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 Blood, 27 August 2009, Vol. 114, No. 9, pp. 1768-1775.
Prepublished online as a Blood First Edition Paper on June 30, 2009; DOI 10.1182/blood-2009-03-213371.

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IMMUNOBIOLOGY

Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells

Yoshinori Katayama1, Miho Sekai2, Masakazu Hattori3, Ichiro Miyoshi4, Yoko Hamazaki1, and Nagahiro Minato1,2

1 Department of Immunology and Cell Biology, Graduate School of Medicine, and 2 Graduate School of Biostudies, Kyoto University, Kyoto; 3 Graduate School of Science, Kitasato University, Kanagawa; and 4 Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

Rap family GTPases consist of multiple members with substantial functional redundancy. With the use of transgenic mice conditionally expressing a bona fide dominant-negative Rap1 mutant, Rap1A17, capable of inhibiting the activation of all Rap family members in B-lineage cells (mb.1-Rap1A17 Tg), we demonstrate that these mice show a defective generation of pre-B cells in bone marrow, resulting in a significant diminution of peripheral mainstream B cells. The effect is attributed to the impaired survival and expansion of B-lineage progenitors in response to IL-7, despite normal IL-7R{alpha} expression. The pre-B cells from mb.1-Rap1A17 Tg mice showed a significantly reduced expression of c-myc and E2A, and the competence of IL-7 response was restored by the transduction of c-myc, but not by constitutively active (CA) Stat5a, CA PI3K-p100, or bcl-2. The residual follicular B cells with complete Cre-mediated recombination proliferated normally in response to B-cell receptor stimulation and showed efficient germinal center reaction in vivo. These results show that endogenous Rap signaling plays a crucial role selectively in B-lineage cell development by sustaining the competence for IL-7 response, whereas it is dispensable for mature B-cell function.


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