Rap signaling is crucial for the competence of IL-7 response and the development of B-lineage cells.
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-7Ralpha 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.
Katayama
Yoshinori
Y
Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Sekai
Miho
M
Hattori
Masakazu
M
Miyoshi
Ichiro
I
Hamazaki
Yoko
Y
Minato
Nagahiro
N
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D005434:Flow Cytometry / Q000379:methods; D015851:Interleukin-7 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000378:metabolism*
D015851:Interleukin-7; D020395:Receptors, Interleukin-7; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C415350:interleukin-7 receptor, alpha chain