech Swat,^§ Roger Ferrini, Laurie Davidson,^* and Frederick W. Alt^*^§

From the ^* Howard Hughes Medical Institute, Boston, Massachusetts 02115; 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 tothe B cell lineage in the context of the recombination-activatinggene 1 (RAG1)-deficient background (referred to as Ras-RAG). Similarto 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 expressionplus expression of $lambda$ 5, RAG2, and germline $kappa$ locus transcripts.However, these Ras-RAG pre-B cells also upregulated surface markerscharacteristic of more mature B cell stages and populated peripherallymphoid tissues, with an overall phenotype reminiscent of B lineagecells generated in a RAG- deficient background as a result ofexpression of an Ig µ HC together with a Bcl-2 transgene. Takentogether, these findings suggest that activated Ras signalingin pro-B cells induces developmental progression by activatingboth differentiation and survival signals.

Key words: B cell development; pre-B cell receptor; signal transduction; Ras; recombinase-activating gene 2-deficient blastocyst complementation

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