Submitted March 27, 2009
Accepted June 23, 2009
Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells
Yoshinori Katayama, Miho Sekai, Masakazu Hattori, Ichiro Miyoshi, Yoko Hamazaki, and Nagahiro Minato*
Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Graduate School of Biostudies, Kyoto University, Kyoto, Japan
Graduate School of Science, Kitasato University, Kanagawa, Japan
Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
* Corresponding author; email: minato{at}imm.med.kyoto-u.ac.jp.
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
expression. The pre-B cells from mb.1-Rap1A17 Tg mice revealed 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 of 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 BCR-stimulation and showed efficient germinal center reaction in vivo. These results disclose 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.
